Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[ClH:2].[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[NH2:11]O.C([O-])(=O)C.[Na+]>CO>[ClH:2].[OH:1][N:11]=[C:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: O=C1CCNCC1
Reactant: NO
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C1CCNCC1
Yield: 29.9 %

Procedure:
1.54 g (10.0 mmol) of 4-piperidone hydrochloride monohydrate was refluxed for one hour in 30 ml of methanol in the presence of 0.70 g (10.0 mmol) of hydroxylamine hydrochloride and 0.82 g (10.0 mmol) of sodium acetate. Then, methanol was distilled off, and the precipitate thereby formed was washed with isopropanol, and the mother liquor was distilled under reduced pressure. Diethyl ether was added to the residue thereby obtained for crystallization to give 0.45 g of the desired product as colorless powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1.C(Cl)[Cl:29].CO.[OH-].[NH4+].[ClH:35]>C(O)C.C(O)CCC>[ClH:14].[ClH:29].[ClH:35].[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH:27][C:12]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:5]([NH:4][CH2:3][CH2:2][NH2:1])[N:13]=2)[CH2:23][CH2:22]1
Reactant: ClCCl
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: CCCCO
Product: NCCNc1nc(N[C@H]2CC[C@H](N)CC2)nc2c1ncn2C1CCCC1
Temperature: 150 °C

Procedure:
160 mg of the product obtained in Stage 1 of Example 7, 10 ml of butanol and 690 mg of trans-1,4-diaminocyclohexane are mixed together, the reaction medium is heated to approximately 150° C. for approximately 4 days. After chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 70/25/05 salification is carried out with a 1.4N solution of HCl in ethanol and in this way 60 mg of expected product is obtained.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]2[CH:14]=1.N12CCCN=C1CCCCC2.[C:26]1([P:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCCl>[Cl-:2].[CH3:13][C:8]1[N:7]2[CH:14]=[C:4]([CH2:3][P+:32]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[CH:9]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(C)n2cc(CCl)nc2n1
Agent: Cl
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(C)n2cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2n1
Product: [Cl-]
Temperature: 140 °C
Yield: 200.7 %

Procedure:
A microwave vial was charged with 2-chloromethyl-5,7-dimethyl-imidazo[1,2-a]pyrimidine hydrochloride (500 mg, 2.15 mmol), and 1,2-dichloroethane (16 mL) and argon was bubbled through the mixture. To this mixture was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.350 mL, 2.34 mmol) and triphenylphosphine (848 mg, 3.23 mmol). The vial was sealed with a crimp-on cap and the mixture was heated at 140° C. for 1 hour using a microwave synthesizer. Evaporation of volatiles afforded crude (5,7-dimethyl-imidazo[1,2-a]pyrimidin-2-ylmethyl)-triphenyl-phosphonium chloride as a dark grey solid (1.976 g) which was used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([C:29]([F:32])([F:31])[F:30])=[CH2:28])[CH:24]=[C:23]([Cl:33])[CH:22]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:28][C:27]([C:25]3[CH:24]=[C:23]([Cl:33])[CH:22]=[C:21]([Cl:20])[CH:26]=3)([C:29]([F:30])([F:32])[F:31])[O:8][N:7]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C=NO)ccc1Br
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 70 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 4-Bromo-3-methyl-benzaldehyde oxime (2.600 g, 12.15 mmol) in DMF (40 mL) was added N-chloro succinimide (1.700 g, 12.73 mmol) and the mixture was heated at 70° C. (bath temperature) for 1 h. After cooling to 0° C., a solution of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (2.900 g, 12.03 mmol) in DMF (8 mL), followed by triethylamine (2.00 g, 2.75 mL, 19.8 mmol) was added. After 1 h at this temperature, the cooling bath was removed and the mixture was stirred over night. The mixture was separated between MTBE and aqueous NH4Cl solution. The organic layer was separated and the solvent was removed in vacuum. Column chromatography on SiO2 with heptane/CH2Cl2 gave the title compound (2.95 g, 54%).
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=[C:14]2[CH2:13]1)=[O:11])=O)C.[ClH:35]>CO>[ClH:35].[ClH:35].[NH2:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[N:20]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2cc(C(F)(F)F)nc2C1)Cc1ccc(F)c(F)c1
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2cc(C(F)(F)F)nc2C1)Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 7-[(3R)-3 -[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (110.8 mg, 0.226 mmol, from Step C) was added 2 mL of methanol saturated with hydrogen chloride. The reaction was stirred at ambient temperature for 1 h. Concentration gave 89.5 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CD3OD) δ 2.97-3.10 (m, 4H), 3.91-4.34 (m, 5H), 4.90-5.04 (m, 2H), 7.16-7.33 (m, 2H), 8.01-8.08 (m, 1H). ESI-MS 389 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([N:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][O:27][C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:37]=4[N:36]=[C:35]([CH3:38])[CH:34]=[CH:33]5)[C:20]=3[Cl:39])[CH3:18])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:51](Cl)(=[O:53])[CH3:52]>C(#N)C>[C:51]([NH:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([N:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][O:27][C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:37]=4[N:36]=[C:35]([CH3:38])[CH:34]=[CH:33]5)[C:20]=3[Cl:39])[CH3:18])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:53])[CH3:52]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)Cc4ccc(C(=O)c5ccc(N)cc5)n4C)c3Cl)c2n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(C(=O)c2ccc(CC(=O)N(C)c3ccc(Cl)c(COc4cccc5ccc(C)nc45)c3Cl)n2C)cc1
Reaction time: 2 h
Yield: 50 %

Procedure:
Compound 56 (0.033 g, 0.056 mmol) was dissolved in 5 mL acetonitrile. To this was added diisopropylethylamine (0.032 mL, 0.184 mmol) and acetyl chloride (0.05 mL, 0.703 mmol). The reaction was allowed to stir for 2 hours then was quenched with the addition of ˜2 ml of methanol. The solvents were evaporated and the residue purified via reverse phase chromatography eluting with a gradient of acetonitrile:water 10-90%.The proper fractions were isolated and the solvents were lyophilized to yield the product (0.021 g, 0.028 mmol) as an off-white powder. 1H NMR (CDCl3): δ 8.61 (d, 1H), 7.84-7.47 (m, 9H), 7.37 (d, 1H), 6.55 (d, 1H), 5.86 (d, 1H), 5.60 (s, 2H), 3.84 (s, 3H), 3.53 (m, 2H), 3.28 (s, 3H), 2.93 (s, 3H), 2.21 (s, 3H); MS: M+1=629.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([O:29]COC)[CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[F:28])=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1.Cl.CO.C1COCC1>>[NH2:1][C:2]1[C:10]2[C:5](=[C:6]([OH:29])[CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[F:28])=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1
Reactant: COCOc1ccc(-c2ccc(NC(=O)Nc3cc(C)ccc3F)cc2)c2c(N)n[nH]c12
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3ccc(O)c4[nH]nc(N)c34)cc2)c1
Temperature: 50 °C
Yield: 37.1 %

Procedure:
A mixture of Example 119B (90 mg) and a 1:1:1 mixture of 3N HCl/methanol/THF (3 mL) was heated to 50° C. for 3 hours, concentrated to half its original volume, and partitioned between saturated NaHCO3 and ethyl acetate. The organic extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 30 mg of the desired product. MS (ESI(+)) m/e 392 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 4.25 (s, 2H), 6.60 (d, J=5.76 Hz, 2H), 6.82 (m, J=5.09, 3.05 Hz, 1H), 7.11 (m, 2H), 7.33 (d, J=8.48 Hz, 1H), 7.54 (d, J=8.81 Hz, 2H), 8.01 (dd, J=7.97, 2.20 Hz, 1H), 8.51 (d, J=2.71 Hz, 1H), 9.14 (s, 1H), 9.84 (s, 1H), 11.58 (s, 1H).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C(C)=CC=CC=1>[I-:20].[NH2:24][C:23]1[CH:22]=[C:21]([P+:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: Nc1cccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [I-]
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
To a 3000 mL 3-necked round-bottomed flask fitted with a condenser, mechanical stirrer and gas inlet, about 329.33 g (1.25 mol) of triphenylphosphine (PPh3), Pd(acetate)2 (2.82 g, 0.0126 mol) and 1600 mL of de-gassed xylene was added. The mixture was stirred under argon until the PPh3 is dissolved. m-Iodoaniline (about 275.00 g; 1.25 mol) was added and the yellow-orange solution was refluxed for around 80 minutes. The product phosphonium compound ((3-aminophenyl)triphenylphosphonium Iodide) separated from solution as a yellow-orange solid. Excessive refluxing was avoided to prevent discoloration of the product phosphonium compound. The progress of the reaction was monitored using thin layer chromatography (TLC) with a 50/50 hexane/ethyl acetate developing solution. After the reflux, the product was filtered. The product 15 was reslurried with hot toluene, and stirred for 15 minutes. The solution was then filtered and rinsed with additional toluene/xylene. After drying in a 150° C. vacuum oven for 20 hours, 585.01 g of off-white product was obtained in a 96% yield. The melting point and NMR data are consistent with the structure of product (15). MP: 316.0° C. 1H NMR (δ, D6-DMSO): 8-6.6 (m, 19H, aromatics), 5.88 (s, 2H).
Reaction SMILES: [OH:1][C@@H:2]([P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])[CH:3]=[C:4]([CH3:6])[CH3:5]>CO.[Pd]>[OH:1][C@@H:2]([P:7](=[O:12])([O:8][CH3:9])[O:10][CH3:11])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: COP(=O)(OC)[C@H](O)C=C(C)C
Agent: [Pd]
Solvent: CO
Product: COP(=O)(OC)[C@H](O)CC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Dimethyl (S)-1-hydroxy-3-methyl-2-butenylphosphonate obtained in Example 31 (68% e.e., 54 mg) was dissolved in 10 ml of methanol, and 10% Pd/C (16 mg) was added thereto. The mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. The reaction mixture was filtered through Celite and the filter cake was washed with ethyl acetate. The solvent was distilled under reduced pressure and the residue was purified by flash column chromatography (acetone/hexane=1/4, on SiO2) to obtain dimethyl (S)-1-hydroxy-3-methylbutylphosphonate as a final product in a yield of 98%. This compound is known to be useful as a raw material for medicines and the like. The chemical reaction in this Reference Example is shown in chemical formula 49.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@@H:15]3[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]3[C@@H:13]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[CH2:12]2)=[C:4]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.[H-].[Na+].[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][OH:52])=[CH:46][CH:45]=1>C1COCC1>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][O:52][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@H:11]3[C@@H:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]4[C@@H:13]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[CH2:12]3)=[C:4]([NH:26][CH2:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:3]=2)=[CH:46][CH:45]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(OCCc4ccc(Cl)cc4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 50 °C
Reaction time: 48 h

Procedure:
The title compound is prepared by adding N-{(3aR,4S,6R,6aS)-6-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl}-propionamide (example 235, step 1) to a premixed solution of sodium hydride (60% in oil) and 2-(4-chloro-phenyl)-ethanol (1 equivalent) in dry THF. The reaction is stirred at 50° C. for 48 hours, before quenching residual sodium hydride with excess aqueous ammonium chloride. The reaction mixture id then partioned between ethyl acetate and water; the organic phase is washed consecutively with water and brine before drying over magnesium sulfate. Filtration and removal of the volatile components under reduced pressure yields the crude product; purification by column chromatography/crystallisation affords the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.C(O)(=O)C.[CH2:26]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47](=O)[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:38][CH2:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C@@H:47]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[O:4][CH2:3]2)[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:40][CH2:41]1)=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(=O)CCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 0.17 h
Yield: 6.4 %

Procedure:
A mixture of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2.4 g), ethanol (30 ml), acetic acid (0.5 g), ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)-2-oxoheptanoate (3.2 g) and molecular sieves 3A (10 g) is stirred for 10 minutes. To the stirred mixture is added dropwise a solution of sodium cyanoborohydride (0.51 g) in ethanol (50 ml) for 3 hours at room temperature. After standing overnight at room temperature, the mixture is concentrated in vacuo and diluted with a mixture of water (50 ml) and ethyl acetate (200 ml). The resulting mixture is agitated thoroughly and filtered. The ethyl acetate layer is washed successively with 0.1N hydrochloric acid, 0.1N sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue is chromatographed on silica gel using hexane-ethyl acetate (2:1) as an eluent. Evaporation of the first fraction affords tert-butyl 3(S)-[6(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5 -tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+].[Cl:13][CH2:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])(=O)C.[Na+]>C(Cl)Cl.CC(O)=O.S(=O)(=O)(O)O.CC(O)=O.O.C(Cl)Cl>[Cl:13][CH2:14][C:15](=[O:22])[CH:16]([N:9]=[N:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=N[O-]
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(N=Nc1ccc(F)cc1)C(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-fluoroaniline (10 g, 90.0 mmol, 1.0 eq.) in DCM/HOAc (1/1, 180 mL, 0.5M) at 0° C. was added dropwise a precooled solution of sodium nitrite (9.02 g, 108 mmol, 1.2 eq.) in conc. sulfuric acid (40 mL). After stirring for 30 min at 0° C. a mixture of ethyl 4-chloroacetoacetate (14.6 mL, 17.8 g, 108 mmol, 1.2 eq.) in HOAc (60 mL) and H2O (120 mL) was added within 5 min. After further 15 min at 0° C. a solution of sodium acetate (100 g, 1.219 mol, 13.5 eq.) in H2O (210 mL) was added slowly. The mixture was stirred for 30 min at 0° C. and 1 h at RT. DCM (200 mL) was added and the organic phase was separated. The aq. phase was extracted with DCM (3×100 mL). The combined organic phase was washed with water, phosphate buffer and subsequent with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the product ethyl 4-chloro-2-(4-fluorophenyl)azo-3-oxo-butanoate as a orange solid. MS (ES) C12H12ClFN2O3 requires: 286. Found: 287 (M+H)+ and 309 (M+Na)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=4)[N:19]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:18]=3)[C:14]([C:40]#[N:41])=[CH:13][N:12]=2)[CH3:9])[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([C@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([C:26]([F:29])([F:27])[F:28])[CH:24]=4)[N:19]([S:30]([C:33]4[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=4)(=[O:31])=[O:32])[CH:18]=3)[C:14]([C:40]#[N:41])=[CH:13][N:12]=2)[CH3:9])[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(O)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(=O)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
2-((R)-1-(4-hydroxycyclohexyl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (442 mg, 0.7561 mmol) was dissolved in dichloromethane (20 mL) and cooled down to 0° C. Dess-Martin periodinane (384.8 mg, 0.9073 mmol) was added and the reaction was allowed to warm up to room temperature. The mixture was stirred for 18 hours. The reaction mixture was partitioned between dichloromethane and a 1:1 saturated solution of sodium hydrosulfite and sodium hydrogen carbonate. The aqueous phase was further extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified on silica gel by flash column chromatography (ISCO Companion|, 40 g column, 0-20% EtOAc/DCM) to afford the title compound as a white solid (411 mg, 93% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(I)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(I)cc1
Yield: 45 %

Procedure:
A mixture of p-iodotoluene (4.36 g, 20 mmol, purchased from Tokyo Kasei) and N-bromosuccinimide (3.92 g, 22 mmol, purchased from Tokyo Kasei) in 60 ml of carbontetrachloride (purchased from Wako Junyaku Kogyo) was refluxed for 4 hours under irradiation by means of an incandescent lamp to give 2.67 g (yield: 45.0%) of 4-iodobenzyl bromide as a white crystalline.
Reaction SMILES: [Mg].C(I)C.II.Br[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=1.S(=O)(=O)(O)O>C1COCC1>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)=[CH2:23])=[CH:9][CH:10]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: Cc1ccc(Br)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCI
Solvent: C1CCOC1
Product: C=C(c1ccc(C)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
Into a 1-liter reaction flask were introduced in a nitrogen stream 15.6 g (0.65 mol) of magnesium and 20 ml of THF. Slight amounts of ethyl iodide and iodine were added thereto to initiate reaction. A solution of 111.15 g (0.65 mol) of p-bromotoluene in 500 ml of THF was then added dropwise at room temperature to 40° C. over a period of 2 hours to prepare a Grignard reagent. Thereto was added dropwise a solution of 83.75 g (0.625 mol) of p-methylacetophenone (10a) in 200 ml of THF at that temperature over a period of 3 hours. This mixture was stirred first at room temperature for 3 hours and then with refluxing for 4 hours. The resulting reaction mixture was cooled and poured into 1 liter of 5% aqueous sulfuric acid solution to conduct hydrolysis. This mixture was extracted with toluene, and the extract was washed with aqueous soda ash solution and then with water and concentrated. Thereto were added 300 ml of toluene and 0.5 g of PTSA. The resulting mixture was stirred with refluxing for 4 hours to conduct azeotropic dehydration, followed by washing with aqueous soda ash solution, washing with water, and concentration. The resulting crude 1,1-di(p-tolyl)ethylene (9b) was distilled with a Claisen flask equipped with a vigreux, giving 98.5 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]([NH:23][C:24]([N:26]2[CH2:35][CH2:34][C:33]3[CH:32]=[N:31][C:30]([NH:36][C@@H:37]([CH3:40])[CH2:38][OH:39])=[N:29][C:28]=3[CH2:27]2)=[O:25])[CH2:13][N:14](C)[C:15](=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(O)(C(F)(F)F)=O.C(Cl)[Cl:49]>>[ClH:49].[F:1][C:2]1[CH:3]=[C:4]([C@H:12]([NH:23][C:24]([N:26]2[CH2:35][CH2:34][C:33]3[CH:32]=[N:31][C:30]([NH:36][C@@H:37]([CH3:40])[CH2:38][OH:39])=[N:29][C:28]=3[CH2:27]2)=[O:25])[CH2:13][NH:14][CH3:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9]
Reactant: C[C@@H](CO)Nc1ncc2c(n1)CN(C(=O)N[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(F)c1)CC2
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC[C@@H](NC(=O)N1CCc2cnc(N[C@@H](C)CO)nc2C1)c1ccc(C(F)(F)F)c(F)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 318 (0.100 g, 0.175 mmol) and DCM (5 mL) at RT was added TFA (2 mL) and the reaction was stirred at RT for 1 h then concentrated to dryness. The crude product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirred solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to afford 0.070 g (78.8%) of I-80: MS m/z (APCI-pos) M+1=471.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]([CH3:11])[CH3:10])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:11])[CH3:10])=[C:4]([C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: CC(C)C(O)c1ccc(Cl)cc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)=Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
8.00 g (42 mmol) 1-(4-chloro-2-trifluoromethyl-phenyl)-2-methyl-propan-1-ol and 2.5 g p-toluenesulphonic acid monohydrate in 200 mL toluene are refluxed overnight, while the water formed is captured using a water separator. The reaction mixture is left to cool, combined with water and the organic phase is separated off. It is extracted with toluene and the organic phases are combined and evaporated down. The residue is added to a short silica gel column and eluted with hexane. Colourless oil.