Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][CH:6]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[CH2:9][CH2:8][CH:7]2[NH2:17])[CH2:4][CH2:3]1.C1([O:24][C:25](=O)[NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][N:31]=[CH:32]3)C=CC=CC=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH:2]1([CH2:5][CH:6]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[CH2:9][CH2:8][CH:7]2[NH:17][C:25]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][N:31]=[CH:32]3)=[O:24])[CH2:3][CH2:4]1
Reactant: NC1CCc2cc(F)ccc2C1CC1CC1
Reactant: O=C(Nc1cccc2cnccc12)Oc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2cnccc12)NC1CCc2cc(F)ccc2C1CC1CC1
Yield: 28.6 %

Procedure:
1-Cyclopropylmethyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride (127 mg, 0.49 mmol), isoquinolin-5-yl-carbamic acid phenyl ester (150 mg, 0.49 mmol), and diisopropylethylamine (193 mg, 1.47 mmol) were combined and stirred at ambient temperature in DMSO (3 mL) overnight. The product was purified by directly injecting the crude reaction onto a reverse phase prep-HPLC (10-90% water:acetonitrile gradient). The appropriate fractions were lyophilized to yield 1-(1-cyclopropylmethyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-isoquinolin-5-yl-urea 71 (68 mg, 0.14 mmol). MS (MH+) 390; 1H NMR (CD3OD) δ 0.08-0.87 (m, 2H), 1.60-1.65 (m, 2H), 2.03 (m, 1H), 2.97 (m, 2H), 3.14 (m, 1H), 4.36 (m, 1H), 6.87 (m, 2H), 7.27 (m, 1H), 7.93 (t, 1H, J=2.6 Hz), 8.14 (d, 1H, J=2.7 Hz), 8.32 (d, 1H, J=2.2 Hz), 8.47 (d, 1H, J=2.6 Hz), 8.53 (d, 1H, J=2.2 Hz), 9.63 (s, 1H). HPLC Rt=3.63 min (10-90% water:acetonitrile gradient, 100% pure).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:38]([O:41][CH3:42])[C:39]#[CH:40]>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:40]=[C:39]([CH2:38][O:41][CH3:42])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCOC
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (18 mg), and CuI (10 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (10 mL), Et3N (0.14 mL), and methyl propargyl ether (0.046 mL). The reaction is stirred at room temperature for 4 days. The reaction mixture is diluted with dichloromethane and partitioned against dilute aqueous sodium carbonate. The aqueous phase is extracted with two portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is flash column chromatographed on silica gel eluting with 1% to 4% methanol in dichloromethane. The product containing fractions are combined and concentrated under reduced pressure to give a yellow solid which is crystallized from toluene to afford 0.13 g of the title compound as tan needles.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)[C:10]([O:12]C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:50][N:51]([CH3:60])[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C)C=O>[CH3:50][N:51]([CH3:60])[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][N:57]([C:10]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)=[O:12])[CH2:56][CH2:55]1
Reactant: CN(C)CCN1CCNCC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Solvent: CN(C)C=O
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)CC1
Reaction time: 3.5 h
Yield: 35.6 %

Procedure:
To [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (130 mg) was added a solution of 1-[2-(dimethylamino)ethyl]piperazine (123 mg) in N,N-dimethylformamide (2.5 ml) at room temperature, followed by stirring for 3.5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (42.3 mg, 36%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[C:20]([N:22]1[CH2:28][CH2:27][CH2:26][N:25]([CH:29]2[CH2:32][CH2:31][CH2:30]2)[CH2:24][CH2:23]1)=[O:21])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:13]([C@H:11]1[CH2:12][NH:8][C@H:9]([C:20]([N:22]2[CH2:28][CH2:27][CH2:26][N:25]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[CH2:24][CH2:23]2)=[O:21])[CH2:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@@H]1C[C@@H](Cc2ccccc2)CN1)N1CCCN(C2CCC2)CC1
Reaction time: 16 h
Yield: 98.2 %

Procedure:
A solution of (2S,4R)-4-benzyl-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (350.8 mg, 0.794 mmol) in CH2Cl2 (2 mL) was treated with TFA (0.5 mL). After 16 h, the mixture was concentrated and the residue was purified by FCC(CH2Cl2 to 10% MeOH/0.1% NH4OH in CH2Cl2) to give the title compound (266.3 mg, 98%). MS (ESI): mass calcd. for C21H31N3O, 341.25; m/z found, 342.3 [M+H]+. 1H NMR (CDCl3): 7.35-7.29 (m, 2H), 7.28-7.22 (m, 1H), 7.16 (d, J=7.9 Hz, 2H), 4.91-4.80 (m, 1H), 4.03-3.38 (m, 4H), 3.20-2.90 (m, 2H), 2.85-2.33 (m, 7H), 2.25-1.56 (m, 11H).
Reaction SMILES: [CH3:1][C:2]1[N:12]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:5]2[C:6](=[O:11])[N:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[C:3]=1[C:21]([O:23]CC)=[O:22].[OH-].[Li+]>C(O)C.O>[CH3:1][C:2]1[N:12]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:5]2[C:6](=[O:11])[N:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[C:3]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1c(C)n(C(C)c2ccccc2)c2c(=O)n(C)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)c2ccn(C)c(=O)c2n1C(C)c1ccccc1
Temperature: 80 °C
Yield: 43 %

Procedure:
A mixture of ethyl 2,6-dimethyl-7-oxo-1-(1-phenylethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (500 mg, 1.5 mmol) and lithium hydroxide (50 mg, 2.1 mmol) in ethanol (20 mL) and water (5 mL) was stirred and heated at 80° C. for 12 hours. Once starting material was consumed, the mixture was concentrated and the residue was dissolved into water (50 mL). Then the solution was extracted with ethyl acetate (20 mL×2). The aqueous layer was collected, adjusted to pH 4, and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give 2,6-dimethyl-7-oxo-1-(1-phenylethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (200 mg, 44%) as a light yellow solid which was used directly in the next step without further purification. LRMS (M+H+) m/z: calcd 310.13. found 310.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:14])[NH:7]2.[H][H]>CN1CCCC1=O.[OH-].[Pd+2].[OH-]>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:14])[NH:7]2
Reactant: COc1ccc(O)c2ccc(=O)[nH]c12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1ccc(O)c2c1NC(=O)CC2
Yield: 98.2 %

Procedure:
5-Hydroxy-8-methoxycarbostyril (12.5 g) in 200 ml of N-methylpyrrolidinone with 500 mg of palladium hydroxide (20%) were hydrogenated at 50° C. under 1,2 bar hydrogen. The catalyst was removed by filtration through Celite and the solvent evaporated to give 12.4 g of 5-hydroxy-8-methoxy-3,4-dihydrocarbostyril (mp=190° C.).
Reaction SMILES: S1CCS[CH:2]1[C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[CH:14]3[CH2:15][C:16]([CH3:19])=[CH:17][CH2:18][CH:13]3[C:12]([CH3:21])([CH3:20])[O:11][C:10]=2[CH:22]=1.B(F)(F)F.[OH2:28]>O1CCCC1>[CH:2]([C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[CH:14]3[CH2:15][C:16]([CH3:19])=[CH:17][CH2:18][CH:13]3[C:12]([CH3:20])([CH3:21])[O:11][C:10]=2[CH:22]=1)=[O:28]
Reactant: O
Reactant: CC1=CCC2C(C1)c1c(O)cc(C3SCCS3)cc1OC2(C)C
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC1=CCC2C(C1)c1c(O)cc(C=O)cc1OC2(C)C

Procedure:
3-(1,3-dithiolan-2-yl)-6a,7,10,10 a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (VI) in the fourth step is then treated with mercuric oxide and boron trifluoride in an aqueous reaction medium containing an organic solvent which is water miscible, such as tetrahydrofuran. The oxidative cleavage is effected at room temperature to produce 3-formyl-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[ b,d]pyran-1-ol which can then be isolated by routine means.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:35][CH2:36][C:37]1[CH:61]=[CH:60][C:40]([CH2:41][NH:42][C:43](=[O:59])[C:44]2[CH:49]=[C:48](F)[CH:47]=[N:46][C:45]=2[O:51][C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[CH:39][CH:38]=1.CN1CCOCC1>CN(C)C=O>[F:58][C:55]1[CH:54]=[CH:53][C:52]([O:51][C:45]2[N:46]=[CH:47][CH:48]=[CH:49][C:44]=2[C:43]([NH:42][CH2:41][C:40]2[CH:60]=[CH:61][C:37]([CH2:36][NH:35][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=3[OH:1])=[CH:38][CH:39]=2)=[O:59])=[CH:57][CH:56]=1
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: NCc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cccc(C(=O)NCc2ccc(CNC(=O)c3cccnc3Oc3ccc(F)cc3)cc2)c1O
Yield: 21.3 %

Procedure:
A solution of 2-Hydroxy-3-methylbenzoic acid (118 mg, 0.773 mmol), 1-hydroxybenzotriazole (157 mg, 1.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (193 mg, 1.01 mmol), N-(4-aminomethyl-benzyl)-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide hydrochloride (300 mg, 0.773 mmol) (see Preparation 3) and N-methyl morpholine (0.17 ml, 1.55 mmol) in N,N-dimethylformamide (6 ml) was stirred under nitrogen at room temperature for 18 hours. The mixture was then partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (10 ml) and dried over anhydrous magnesium sulphate. The solvent was then removed in vacuo and the residue was triturated with diethylether (3-fold 10 ml) giving 2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-3-methyl-benzoylamino)-methyl]-benzyl}-nicotinamide (80 mg) as an off-white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[C:32]1([S:42](Cl)(=[O:44])=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:42]([C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][CH:33]=4)(=[O:44])=[O:43])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc5ccccc45)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and naphthalene-1-sulfonyl chloride. Purity (ELSD, based on MW=611.7)=81%.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]([F:13])([F:12])[CH2:10][OH:11].[F:14][C:15]1([F:36])[C:33]2[C:18](=[CH:19][C:20]3[O:24][C:23]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][C:26]=4F)=[N:22][C:21]=3[CH:32]=2)[C:17]([F:35])([F:34])[O:16]1>O>[F:36][C:15]1([F:14])[C:33]2[C:18](=[CH:19][C:20]3[O:24][C:23]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][C:30]=4[O:11][CH2:10][C:9]([F:13])([F:12])[F:8])=[N:22][C:21]=3[CH:32]=2)[C:17]([F:34])([F:35])[O:16]1
Reactant: Fc1cnccc1-c1nc2cc3c(cc2o1)C(F)(F)OC3(F)F
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cnccc1-c1nc2cc3c(cc2o1)C(F)(F)OC3(F)F
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 44 mg of 60% sodium hydride (in oil) and 2 ml of DMF was stirred at room temperature. To the mixture, a mixture solution of 0.11 g of 2,2,2-trifluoroethanol and 0.5 ml of DMF was added. The mixture solution was stirred for 15 minutes, and then, 0.28 g of 5,5,7,7-tetrafluoro-2-(3-fluoropyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole was added and stirred at room temperature for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 5,5,7,7-tetrafluoro-2-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole (hereinafter, referred to as “active compound 89”).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].Cl.Cl[CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([CH3:30])=[CH:24][N:23]=1.[OH-].[Na+]>O>[CH3:29][O:28][C:26]1[C:25]([CH3:30])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:13]=[C:12]4[C:8](=[CH:7][C:5]=3[N:6]=2)[C:9]([CH3:18])([CH3:17])[C:10](=[O:16])[C:11]4([CH3:14])[CH3:15])[CH:27]=1
Reactant: COc1cc(CCl)ncc1C
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)ncc1C

Procedure:
7.8 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(lH)-one were suspended in 200 ml of alcohol and the suspension was treated while cooling with ice with 6.3 g of 2-chloromethyl-4-methoxy-5-methylpyridine hydrochloride. Thereafter, 2.4 g of sodium hydroxide in 100 ml of water were added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 500 ml of methylene chloride. The solution was washed firstly with 250 ml of 1.5N sodium hydroxide solution and then with 3×250 ml of water, dried over ium sulfate and evaporated in vacuo. The product was purified on 150 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 5.7-dihydro-2-[[(4-methoxy-5-methyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(lH)-one of melting point 204-205° .
Reaction SMILES: C(O)C(N)(CO)CO.[CH3:9][O:10][C:11]([C:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[NH:17][C:16](=[O:27])[NH:15][C:14]=1[CH2:28][O:29][CH3:30])=[O:12]>C(#N)C>[CH3:9][O:10][C:11]([C:13]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[NH:17][C:16](=[O:27])[NH:15][C:14]=1[CH2:28][O:29][CH3:30])=[O:12]
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)NC(=O)N1
Agent: NC(CO)(CO)CO
Solvent: CC#N
Product: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)NC(=O)N1
Reaction time: 216 h

Procedure:
A 100-L reaction vessel was charged with 50 mM Tris buffer (Tris HCl (77.4 g) and Tris Base (196.7 g) in deionized water (42.3 L)), 12.0 L of subtilisin (PURAFECT® 4000L, available from Genencor International), acetonitrile (5.7 L), and (+) 5-methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxopyrimidine, (2), (120 g, 0.38 mol) and the mixture was allowed to react at 37° C., pH 8.3 for 9 days. The reaction mixture was extracted with toluene (10 L). The aqueous layer was separated and washed with toluene (5 L). The combined organic extracts were washed with brine (10 L). The organic layer was concentrated by rotary evaporation, filtered, then adjusted to 400 mL volume with toluene. The (+)-2 was crystallized by adding heptane (80 mL), followed by seeding. The mixture was stirred for 1 hr, then heptane (520 mL) was added over 8 hrs. The crystals were filtered, washed with 3:2 heptane-toluene (150 mL), then dried under high vacuum to yield (+)-(6S)-5-methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxopyrimidine, ((+)-2) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=[CH:17][N:18]([CH3:20])[CH3:19])[CH2:3]1
Reactant: CCOC(OCC)N(C)C
Reactant: CC1(C)CCC(=O)c2ccccc21
Product: CN(C)C=C1CC(C)(C)c2ccccc2C1=O

Procedure:
The 3,4-dihydro-4,4-dimethyl-2-(dimethylaminomethylene)-1-(2H)-naphthalenone starting material was prepared from 4,4-dimethyl-1-tetralone (3.48 g, 20 mmol) and N,N-dimethylformamide diethyl acetal (10.5 ml, 60 mmol) to give the desired compund as bright yellkow crystals (3.53 g). δH (CDCl3) 8.05 (1H, ddd, J 7.7, 1.5, 0.5 Hz), 7.78 (1H, s), 7.42 (1H, m), 7.33-7.25 (2H,m), 3.12 (6H, s), 2.80 (2H, s) and 1.33 (6H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([N:45]([CH2:60][CH3:61])[C:46]([C@@H:48]1[CH2:53][CH2:52][CH2:51][N:50]([CH:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:49]1)=[O:47])[CH3:44]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:57]3[CH2:56][CH2:55][CH:54]([N:50]4[CH2:51][CH2:52][CH2:53][C@@H:48]([C:46](=[O:47])[N:45]([CH2:60][CH3:61])[CH2:43][CH3:44])[CH2:49]4)[CH2:59][CH2:58]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)[C@@H]1CCCN(C2CCNCC2)C1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CCN(CC)C(=O)[C@@H]1CCCN(C2CCN(C(=O)C34CCC(N(CC(=O)N5C[C@@H](F)C[C@H]5C#N)C(=O)OCc5ccccc5)(CC3)CC4)CC2)C1
Yield: 77.8 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (74.9 mg) and (3R)—N,N-diethyl-1-(piperidin-4-yl)piperidine-3-carboxamide (61.0 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[4-[(3R)-3-(N,N-diethylcarbamoyl)piperidin-1-yl]piperidin-1-yl]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (71.7 mg).
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][C:9]=2[CH3:16])=O)C.[OH-].[K+]>O.C(O)C>[Br:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:16])[CH:10]=1)[NH:7][CH:6]=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Br)cc(C)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Br)cc2cc[nH]c12
Temperature: 25 °C

Procedure:
5-Bromo-7-methyl-1H-indole-2-carboxylic acid ethyl ester (5.3 g, 18.7 mmol) was added to a potassium hydroxide solution in 1:1 water/ethanol mixture (20 mL) and heated at reflux for 12 h. After cooling to room temperature, the solvents were removed in vacuo and the resultant residue transferred to a 6N hydrochloric acid solution (20 mL). The white precipitate that formed was filtered, washed severally with water, and dried for several hours. The crude solid was dissolved in quinoline (14 mL) and heated at reflux for 4 h. After cooling to room temperature, the crude mixture was poured into a mixture of ice water (100 mL) and concentrated hydrochloric acid (16 mL), extracted with ethyl acetate (2×), brine (2×), dried over sodium sulfate, and concentrated. Attempts to recrystallize the desired product from isopropanol resulted in significant decomposition. The title compound was obtained by flash chromatography on silica get to afford 1.5 g (38%, 2 steps). LC/MS: tR=1.72 min, 210.05 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([N:11]1[C:19]3[C:14](=[CH:15][C:16]([CH:20]=O)=[CH:17][CH:18]=3)[CH:13]=[N:12]1)[CH2:6][CH2:5]2.[N:22]1([CH2:27][CH2:28][N:29]2[C:33](=[O:34])[CH2:32][S:31][C:30]2=[O:35])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([N:11]1[C:19]3[C:14](=[CH:15][C:16](/[CH:20]=[C:32]4/[C:33](=[O:34])[N:29]([CH2:28][CH2:27][N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[C:30](=[O:35])[S:31]/4)=[CH:17][CH:18]=3)[CH:13]=[N:12]1)[CH2:6][CH2:5]2
Reactant: O=Cc1ccc2c(cnn2[C@@H]2CCc3cc(Cl)ccc32)c1
Reactant: O=C1CSC(=O)N1CCN1CCCC1
Product: O=C1S/C(=C\c2ccc3c(cnn3[C@@H]3CCc4cc(Cl)ccc43)c2)C(=O)N1CCN1CCCC1

Procedure:
(5Z)-5-({1-[(1R)-5-Chloro-2,3-dihydro-1H-inden-1-yl]-1H-indazol-5-yl}methylidene)-3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione was prepared by the method described for Example 172, using the isomeric (1R)-(5-chloroindan-1-yl)-1H-indazole-5-carbaldehyde and 3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione following General Procedure F.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[CH:12]=2)=[C:9]([Cl:17])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:18][C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[Cl:1][C:2]1[C:10]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[CH:12]=2)=[C:9]([Cl:17])[CH:8]=[CH:7][C:3]=1[C:4]([C:20]1[CH:21]=[N:22][N:23]([CH3:24])[C:19]=1[OH:18])=[O:5]
Reactant: Cc1cc(-c2c(Cl)ccc(C(=O)Cl)c2Cl)on1
Reactant: Cn1nccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1cc(-c2c(Cl)ccc(C(=O)c3cnn(C)c3O)c2Cl)on1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73 %

Procedure:
At 0 to 5° C., the 2,4-dichloro-3-(3-methylisoxazol-5-yl)benzoyl chloride obtained above (step e) in 40 ml of dimethoxyethane was added to 0.7 g (7.35 mmol) of 5-hydroxy-1-methyl-1H-pyrazole in 30 ml of dimethoxyethane and 2.0 g (14.7 mmol) of potassium carbonate. The mixture was stirred at room temperature for 3.5 hours, heated under reflux for 1 hour and stirred at room temperature for 12 hours. The precipitate that had formed was filtered off with suction and introduced into 50 ml of water. The mixture is acidified to pH=1 and the solid is filtered off with suction and dried. Likewise, the first-mentioned filtrate was taken up in 400 ml of water, washed with methyl t-butyl ether, adjusted to pH 3 and extracted with methylene chloride. The combined organic phases were dried and concentrated. 1.9 g (73% of theory) of 4-[2,4-dichloro-3-(3-methylisoxazol-5-yl)benzoyl]-5-hydroxy-1-methyl-1H-pyrazole were obtained.