Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH2:6][C:7]([N:9]2[C@@H:15]3[CH2:16][CH2:17][CH2:18][C@@H:14]3[C:13](=[O:19])[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.[H-].[Na+].Cl[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.O>CN(C)C=O>[C:4]1(=[O:24])[N:5]([CH2:6][C:7]([N:9]2[C@@H:15]3[CH2:16][CH2:17][CH2:18][C@@H:14]3[C:13](=[O:19])[N:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])[C:1](=[O:29])[C:2]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:3]12
Reactant: ClCc1ccccn1
Reactant: O=C1Nc2ccccc2N(C(=O)CN2C(=O)c3ccccc3C2=O)[C@@H]2CCC[C@H]12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccn2)C(=O)[C@H]2CCC[C@H]21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
In a mixture of water (0.5 mL) and ethyl acetate (1 mL)was dissolved 2-(chloromethyl)pyridine hydrochloride (246 mg, 1.5 mmol). This solution was neutralized with the addition of sodium hydrogencarbonate. The organic layer was separated, and the remaining aqueous layer was subjected to extraction twice with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, followed by concentration under reduced pressure to give 2-(chloromethyl)pyridine. To a suspension of (3aR*,10aS*)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (389 mg, 1.0 mmol) in N,N-dimethylformamide (3 mL), which was cooled to 0° C., was added sodium hydride (60% liquid paraffin dispersion, 44 mg, 1.1 mmol). The mixture was stirred for 3 minutes at the same temperature and for 10 minutes at room temperature. To this mixture was added a solution of the 2-(chloromethyl)pyridine, which was produce by the above-mentioned procedure, in N,N-dimethylformamide (0.5 mL). The mixture was stirred for 3 hours at room temperature. To the reaction mixture was added water, and resulting precipitate was collected by filtration, which was recrystallized from chloroform-ethanol-diisopropylether to give 232 mg (yield 48%) of the titled compound, m.p. 227°-229° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:18]C=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
To a solution of 2-amino-6-chloronicotinic acid (1.0 g, 5.79 mmol), HOBT (932 mg, 6.95 mmol) and EDCI (2.22 g, 11.6 mmol) in 15 mL of DMF was added triethylamine (5.86 g, 57.9 mmol) and NH4Cl (1.55 g, 28.9 mmol). Then the mixture was stirred at room temperature for 16 h. The solution was concentrated in vacuo to remove DMF and the residue was suspended in saturated NaHCO3 Finally the 2-amino-6-chloronicotinamide (800 mg, yield: 81%) was obtained by filtration without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 7.95 (d, J=8.4 Hz, 1H), 7.62 (s, 2H), 7.39 (s, 2H), 6.59 (d, J=8.4 Hz, 1H). MS (M+H)+: 172/174.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:16])[CH2:14][NH2:15]>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[C:4]([NH:15][CH2:14][CH2:13][NH2:16])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:15][CH2:14][CH2:13][NH2:16])[CH:7]=1
Reactant: NCCN
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Solvent: C1COCCO1
Product: NCCNc1cc(Cl)cc(NCCN)c1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
0.35 mole (79 g) of 2,4,6-trichloronitrobenzene is added to 280 ml of ethylenediamine diluted with 140 ml of dioxan, the temperature being maintained at 10° C. The mixture is heated for 2 hours at 50° C. The product expected precipitates on standing overnight at ambient temperature. After draining and re-impasting in water, the product is recrystallized from isopropanol in order to remove an insoluble product by filtering in the heated state. After drying under reduced pressure in the presence of phosphorous pentoxide, it melts at 113° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19](Cl)=[O:20]>CN(C=O)C.C(OCC)(=O)C.Cl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)=[O:20]
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reaction time: 12 h
Yield: 38 %

Procedure:
4-Aminophenol (1.9 g, 17 mmol) was diluted with DMF (40 mL) followed by the addition of pyridine (0.978) (1.4 mL, 17 mmol) and 3,4-dichlorobenzoyl chloride (3.0 g, 14 mmol) in 5 mL of DMF. After stirring for 12 hours, the reaction mixture was diluted with ethyl acetate and 2N HCl. The aqueous layer was extracted once with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, filtered and concentrated onto silica gel. The material was purified using a biotage 40M column eluting with hexanes:ethyl acetate (9:1) using 2 L and then (60:40) 1 L to yield 3,4-dichloro-N-(4-hydroxyphenyl)-benzamide (1.5 g, 37% yield) as a white solid.
Reaction SMILES: C[O-].[Na+].[Cl-].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20]>CO>[Br:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:13][CH2:12][N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]1=[NH:5]
Reactant: Nc1cccc[n+]1CSc1ccccc1Br
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: N=c1ccccn1CSc1ccccc1Br

Procedure:
To a solution of 5.4 g of sodium methoxide in 400 ml of methanol is added 33.2 g of 2-amino-1-[[(o-bromophenyl)thio]methyl]pyridinium chloride, and the mixture is stirred and heated under reflux for about 5 hours, and filtered while hot. The filtrate is concentrated in vacuo to dryness to give 1-[(o-bromophenylthio)methyl]-2-iminopyridine as a pale yellow crystalline solid after recrystallization from cyclohexane.
Reaction SMILES: CS[C:3]1[N:12]2[C:6]([CH:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1>[Ni]>[C:17]1([CH:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11][N:12]3[CH:3]=[N:4][N:5]=[C:6]23)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CSc1nnc2n1C=Cc1ccccc1C2c1ccccc1
Agent: [Ni]
Product: C1=Cn2cnnc2C(c2ccccc2)c2ccccc21

Procedure:
3-Methylthio-11-phenyl-11H-s-triazolo[3,4-b][3]benzazepine was treated with Raney nickel as described. This procedure provided 11-phenyl-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Colorless prisms (as recrystallized from ethanol), m.p. 217°-218° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=3)[CH2:26][CH2:25]2)=[CH:14][CH:13]=1.Cl>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(=O)c1cccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.41 (s, 1H), 7.72-6.84 (m, 12H), 5.18-5.10 (m, 1H), 3.62-3.50 (m, br, 2H), 3.00-2.92 (m, 2H), 2.90-2.58 (m, 4H), 2.54 (s, 3H), 2.50-2.12 (m, 2H), 2.02-1.70 (m, br, 6H), 1.64-1.50 (m, br, 1H), 1.50-1.14 (m, br, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 575.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[CH2:29](Br)[CH:30]([CH3:32])[CH3:31]>>[CH2:29]([N:25]1[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=2)[CH2:27][CH2:26]1)[CH:30]([CH3:32])[CH3:31]
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CC(C)CBr
Product: Cc1nc(OCC(=O)N(C)C2CCN(CC(C)C)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and isobutyl bromide in the same manner as in Example 32.
Reaction SMILES: C(C=P(CCCC)(CCCC)CCCC)#N.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36](O)[CH2:37][N:38]([CH2:51][CH2:52][OH:53])[S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[N+:48]([O-:50])=[O:49])(=[O:41])=[O:40])=[CH:32][CH:31]=1)(=[O:28])=[O:27])([O-:19])=[O:18]>C1(C)C=CC=CC=1>[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[O:53][CH2:52][CH2:51][N:38]([S:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[N+:48]([O-:50])=[O:49])(=[O:40])=[O:41])[CH2:37]2)=[CH:32][CH:31]=1)(=[O:27])=[O:28])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Oc1ccc(C(O)CN(CCO)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Oc1ccc(C2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CCO2)cc1
Temperature: 25 °C
Yield: 54 %

Procedure:
A 1 M toluene solution of 5.87 ml (5.87 mmol) of (cyanomethylene)tributylphosphorane was added to a solution of 2.22 g (3.91 mmol) of the title compound produced in step (ii) of Reference Example 12 in toluene (55.0 ml), and the mixture was stirred with heating under reflux for 1 hr 20 min. The reaction solution was then cooled to room temperature, and the solvent was removed under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 1.16 g (yield 54%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1>N.[Ni].CO.C(Cl)(Cl)Cl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:8]=1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NCCc1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
(4-Trifluoromethyl-phenyl)-acetonitrile (2 g, 10.81 mmol) in methanolic ammonia (50 mL) was added to Raney nickel (400 mg) in methanol taken in a parr hydrogenator. The flask was stirred at 50 PSI overnight. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was filtered through celite bed and the filtrate was dried under reduced pressure to afford 2 g of the product (97.89% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][C:19]([NH2:21])=O)[CH:14]=3)[C:9]2=[O:22])=[CH:5][CH:4]=1.N1C(Cl)=NC(Cl)=NC=1Cl>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][C:19]#[N:21])[CH:14]=3)[C:9]2=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2CCc3cc(CC(N)=O)ccc3C2=O)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCc3cc(CC#N)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
The amide (III) (1.3 g, 4 mmole) was suspended in 5 ml THF and 10 ml DMF. To this mixture was added cyanuric chloride (0.370 g, 2 mmole) and after stirring at room temperature for 0.5 hour, the reaction mixture was partitioned between ethylacetate and brine; the organic layer was washed with 5% sodium bicarbonate, followed by brine and then dried over sodium sulfate. Purification by flash chromatograpy on silica gel column using 75% ethylacetate in hexane as eluent afforded 1.2 g (98% yield) of nitrile (IV).
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[C@H:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH3:4].[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O>[OH:1][C:2]([CH3:20])([CH3:21])[C@H:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:17])[F:18])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)[CH3:4]
Reactant: C[C@@H](n1ccc2c(C(F)(F)F)c(C#N)ccc21)C(C)(C)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N1CCc2c1ccc(C#N)c2C(F)(F)F)C(C)(C)O
Reaction time: 1 h

Procedure:
To a solution of (R)-1-(3-hydroxy-3-methylbutan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 22) (0.017 g, 0.057 mmol) in TFA (1.5 mL), in an ice bath, was added NaCNBH3 (0.0721 g, 1.148 mmol) in portions. After stirring in the cold bath for 1 h, the reaction mixture was partially concentrated. The residue was dissolved in CH2Cl2 (20 mL) and washed with 0.5 N NaOH (10 mL). The organic phase was washed with 0.5 N NaOH (1×10 mL) and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using a 10-40% EtOAc-hexane gradient to give (R)-1-(3-hydroxy-3-methylbutan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile: MS (ESI): m/z 299 (M+H).
Reaction SMILES: CC([N:5]([C:9]([C@H:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=3)[N:22]=[CH:21][C:20]=2[F:31])[CH2:13]1)([CH3:11])[CH3:10])C(=O)[O-])(C)C.Cl>C(Cl)Cl>[F:31][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:19]=1[CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][C@@H:12]([C:9]([NH2:5])([CH3:11])[CH3:10])[CH2:13]1)=[N:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2
Reactant: COc1ccc2ncc(F)c(CCN3CC[C@H](C(C)(C)N(C(=O)[O-])C(C)(C)C)C3)c2n1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCN3CC[C@@H](C(C)(C)N)C3)c2n1
Reaction time: 24 h

Procedure:
To a solution of 1,1-dimethylethyl[1-((3S)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)-1-methylethyl]carbamate (0.46 g, 1.06 mmol) in DCM (10 mL) at 25° C. was added dropwise an HCl solution (4.22 mL, 4.24 mmol, 1M HCl in dioxane). After 24 h, the solution was concentrated to afford the hydrochloride salt of the title compound as an off-white residue (0.43 g, quantit.), which was used without further purification: LC/MS (ES) m/e 333 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrBr>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
2.0 g of cis-chrysanthemic acid and 43 mg of benzoyl peroxide were dissolved in 20 ml of toluene and thereto was added dropwise a solution of bromine (28 mg) in carbon tetrachloride with stirring at 80° C. over a period of 20 minutes, and the reaction mixture was stirred at the same temperature for 20 minutes. Then, a post-treatment similar to Example 1 was effected to obtain 1.87 g of chrysanthemic acid. Gas chromatographic assay thereof showed the composition: cis, 5.9%; and trans, 94.1%.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.[NH2:29][OH:30]>>[OH:30][NH:29][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([C@H:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[NH:27]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@H](C2CCN(C#N)CC2)C3)CC1
Reactant: NO
Agent: Cl
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@H](C2CCN(C(=N)NO)CC2)C3)CC1

Procedure:
The title compound is prepared from (S)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine-2-yl]-piperidine-1-carbonitrile (Intermediate 46, the configuration of the stereocenter is arbitrarily assigned) and hydroxylamine hydrochloride following a procedure analogous to that described for Intermediate 11. LC (method 6): tR=0.75 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C[O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)=[CH:33][CH:32]=3)=[O:29])=[CH:25][C:24]([C:44]([CH3:47])([CH3:46])[CH3:45])=[N:23]2)=[CH:18][CH:17]=1>ClCCCl>[C:44]([C:24]1[CH:25]=[C:26]([NH:27][C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)=[CH:35][CH:36]=2)=[O:29])[N:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([NH:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:14])=[CH:21][CH:20]=2)[N:23]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Reactant: NCCN1CCCC1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(C(=O)NCCN3CCCC3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of 2-pyrrolidin-1-yl-ethylamine in DCE was added trimethyl aluminum (1.03 mmol, 0.51 mL of 2N solution in DCM). After the reaction was stirred at ambient temperature for 30 minutes, a solution of 4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)phenyl]ureido}pyrazol-1-yl}benzoic acid methyl ester (100 mg, 0.21 mmol) in DCE was added, and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was quenched with two drops of water, dried over MgSO4, filtered, and evaporated at reduced pressure. Purification using MPLC (eluting with 15% NH3 in MeOH (2N)/EtOAc) afforded 34 mg (29%) of the title compound. 1H-NMR (acetone-d6) δ 8.43 (d, J=9.0 Hz, 2H), 7.94 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 7.60 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 6.84 (d, J=4.0 Hz, 2H), 6.48 (s, 1H), 3.52 (t, J=7.5 Hz, 2H), 2.67 (t, J=3.0 Hz, 2H), 2.50 to 2.64 (m, 4H), 1.70 to 1.72 (m, 4H), 1.31 (s, 9H); MS LC-MS [M+H]+=568, RT=2.48 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1>>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([N:16]2[CH:17]=[C:13]([C:12]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][O:10][C:11]=3[C:18]([F:21])([F:19])[F:20])[N:14]=[CH:15]2)=[N:24][CH:25]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Fc1cccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)c1
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4cccc(F)c4)noc3C(F)(F)F)c2)nc1
Yield: 68 %

Procedure:
As described for Example 4, 3-(3-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (500 mg, 1.68 mmol) instead of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole was converted, using methyl 6-chloronicotinate instead of 4-fluorobenzotrifluoride, to the title compound (495 mg, 68%) which was obtained as a white solid. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH2:23][OH:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH2:23][O:24][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc2c(cc1COCC1CC1)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 1 intermediate d) from (4R,9aR)-7-hydroxymethyl-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 15, intermediate b), sodium hydride and (bromomethyl)cyclopropane.
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[CH2:6]([OH:9])[CH:7]=[CH2:8].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+]>O>[CH2:1]([P:3]([CH2:8][CH2:7][CH2:6][OH:9])(=[O:5])[OH:4])[CH3:2]
Reactant: CCP(O)O
Reactant: C=CCO
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CCCO
Temperature: 100 °C
Yield: 89 %

Procedure:
564 g (6 mol) of ethylphosphonous acid (produced as in Example 1) are dissolved in 860 g of water and initially charged to a 5 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. The reaction mixture is heated to 100° C. and 406 g (7 mol) of allyl alcohol and 500 g of a 5% sodium peroxodisulfate solution (1.5 mol % based on ally alcohol) is added dropwise at atmospheric pressure over 1 h. Then, the water is distilled off in vacuo, and the residue is taken up in THF and the insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo to leave 812 g (89% of theory) of ethyl-3-hydroxypropylphosphinic acid as oil.
Reaction SMILES: F[C:2]1[C:11]([B:12]([OH:14])[OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][OH:16]>Cl>[CH3:15][O:16][C:2]1[C:11]([B:12]([OH:14])[OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: OB(O)c1cc2ccccc2nc1F
Reactant: CO
Agent: Cl
Product: COc1nc2ccccc2cc1B(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2-Fluoroquinolin-3-yl)boronic acid was dissolved in 1.25M HCl in MeOH and stirred for 1 hr at RT. The mixture was quenched with sat. aq. NaHCO3 solution and the mixture was extracted with DCM (3×). The organics were dried (Na2SO4) and concentrated under reduced pressure to yield the crude product as a pale yellow solid which was used in the next step without further purification. MS (ES) C10H10BNO3 requires: 203, found: 204 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C1C(=O)N([I:17])C(=O)C1>CC(O)=O>[I:17][C:3]1[C:4]([OH:9])=[N:5][C:6]([OH:8])=[N:7][C:2]=1[CH3:1]
Reactant: Cc1cc(O)nc(O)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Cc1nc(O)nc(O)c1I
Reaction time: 7 h
Yield: 95 %

Procedure:
The mixture of all materials (6-methylpyrimidine-2,4-diol, 20.00 g, 0.159 mol, 1.0 eq; NIS, 39.25 g, 0.174 mol, 1.1 eq; AcOH, 150 mL) was stirred well for about 7 h. It affords white solid product 5-iodo-6-methylpyrimidine-2,4-diol (37.93 g, 95%), isolated by filtration, washed with ethyl acetate. LC-MS (m/z)=252.9 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13]C)=[O:12])[CH:2]=[CH2:3].[OH-].[Li+]>O1CCCC1.O>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of the Methyl 2-allylphenylacetate (Step 1, 0.400 mg. 2.10 mmol) in tetrahydrofurane (10 mL) was added Lithium hydroxide (0.097 g, 2.31 mmol) in water (10 mL). The solution was stirred at room temperature for 3 h and was concentrated in vacuo. Water (40 mL) was added and the pH was adjusted to 1. The solution was extracted with dichloromethane and the combined organic layers were dried and concentrated to give 2-allyl phenyl acetic acid (yellow oil, 363 mg, 98%); C11H12O2; MW: 176.22; ES− 175; IR 1702 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.16-7.38 (4H, m), 5.99 (1H, m), 5.11 (1H, m), 5.04 (1H, m), 3.73 (2H, s), 3.47 (2H, dt) ppm.