Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:23](C#N)#[N:24].N1C=CC=CC=1.CN1CCCC1=O>Cl>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:24]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(Br)cc3)CC2)CC1
Reactant: N#CC#N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)CC1

Procedure:
A mixture of 36.3 g of trans-1-p-bromophenyl-4-(trans-4-propylcyclohexyl)-cyclohexane, 10 g of Cu2 (CN)2, 120 ml of pyridine and 60 ml of N-methylpyrrolidone is heated to 160° for 2 hours. The mixture is cooled, a solution of 120 g of FeCl3.6H2O in 600 ml of 20% hydrochloric acid and the mixture is warmed to 70° for 1.5 hours, while stirring, and worked up in the customary manner to give trans-1-p-cyanophenyl-4-(trans-4-propylcyclohexyl)-cyclohexane, m.p. 55°, c.p. 184°.
Reaction SMILES: C1N(CCS(O)(=O)=O)CC[O:3]C1.[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16].O=C(CCC(O)=O)C(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:3][C@H:19]1[CH2:20][NH:13][C@H:14]([C:15]([OH:17])=[O:16])[CH2:18]1
Reactant: O=S(=O)(O)CCN1CCOCC1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C(O)CCC(=O)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
The enzyme preparation to be determined is added to 80 mM MES buffer (pH 6.5) containing 4 mM L-proline, 8 mM 2-ketoglutaric acid, 2 mM ferrous sulfate and 4 mM L-ascorbic acid to make 250 in total, and the mixture was allowed to stand at 30° C. for 20 minutes. The reaction mixture is heated at 100° C. for 2 minutes so as to stop the reaction, and the amount of the trans-4-hydroxy-L-proline produced in the reaction mixture is determined by high performance liquid chromatography (hereinafter referred to as HPLC).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12.[Cl:23][C:24]([Cl:29])([Cl:28])[CH:25](O)[OH:26].N1C=CC=CC=1.C(Cl)Cl>O>[OH:26][CH:25]([C:24]([Cl:29])([Cl:28])[Cl:23])[CH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12
Reactant: Cc1nnccc1-c1c(-c2ccccc2)nn2ccccc12
Reactant: OC(O)C(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: OC(Cc1nnccc1-c1c(-c2ccccc2)nn2ccccc12)C(Cl)(Cl)Cl
Reaction time: 20 h
Yield: 42.9 %

Procedure:
A mixture of 3-(3-methylpyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.40 g), chloral hydrate (0.70 g) and pyridine (4 ml) was stirred for 20 hours at 90°-100° C. After cooling, to the reaction mixture was added methylene chloride (4 ml) and water (4 ml) at room temperature, and stirred for 3 hours. The precipitates were collected by filtration to give 3-[3-(2-hydroxy-3,3,3-trichoropropyl)pyridazin-4-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.26 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:3]=1.Cl[C:17]1[C:18]2[C:25]([CH3:26])=[C:24]([Cl:27])[S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[OH-].[NH4+]>O1CCOCC1.O>[Cl:27][C:24]1[S:23][C:19]2[N:20]=[CH:21][N:22]=[C:17]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=3[O:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:18]=2[C:25]=1[CH3:26]
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Reactant: Cc1c(Cl)sc2ncnc(Cl)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(Cl)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 25 °C
Yield: 11.3 %

Procedure:
4-Fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.057 g, 0.27 mmol), 4,6-dichloro-5-methylthieno[2,3-d]pyrimidine (0.06 g, 0.27 mmol, CA56844-14-5) and para-toluene sulfonic acid (0.005 g, 0.03 mmol) were heated at 90° C. in anhydrous 1,4-dioxane (1.5 mL) for 18 hours. The solution was cooled to ambient temperature, diluted with water (2 mL) and adjusted to pH 10 (4:1 water/ammonium hydroxide solution). The precipitate was collected, washed with water and diethyl ether to yield the title compound as yellow solid (0.012 g, 11%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:43])=[CH:9][C:10]([CH3:42])=[C:11]([CH:13]([S:18][CH:19]([C:24]3[CH:29]=[C:28]([N:30]4[C:34]([NH2:35])=[N:33][C:32]([C:36]([F:39])([F:38])[F:37])=[N:31]4)[C:27]([Cl:40])=[CH:26][C:25]=3[CH3:41])[C:20]([F:23])([F:22])[F:21])[C:14]([F:17])([F:16])[F:15])[CH:12]=2)[N:5]=[C:4]([C:44]([F:47])([F:46])[F:45])[N:3]=1.ClC1C=CC=C(C(OO)=[O:56])C=1>C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:43])=[CH:9][C:10]([CH3:42])=[C:11]([CH:13]([S:18]([CH:19]([C:24]3[CH:29]=[C:28]([N:30]4[C:34]([NH2:35])=[N:33][C:32]([C:36]([F:39])([F:37])[F:38])=[N:31]4)[C:27]([Cl:40])=[CH:26][C:25]=3[CH3:41])[C:20]([F:21])([F:22])[F:23])=[O:56])[C:14]([F:17])([F:16])[F:15])[CH:12]=2)[N:5]=[C:4]([C:44]([F:47])([F:46])[F:45])[N:3]=1
Reactant: Cc1cc(Cl)c(-n2nc(C(F)(F)F)nc2N)cc1C(SC(c1cc(-n2nc(C(F)(F)F)nc2N)c(Cl)cc1C)C(F)(F)F)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)c(-n2nc(C(F)(F)F)nc2N)cc1C(S(=O)C(c1cc(-n2nc(C(F)(F)F)nc2N)c(Cl)cc1C)C(F)(F)F)C(F)(F)F
Yield: 90.4 %

Procedure:
1.3 g of [5-(5-amino-3-trifluoromethyl-1,2,4-triazolyl)-4-chloro-2-methylphenyl]2,2,2-trifluoroethyl sulfide was dissolved in 80 ml of ethyl acetate, and 0.9 g (purity 75%) of m-chloroperbenzoic acid was added under cooling with ice. The mixture was stirred under cooling with ice for 2 hours, washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogencarbonate solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with carbon tetrachloride to obtain 1.2 g of [5-(5-amino-3-trifluoromethyl-1,2,4-triazolyl)-4-chloro-2-methylphenyl]2,2,2-trifluoroethyl sulfoxide as white crystals (melting point 235 to 237° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[O:9][C:10]=1[CH2:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:5])C.[OH-].[Na+].OP(O)(O)=O>C(O)C>[C:13]12([CH2:12][CH2:11][C:10]3[O:9][C:8]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[N:7][C:6]=3[C:4]([OH:5])=[O:3])[CH2:14][CH:15]3[CH2:16][CH:17]([CH2:18][CH:19]([CH2:21]3)[CH2:20]1)[CH2:22]2
Reactant: CCOC(=O)c1nc(-c2ccccc2C)oc1CCC12CC3CC(CC(C3)C1)C2
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)o1
Yield: 91.9 %

Procedure:
A solution of the product from step b (540 mg, 1.37 mmol) in ethanol (48m1) and 2M sodium hydroxide (4.8 ml, 9.60 mmol) were refluxed for 16 h. The resulting hot suspension was acidified (pH=3, 1M H3PO4), the ethanol was evaporated, the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4), and the solvent was evaporated to afford the product as a white solid (460 mg, 92%). 1H NMR (300 MHz, CDCl3) 8.00 (1H, d), 7.33 (3H, m), 3.11 (2H, m), 2.70 (3H, s), 2.00 (3H, s), 1.77-1.49 (14H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[F:32][C:33]([F:44])([F:43])[O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:40][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:34][C:33]([F:43])([F:44])[F:32])=[CH:36][CH:37]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(trifluoromethoxy)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=620.94 (M+H+); retention time=1.04 minutes.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])[CH2:30][CH3:31])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:39]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:39])=[O:26])=[C:21]([O:28][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])[CH2:30][CH3:31])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: N
Reactant: CCC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(=O)OC)c1ccccc1Cl
Solvent: CO
Product: CCC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1Cl

Procedure:
In a similar manner as described for example A5, 3.64 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{[1-(2-chlorophenyl)propyl]oxy}thiophene-2-carboxylate and 115 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([C:14](=[O:24])[CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.O>CCO.[Fe]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:25])([CH3:1])[CH2:3][N:4]2[C:14](=[O:24])[CH2:15][NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N1CC(C)(C)c2ccc(N)cc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-2-(N-Boc-amino)-ethanone (3.9 g) was dissolved in EtOH (30 ml) and Fe powder (3.1 g) NH4Cl (299 mg) and H2O (5 ml) were added. The reaction was stirred at 80° C. overnight. The reaction was filtered through Celite® and evaporated off the MeOH. The residue was partitioned between CH2Cl2 and sat'd NaHCO3. The organic layer was removed, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 25% EtOAc/hexane). The purified fractions were concentrated in vacuo to afford the compound as a white powder.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:7]1)[CH3:2].C[O:22][C:23](=[O:35])[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[O:31][CH2:32][CH2:33]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:33][CH2:32][O:31][C:25]3[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=3[C:23]([OH:35])=[O:22])[CH2:19][CH2:20]2)=[CH:7]1)[CH3:2]
Reactant: CCOCCn1cc(C2CCNCC2)c2ccccc21
Reactant: COC(=O)c1cc(C)ccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOCCn1cc(C2CCN(CCOc3ccc(C)cc3C(=O)O)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 152 (parts D and E) starting with 0.85 g (3.1 mmol) of 1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-indole, 0.97 g (4.0 mmol) of 2-(2-chloroethoxy)-5-methyl-benzoic acid methyl ester, 0.65 g (4.7 mmol) of potassium carbonate and 0.38 g (2.3 mmol) of potassium iodide. After the saponication and purification through silica gel 0.52 g (36%) of the corresponding carboxylic acid were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1)#[N:2].CN1CCOCC1.ClC(OCC(C)C)=O.[C:27]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH2:41])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:30]([O:29][C:27](=[O:28])[NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:7]([C:6]1[CH:5]=[N:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=1)=[O:9])([CH3:33])([CH3:31])[CH3:32]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C#N)nc1
Temperature: 5 °C
Yield: 78.3 %

Procedure:
To a solution of 444 mg (3.0 mmol) 6-cyano-nicotinic acid and 354 mg (3.5 mmol) N-methylmorpholine in 7 ml DMF at −20° C. was added 450 mg (3.3 mmol) isobutyl chloroformate. The reaction mixture was warmed to 5° C., and 625 mg (3.0 mmol) mono-boc-ortho-phenylenediamine was added. The reaction mixture was warmed to rt overnight and then poured into 50 ml 5% aqueous citric acid. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with bicarbonate and brine and dried over Na2SO4. The solvent was evaporated and the residue was subjected to silica gel chromatography (petrol ether/ethyl acetate 2:1) to yield 795 mg (2.35 mmol) {2-[(6-Cyano-pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid t-butyl ester; mp.183–184° C.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:5]=[CH:6][N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc(-c2ccncc2)cc1
Product: Clc1cc(-c2ccncc2)ccn1
Temperature: 110 °C

Procedure:
The suspension of 4,4′-bipyridine-1-oxide (8.50 g, 49.36 mmol) in phosphorus oxychloride (80 mL) was heated to 110° C. overnight. The mixture was concentrated and the residue was treated with saturated aqueous NaHCO3 solution (150 mL) slowly and then Na2CO3 solution (2M) until it was basic. The alkaline solution was extracted with chloroform (4×300 mL). The combined organic layer was dried, treated with activated carbon and filtered through celite. The filtrate was concentrated and the resulting solid was purified by flash column chromatography (4% MeOH in CH2Cl2) to give 2-Chloro-4,4′-bipyridine (3-2) as a off-yellow solid. 1H NMR (CDCl3) δ 8.77 (dd, 2H, J=4.5, 1.6), 8.53 (d, 1H, J=5.1), 7.58 (s, 1H), 7.52 (dd, 2H, J=4.7, 1.7), 7.46 (dd, 1H, J=5.2, 1.5).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[C:17](Cl)(=[O:26])[C:18]1[C:19]([O:24][CH3:25])=[CH:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Reactant: COc1ccccc1C(=O)Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccccc1OC
Reaction time: 8 h
Yield: 30.4 %

Procedure:
A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286 mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parr bottle over 5% palladium on carbon (6.5 g) at room temperature for 1 hour. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. A 235-ml portion of the filtrate was used in this reaction. Under nitrogen atmosphere, o-anisoyl chloride (9.72 g, 0.057 mole) and triethylamine (6.33 g, 0.063 mole) were added dropwise simultaneously to the above-stirred filtrate at room temperature. The reaction mixture was allowed to stir overnight. The reaction mixture was filtered, and the filtrate was treated with Florisil® (30 g), and evaporated to a solid. The solid was recrystallized from hot tetrahydrofuran (minimum). The solid was filtered off, washed with cold tetrahydrofuran, and dried under high vacuum at room temperature to give 5.7 g of title compound, mp 111°-12° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.O[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.[SH:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1>>[CH3:34][N:30]1[CH:31]=[CH:32][N:33]=[C:29]1[S:28][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1
Reactant: Cn1ccnc1S
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCSc2nccn2C)cc1)c1ccccc1
Yield: 37 %

Procedure:
The title compound was prepared as its TFA salt in 37% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-mercapto-1-methylimidazole. NMR (400 MHz; CDCl3): δ 3.01 (t, 2H), 3.40 (br s, 3H), 3.47 (s, 1H), 3.64 (t, 2H), 6.92 (br d, 2H), 6.98 (s, 1H), 7.08 (d, 2H), 7.26-7.43 (m, 6H); HPLC-MS: m/z=368.2 (M+1); Rt=2.30 min.
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]3)[CH:42]=2)[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1-c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 120 °C
Yield: 93.1 %

Procedure:
Into a microwave vial was added N-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.032 g, 0.066 mmol, from Example 113, Step 2, chiral intermediate), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.030 g, 0.080 mmol, from Combi-Blocks), sodium carbonate (0.014 g, 0.13 mmol), 1,4-dioxane (0.6 mL)/water (0.2 mL) and tetrakis(triphenylphosphine)palladium(0) (4.6 mg, 0.0040 mmol). The mixture was degassed with N2 for 5 minutes, and then heated at 120° C. overnight. The mixture was diluted with EtOAc, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated to give the crude product (0.040 g) which was used in the next step directly. LCMS calculated for C33H44ClN8O4 (M+H)+: m/z=651.3. found: 651.2.
Reaction SMILES: [OH:1][C:2]([C:4]([F:15])([F:14])[CH:5]([O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH3:7])=[O:3].C1COCC1.C(N(CC)CC)C.Cl[C:29]1([CH2:34][CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>O>[CH2:34]([C:29]1([O:3][C:2]([C:4]([F:14])([F:15])[CH:5]([O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH3:7])=[O:1])[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:35]
Reactant: CCC1(Cl)CCCC1
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OC1(CC)CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
A 2 L reactor was charged under nitrogen with 5.6 g (purity 78%, 20.0 mmol) of methacrylic acid 1-hydroxycarbonyl-1,1-difluoro-2-butyl ester and 240 mL of THF (dehydrated), followed by cooling down to 0° C., adding 5.2 mL (37.6 mmol/1.9 equivalents) of triethylamine, and stirring at 0° C. for 10 minutes. Then, furthermore 14.24 g (3.2 mmol/1.6 equivalents) of 1-chloro-1-ethylcyclopentane was added, followed by stirring at 0° C. for 20 minutes. To the reaction liquid 800 mL of water was added, followed by extraction two times with diisopropyl ether, removing water by magnesium sulfate, conducting a filtration, and distilling diisopropyl ether out, thereby obtaining 5.52 g of the target methacrylic acid 1-(1-ethylcyclopentyloxycarbonyl)-1,1-difluoro-2-butyl ester. Upon this, purity was 96%, and yield was 83%.
Reaction SMILES: ClC(N(C)C)=C(C)C.[Cl:9][C:10]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:13]=[C:12]([NH:26][CH:27]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[C:28]2[N:29]([CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[C:33]([OH:35])=O)[CH:11]=1>C(Cl)Cl>[Cl:9][C:10]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH:13]=[C:12]([N:26]2[C:33](=[O:35])[C:32]3[CH:31]=[CH:30][N:29]([CH:36]([CH3:37])[CH3:38])[C:28]=3[CH:27]2[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[CH:11]=1
Reactant: COc1ccc(Cn2cc(NC(c3ccc(Cl)cc3)c3c(C(=O)O)ccn3C(C)C)cc(Cl)c2=O)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2cc(N3C(=O)c4ccn(C(C)C)c4C3c3ccc(Cl)cc3)cc(Cl)c2=O)cc1
Reaction time: 2 h

Procedure:
1-Chloro-N,N,2-trimethylpropenylamine [26189-59-3] (2.90 mmol) was added to a solution of 2-[[5-chloro-1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridin-3-ylamino]-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid (Step O2) (1.943 mmol) in CH2Cl2 (20 mL) at 0° C. After stirring for 2 h, the reaction mixture was diluted with CH2Cl2 and successively washed with a saturated aqueous solution of NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a light brown solid. tR: 6.81 min (HPLC 2); ESI-MS: tR=1.13 min, [M+H]+ 522/524/526 (LC-MS 1); TLC: Rf=0.48 (EtOAc).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH:1]([N:14]1[CH2:17][C:16]([O:18][S:21]([CH3:20])(=[O:23])=[O:22])([CH3:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -20 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
10 g (0.0394 mol) of 1-benzhydryl-3-methylazetidin-3-ol (S. S. Chattergee and A. Shoeb, Synthesis 1973, p. 153-154) are dissolved in 100 ml of anhydrous pyridine, the mixture is cooled to -20° C. and 7.3 g (0.063 mol) of methanesulphonyl chloride are added dropwise. The temperature is kept below -10° C., stirring is carried out at this temperature for 1 hour and the reaction mixture is left between 0° C. and 3° C. for two days. It is poured into 600 ml of water/ice, the precipitate is recovered by filtration and is washed with water. After drying in the oven at 50° C. for 2 hours the product is taken up in isopropyl ether (100 ml), is filtered and is dried in the oven at 50° C. overnight to obtain approximately 10 g of 1-benzhydryl-3-methanesulphonyloxy-3-methylazetidine.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.[Cl:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:13][C:14]1[CH:21]=[C:20]([N:6]2[CH2:7][CH2:8][C@@:4]([OH:12])([CH3:1])[C@@H:5]2[CH2:9][CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(Cl)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (195 mg), 2-chloro-4-fluorobenzonitrile (320 mg) and lithium carbonate (200 mg), the title compound was obtained as a colorless solid (yield: 221.4 mg, yield: 75%).