Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@@H:21]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:20][C@@H:7]([O:8][CH:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[C@@H:6]1[NH:32][C:33]([O:35]CC(Cl)(Cl)Cl)=O)(=[O:3])[CH3:2].[C:41](O)(=O)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]C>>[C:1]([O:4][C@H:5]1[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@@H:21]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:20][C@@H:7]([O:8][CH:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[C@@H:6]1[NH:32][C:33](=[O:35])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH3:41])(=[O:3])[CH3:2]
Reactant: COC(=O)CC(CC(=O)OC)O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(=O)OCC(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCC(=O)N[C@H]1[C@H](OC(CC(=O)OC)CC(=O)OC)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
2-Methoxycarbonyl-1-(methoxycarbonylmethyl)ethyl 3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-β-D-glucopyranoside was reacted with tetradecanoic acid in the same manner as in Example 8, Step 1 to obtain the titled compound as a white waxy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7]C=1.S(Cl)(Cl)(=O)=O.O.[CH2:16]([Cl:18])Cl.[CH:19](Cl)(Cl)Cl>>[Cl:18][C:16]1[CH:7]=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[O:2][CH2:1][CH3:19]
Reactant: ClCCl
Reactant: COc1cccc(O)c1
Reactant: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: CCOc1cc(O)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
3-Methoxyphenol (14.9 g, 120.0 mmol) was dissolved in 60 ml chloroform. At 0° C. 17.12 g (126.0 mmol) sulfurylchloride were added dropwise over 1 hour. After 2 hours stirring at 0° C. 100 ml water and 50 ml DCM were added. The organic layer was separated and washed with water and saturated sodium chloride solution. The title compound was purified by chromatography (SiO2, ethyl acetate/c-hexane 2/8) and was isolated as a yellow liquid (7.50 g, 39%)
Reaction SMILES: [NH:1]([C:3]([O:5][CH3:6])=[O:4])[NH2:2].N1C=CC=CC=1.[C:13]([CH2:17][C:18](Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14]>ClCCl>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:17][C:18]([NH:2][NH:1][C:3]([O:5][CH3:6])=[O:4])=[O:19]
Reactant: COC(=O)NN
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NNC(=O)CC(C)(C)C
Yield: 95 %

Procedure:
A solution of 65.5 g of hydrazinecarboxylic acid, methyl ester, 150 ml of dry pyridine and 500 ml of dry dichloromethane was stirred at 0° C. and 100 g of distilled t-butylacetyl chloride was added dropwise. After 2 hours at 0°-5° C. the solvent was removed in vacuo. The residue was taken up in 1.2 liters of ethyl acetate, washed with saturated sodium chloride and filtered through a bed of hydrous magnesium silicate with additional ethyl acetate. The filtrate was concentrated and the solid recrystallized from diisopropyl ether, giving 130 g of 2-(3,3-dimethyl-1-oxobutyl)hydrazinecarboxylic acid, methyl ester as white platelets, mp 83°-84.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH:20]1[OH:29]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([C:19]2([NH2:18])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][CH:20]2[OH:29])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1c2ccccc2CCC1O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)c2ccccc2CCC1O

Procedure:
Following General Procedure C and using using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 1-amino-1,2,3,4-tetrahydro-2-naphthol, the title compound was prepared.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH:14]=O)[CH3:2].Cl.[CH2:18]([O:20][C:21](=[O:24])[CH2:22][NH2:23])[CH3:19].CCN(CC)CC.O>ClCCl>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1/[CH:14]=[N:23]/[CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Br)cc1C=O
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C/N=C/c1cc(Br)ccc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Bromo-2-formylphenoxyacetic acid ethyl ester (1.44 g, 5 mmol) was dissolved in dichloromethane (50 mL) and glycine ethyl ester hydrochloride (1.39 g, 10 mmol) as well as Et3N (1.4 mL, 10 mmol) was added. The mixture was stirred at room temperature for 4 h. Water and dichloromethane was added and the organic phase was passed through a phase separation filter and then evaporated to give {4-bromo-2-[(E)-ethoxycarbonylmethyliminomethyl]phenoxy}acetic acid ethyl ester, which was redissolved in dichloromethane (50 mL) and treated with NaBH(OAc)3 (2.11 g, 10 mmol) and AcOH (1 mL), and then stirred at room temperature for 5 h. Saturated Na2CO3, water and dichloromethane was added, and the organic phase was passed through a phase separation filter and evaporated to give the title compound (1.56 g, 84% overall yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.C([O:32][CH2:33][C:34](Cl)=[O:35])(=O)C>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][N:20]([C:33](=[O:32])[CH2:34][OH:35])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCNC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)CO)C1
Temperature: 4 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride (0.25 g; prepared as described in Example 29) was dissolved in a mixture of methylene chloride (10 ml) and diisopropylethylamine (0.3 ml). The solution was cooled in an ice/water bath to 4° C. and acetoxyacetyl chloride (0.069 ml) added. The reaction mixture was stirred cold for two hours and then partitioned between methylene chloride and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in 7M methanolic ammonia (10 ml) and the resulting solution stirred overnight. The solvent was evaporated and the residue purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) 98/2 to 92/8 The fractions containing the expected product were evaporated and the residue was triturated with diethylether to give the title product as a pale yellow solid (0.161 g, 61%); 3H NMR Spectrum: (DMSO-d6 @ 393K, 500 MHz) 2.10-2.40 (m, 2H), 3.50-3.70 (m, 3H), 3.70-3.85 (m, 1H), 3.95 (s, 3H), 4.05 (s, 2H), 5.15 (s, 1H), 7.15-730 (m, 2H), 7.30-7.45 (m, 1H), 7.50-7.70 (m, 1H), 7.85 (s, 1H), 8.40 (s, 1H), 9.20 (bs, 1H); Mass Spectrum: (M+H)+ 447.
Reaction SMILES: Br.COC1C=CC(C[NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[N:13]=[CH:12][CH:11]=2)=CC=1.C([O-])(O)=O.[Na+]>>[NH3:9].[N:13]1[C:14]2[C:19](=[N:18][CH:17]=[CH:16][CH:15]=2)[C:10]([NH2:9])=[CH:11][CH:12]=1
Reactant: COc1ccc(CNc2ccnc3cccnc23)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: N
Product: Nc1ccnc2cccnc12
Temperature: 80 °C
Yield: 183.2 %

Procedure:
48% HBr (13 ml) was added to (4-methoxy-benzyl)-[1,5]naphthyridin-4-yl-amine 485 (0.5 g, 1.88 mmol) and the mixture was heated at 80° C. for 2 h. After cooling, the mixture was neutralized with sat. NaHCO3 solution and the aqueous phase was extracted with EtOAc (80 ml). The organic phase was washed with water, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH/Aq. NH3 (97:2:1) as the eluent to give the title compound (0.25 g, 90%).
Reaction SMILES: C1(C)C(S([N:10]=C=O)(=O)=[O:8])=CC=CC=1.[C:14]([O-:27])(=[O:26])[CH2:15][CH2:16][CH2:17]CCCCCCCC.[C:28]([O-:41])(=O)[CH2:29]CCCCCCCCCC.C([Sn+2]CCCC)CCC>O1CCCC1>[C:14]1(=[O:27])[O:26][C:17](=[O:8])[CH2:16][CH2:15]1.[NH:10]([CH2:15][CH2:14][OH:27])[CH2:29][CH2:28][OH:41]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: O=C1CCC(=O)O1
Product: OCCNCCO

Procedure:
17.8 g of polypropylene glycol (M=480), 0.24 g of toluenesulfonyl isocyanate and 150 g of anhydrous tetrahydrofuran were stirred for 15 minutes in a three-necked flask with a capacity of 250 ml. 13.0 g of tolylene 2,4-diisocyanate and 0.17 g of dibutyltin dilaurate were then added, the mixture was refluxed for one hour, and the solution obtained was added dropwise to a mixture of 7.6 g of the monoamide formed from 1 mol of succinic anhydride and 1 mol of diethanolamine in 184 g of tetrahydrofuran and heated for 22 hours under reflux until isocyanate was no longer present in the solution. A weight average of the molecular weight (Mw) of 8500 was determined with the aid of gel permeation chromatography (polystyrene standard).
Reaction SMILES: [N:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[N:4]=[CH:3][CH:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19]([OH:21])=O)=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[N:1]=[CH:2][CH:3]=[N:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:21]
Reactant: O=C(O)c1cccc2nc3ccc4nccnc4c3nc12
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4nccnc4c3nc12

Procedure:
Pyrazino[2,3-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from pyrazino[3,2-α]phenazine-11-carboxylic acid (II.6) and N,N-dimethylethylenediamine
Reaction SMILES: Cl.[C:2]1([NH:8][C:9]([NH:11][CH2:12][CH2:13][NH2:14])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:22]1[CH2:36][CH:23]1[CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>CO>[OH:22][CH:23]([CH2:36][NH:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: NCCNC(=O)Nc1ccccc1
Reactant: COC(=O)c1ccccc1OCC1CO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccccc1OCC(O)CNCCNC(=O)Nc1ccccc1
Yield: 7.5 %

Procedure:
4.8 g of N-phenyl-N'-(2-aminoethyl)urea HCl salt (0.024 mole) was placed in 100 ml of methanol, and 2.5 g of triethylamine (0.024 mole) was added. While this reaction mixture was being stirred, a solution of 5 g of methyl 2-(2,3-epoxypropoxy)benzoate (0.024 mole) in 25 ml methanol was added slowly. The solution was then heated to reflux for 4 hours. The methanol was removed under reduced pressure and the resulting gel-like solid was dissolved in 100 ml of methylene chloride. The organic layer was washed twice with 100 ml of water and dried over anhydrous magnesium sulfate. Removal of the methylene chloride left an oil which was dissolved in 50 ml of methanol/ethyl ether (1:1) from which the product crystallized slowly upon refrigeration to afford 0.7 g (7.5%) of product having a melting point of 133°-134° C. The compound was identified by its NMR spectrum and elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7](O)[CH:6]=[CH:5]2.CN(C=O)C.C(Cl)(=O)C([Cl:22])=O.C(Cl)Cl>ClCCCl>[Cl:22][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Oc1ccc2cc(F)cc(F)c2n1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: Fc1cc(F)c2nc(Cl)ccc2c1
Temperature: 70 °C

Procedure:
6,8-Difluoroquinolin-2-ol (9.89 g, 54.6 mmol) was slurried in 1,2-dichloroethane (550 mL) and treated with DMF (1 mL), and then 2M oxalyl chloride in CH2Cl2 (81.9 mL, 164 mmol) was added dropwise. The reaction was heated to 70° C. for 1 hour and then cooled and concentrated in vacuo. The residue was dissolved in CHCl3 and washed with 50% saturated NaHCO3. The aqueous layer (pH 8) was washed twice with CHCl3 and the combined organics were dried over Na2SO4 and charcoal, filtered, and concentrated in vacuo to a brown solid. The solid was purified by recrystallization from hot hexanes and 1,2-dichloroethane (minimum volume). The solid was collected, washed with hexanes and air-dried to provide the desired product as an off-white solid (5.78 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH2:23])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:26](Cl)(=[O:28])[CH3:27]>O1CCCC1.C(N(CC)CC)C.ClC(Cl)C>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH:23][C:26](=[O:28])[CH3:27])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)Oc1ccc(Oc2ccc(-c3cc(C(C)N)on3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)NC(C)c1cc(-c2ccc(Oc3ccc(OC(C)C)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A solution of Example 17F (600 mg, 1.79 mmol) in tetrahydrofuran (5 mL) and triethyl amine (1.0 mL) was cooled to 0° C. To this was added acetyl chloride (300 μL, 4.22 mmol) at 0° C. The mixture was stirred at room temperature for 30 minutes. The reaction was diluted with dichloroethane, which was washed with water and concentrated. The residue was purified on silica gel eluting with hexane and ethyl acetate gradient to give the desired product as a white solid (500 mg, 77%). MS (DCI): m/z 381 (M+H); 1H NMR (300 MHz, CDCl3) δ ppm 7.66-7.76 (m, 2H), 6.95-7.04 (m, 4H), 6.86-6.93 (m, 2H), 6.40 (s, 1H), 5.82 (d, J=8.46 Hz, 1H), 5.32-5.47 (m, 1H), 4.43-4.59 (m, 1H), 2.04 (s, 3H), 1.58 (d, J=6.99 Hz, 3H), 1.35 (d, J=6.25 Hz, 6H).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.[C:7]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([C@@H:27]3[C:35]4[C:30](=[C:31](Br)[CH:32]=[C:33]([F:36])[CH:34]=4)[CH2:29][C@H:28]3[OH:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[C:12]=2[CH2:11]1)(=[O:9])[CH3:8].C([O-])([O-])=O.[K+].[K+]>CC#N.O.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>[C:7]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([C@@H:27]3[C:35]4[C:30](=[C:31]([CH:1]5[CH2:3][CH2:2]5)[CH:32]=[C:33]([F:36])[CH:34]=4)[CH2:29][C@H:28]3[OH:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[C:12]=2[CH2:11]1)(=[O:9])[CH3:8]
Reactant: OB(O)C1CC1
Reactant: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(Br)c3C[C@H]2O)C1
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: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(C4CC4)c3C[C@H]2O)C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
According to Scheme 14: A mixture of cyclopropylboronic acid (28 mg, 0.33 mmol), 3-[5-acetyl-1-((1R,2R)-4-bromo-6-fluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (11d) (0.05 g, 0.10 mmol), K2CO3 (83 mg, 0.606 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.005, 0.015 mmol) in CH3CN (2 ml) and water (0.75 ml) was stirred at 110° C. for 2 h under microwave irradiation. The mixture was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 9 mg of 3-[5-acetyl-1-((1R,2R)-4-cyclopropyl-6-fluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (20a).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][OH:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1cc(CO)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(COS(C)(=O)=O)c2ccccc21
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
A well-stirred solution of 3-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (10, 450 mg, 1.82 mmol) [as prepared following the procedure of D. J. Oliveira and F. Coelho, Synth. Commun. 30 (12) pg. 2143 (2000)] in 10 mL of dichloromethane was cooled in an ice-bath, then treated successively with triethylamine (TEA) (283 mg, 2.18 mmole) and methanesulfonyl chloride (229 mg, 2.0 mmol). This was allowed to stir under nitrogen for 15 min. diluted with dichloromethane, then washed with saturated NaHCO3, dried (Na2SO4) and evaporated. This residue was purified by chromatography to give 0.43 g (73% yield) of the desired compound as an unstable brown solid. 1H NMR (CDCl3) δ 1.67 (s, 12H), 4.79 (s, 2H), 7.28 (t, 1H), 7.36 (t, 1H), 7.67 (m, 2H), 7.51 (bd, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[OH:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>>[N:25]1([C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:10]4[O:9][C:8]([CH2:7][CH2:6][N:34]5[CH2:35][CH2:36][C@@H:32]([OH:31])[CH2:33]5)=[CH:12][C:11]=4[CH:13]=3)=[N:18][CH:19]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: O[C@@H]1CCNC1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CC[C@@H](O)C4)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and 3-(R)-hydroxypyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 4.55 (m, 1H), 3.3-3.8 (m, 16H), 2.0-2.4 (m, 2H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([Cl:10])[CH:3]=1.[OH:11][C:12]1[CH:21]=[CH:20][C:15]2[NH:16][C:17](=[O:19])[O:18][C:14]=2[CH:13]=1.[K].[CH3:23]C(C)([O-])C>CN1C(=O)CCC1>[Cl:10][C:4]1[CH:3]=[C:2]([O:11][C:12]2[CH:21]=[C:20]([CH3:23])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)[C:7]([C:8]#[N:9])=[CH:6][N:5]=1
Reactant: O=c1[nH]c2ccc(O)cc2o1
Reactant: N#Cc1cnc(Cl)cc1Cl
Reactant: CC(C)(C)[O-]
Agent: [K]
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2cc(Cl)ncc2C#N)cc2oc(=O)[nH]c12
Temperature: 0 °C

Procedure:
0.12 g (0.69 mmol) 4,6-dichloro-nicotinonitrile, 0.15 g (0.91 mmol) 6-hydroxy-2-benzoxazolinone and 90 mg (0.80 mmol) potassium-tert.-butoxide in 0.8 mL NMP were stirred for 2 h at 70° C. The reaction mixture was combined with ice water. The precipitate formed was suction filtered and dried.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[CH2:9][C@H:8]2[O:10][C@@:7]2([CH3:11])[CH2:6][CH2:5]1)=[CH2:3].[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.Cl.[K+].[Br-]>C(OCC)C.C(Cl)(Cl)Cl.O>[N:12]1([C@H:8]2[CH2:9][C@H:4]([C:2]([CH3:1])=[CH2:3])[CH2:5][CH2:6][C@:7]2([CH3:11])[OH:10])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1c[nH]cn1
Reactant: C=C(C)[C@@H]1CC[C@]2(C)O[C@@H]2C1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: C=C(C)[C@@H]1CC[C@](C)(O)[C@@H](n2ccnc2)C1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To (R)-(+)-limonene oxide (6.88 mmol, 1.047 g, 1.13 mL) were added 6 mL of deionized water and imidazole (21 mmol, 1.43 g) at 25° C. A reflux condenser was attached and the flask was set in an oil bath that was heated to 100° C. After 5.0 h at 100° C., the reaction mixture was cooled to 25° C., acidified with 12M hydrochloric acid, and extracted with diethyl ether (7×30 mL). The aqueous layer was cooled to 0° C. and treated with solid sodium hydroxide until the solution was strongly basic to litmus (pH 10). The solution was extracted with methylene chloride (10×30 mL) and the combined extracts were dried. The solvent was removed in vacuo leaving a semi-solid material that was taken up in hot diethyl ether. The solution was cooled to give a white, crystalline solid, mp 126-128° C.; [α]25D=+11.4 (c=3.5 in CHCl3); IR (KBr) 3210.0, 2850.0 cm−1.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[H-].[Na+].CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O>CN(C=O)C.CCOC(C)=O>[F:1][C:2]([F:6])([F:5])[CH2:3][S:4][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]1
Reactant: FC(F)(F)CS
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CSCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
2,2,2-Trifluoroethane-1-thiol (0.151 mL, 1.636 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.065 g, 1.636 mmol) in anhydrous DMF (3 mL) at 0 C. A solution of tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) in DMF (4 mL) was then added dropwise and the reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc (30 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL) followed by brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by FCC (EtOAc: heptane, 20:80) to provide the title compound as a colourless oil (0.288 g, 82%). Method B HPLC-MS: MH+ requires m/z=313 Found: m/z=257 (M minus tert-butyl), Rt=2.28 min (97%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:20]=1[CH2:21]O>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:21][C:20]3[C:19]([F:18])=[CH:26][C:25]([F:27])=[CH:24][C:23]=3[F:28])=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: OCc1c(F)cc(F)cc1F
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(O)cc2)C1
Product: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3c(F)cc(F)cc3F)cc2)C1

Procedure:
In an analogous manner to that described in Example 28b), the alkylation of the (R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 28a)] with 2,4,6-trifluorobenzylalcohol yields the (R)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester as a white solid. MS: m/e=380 (M+H)+.