Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:36])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:35])[CH2:12][CH2:13][C@@:14]3([CH:31]([OH:34])[CH:32]=O)[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:38])[CH3:37])(=[O:3])[CH3:2].Cl.[Cl:40][C:41]1[CH:42]=[N:43][C:44]([C:47]2([NH2:50])[CH2:49][CH2:48]2)=[N:45][CH:46]=1.C([BH3-])#N.[Na+]>CO.ClCCCl.[Cl-].[Zn+2].[Cl-]>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:36])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:35])[CH2:12][CH2:13][C@@:14]3([CH:31]([OH:34])[CH2:32][NH:50][C:47]4([C:44]5[N:43]=[CH:42][C:41]([Cl:40])=[CH:46][N:45]=5)[CH2:48][CH2:49]4)[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:29])[CH3:30])=[C:15]32)[C:6]1([CH3:37])[CH3:38])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C(O)C=O)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Reactant: NC1(c2ncc(Cl)cn2)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Solvent: ClCCCl
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C(O)CNC5(c6ncc(Cl)cn6)CC5)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.04 %

Procedure:
To a solution of (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(1-hydroxy-2-oxoethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (104) (545 mg, 1.035 mmol) and 1-(5-chloropyrimidin-2-yl)cyclopropanamine, hydrochloride (105) (213 mg, 1.035 mmol) in methanol (5 ml) and 1,2-dichloroethane (5 ml) was added zinc chloride (141 mg, 1.035 mmol). The reaction mixture was stirred at room temperature overnight. and then sodium cyanoborohydride (65.0 mg, 1.035 mmol) was added. The reaction mixture was allowed to stir for 1 h, then silica gel was added to the mixture and the solvents removed in vacuo to give the residue-silica gel powder which was purified on a silica gel column using petroleum ether/EtOAc (5:1 to 3:1) to afford (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((1-(5-chloropyrimidin-2-yl)cyclopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (105) as a mixture of diastereomers (200 mg, 0.166 mmol, 16.04% yield) as a yellow foam. LC/MS: m/z calculated 679.4. found 680.3 (M+1)+.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][CH:27]([C:29](=[O:36])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:28])[CH:24]=2)[N:19]([CH3:37])[CH:18]=1)[C:9]([O:11]C)=[O:10]>O.CO.O1CCCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][CH:27]([C:29](=[O:36])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:28])[CH:24]=2)[N:19]([CH3:37])[CH:18]=1)[C:9]([OH:11])=[O:10]
Reactant: CCCCCNC(=O)C(C)Cc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCNC(=O)C(C)Cc1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
A solution of lithium hydroxide monohydrate (0.29 g) in water (5 ml) was added to a solution of methyl 3-methoxy-4-[1-methyl-5-[2-(pentylcarbamoyl)propyl]indol-3-ylmethyl]benzoate (0.65 g) in methanol (25 ml) and tetrahydrofuran (5 ml). The mixture was stirred under an atmosphere of nitrogen for 48 hr, and the solvents evaporated. The residue was taken up in water (5 ml), acidified with 1M hydrochloric acid (10 ml), and the precipitate which formed isolated by filtration to give the title compound (0.63 g, 94%) as a white powder; mp 85°-95°.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]C)=O)#[N:2].[CH2:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[C:12]([F:18])[CH:11]=1)[CH3:9]>C(O)C.CN(C1C=CN=CC=1)C>[C:1]([CH2:3][C:4]([NH:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([CH2:8][CH3:9])=[CH:11][C:12]=1[F:18])=[O:6])#[N:2]
Reactant: CCc1ccc(CN)c(F)c1
Reactant: COC(=O)CC#N
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CCc1ccc(CNC(=O)CC#N)c(F)c1
Temperature: 60 °C
Yield: 39.5 %

Procedure:
Methyl cyanoacetate (1.16 mL, 13 mmol) and 4-ethyl-2-fluoro-benzylamine (1.15 g, 7.5 mmol) were combined in ethanol (20 mL). 4-(N,N-dimethylamino)pyridine (catalytic) was added and the reaction was heated in a 60° C. oil bath. After 16 hours heating, the reaction was concentrated under reduced pressure to afford crude product which was purified by flash chromatography eluting with a gradient from hexane to 60% ethyl acetate/hexane to afford 2-cyano-N-(4-ethyl-2-fluoro-benzyl)-acetamide (652 mg, 40% yield). 1H-NMR (400 MHz, CDCl3): δ 7.26-7.20 (1H, m), 6.98-6.90 (2H, m), 6.39 (1h, br s), 4.49 (2H, d, J=5.8 Hz), 3.38 (2H, s), 2.64 (2H, q, J=7.6 Hz), 1.23 (3H, t, J=7.6 Hz).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:33])[C:10]([NH:13]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH2:45]Br>C1COCC1.ClCCl>[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH2:45][O:33][C:9]1[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1
Reactant: COc1cccc(CBr)c1
Reactant: Oc1cc(-c2ccccc2)cnc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc(COc2cc(-c3ccccc3)cnc2N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
To a solution of 5-phenyl-2-(trityl-amino)-pyridin-3-ol (100 mg, 0.24 mmol) in THF (3 mL) was added Cs2CO3 (79 mg, 0.24 mmol). The mixture was stirred at room temperature for 20 minutes, and then 3-methoxybenzylbromide (0.037 mL, 0.26 mmol) was added. The reaction was stirred at room temperature overnight, diluted with dichloromethane (5 mL), and filtered to remove the salts. The solvents were evaporated, and the residue was dissolved in 10% trifluoroacetic acid in dichloromethane (2 mL). The reaction was stirred for 2 hr, and evaporated. The residue was dissolved in dichloromethane, washed by sat. NaHCO3, and dried over Na2SO4. After filtration and concentration, the crude product was purified on a silica gel column eluting with methanol-dichloromethane (from 3% to 15% gradient) to provide 3-(3-methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine as a white solid (43.5 mg, 60% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.[OH:35][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:37][CH2:36][O:35][C:2]2[N:7]=[CH:6][C:5]([C:8]([C:10]3[C:11]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:12]=4[S:13][C:14]=3[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:17][CH:16]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: COc1ccc2c(C(=O)c3ccc(Cl)nc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reactant: OCCN1CCCC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCC4)nc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 84 %

Procedure:
The title compound was prepared in 84% yield from 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 6-chloropyrid-3-yl ketone (Part A) and 1-(2-hydroxyethyl)pyrrolidine by essentially following the procedures described in Example 9, Part B.
Reaction SMILES: Br[C:2]1[C:3]([CH3:28])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:37](B(O)O)[CH2:38][CH2:39][CH3:40]>C1(C)C=CC=CC=1.O>[CH2:37]([C:2]1[C:3]([CH3:28])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCB(O)O
Reactant: Cc1c(Br)ccc(NS(=O)(=O)c2cccnc2)c1C(=O)OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1ccc(NS(=O)(=O)c2cccnc2)c(C(=O)OCc2ccccc2)c1C
Temperature: 100 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
A mixture of Example 112A (115 mg, 0.25 mmol), K3PO4 (185 mg, 0.875 mmol), n-butylboronic acid (34 mg, 0.325 mmol), and bis(tricyclohexylphosphine)palladium dichloride (18 mg, 0.025 mmol) in toluene (4 mL) and water (0.2 mL) was purged with nitrogen and stirred at 100° C. for 24 hours. The mixture was then directly chromatographed on a silica gel column, eluting with 30% ethyl acetate/hexanes to provide the desired product (87 mg, 39.7%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]2[C:21]([C:22]3[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]4[C:34]5[N:35]=[C:36]([NH2:38])[S:37][C:33]=5[CH:32]=[CH:31][CH:30]=4)[CH:23]=3)=[CH:20][CH:19]=[C:18]([C:39]([F:42])([F:41])[F:40])[N:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]2[C:21]([C:22]3[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]4[C:34]5[N:35]=[C:36]([NH:38][C:43](=[O:45])[CH3:44])[S:37][C:33]=5[CH:32]=[CH:31][CH:30]=4)[CH:23]=3)=[CH:20][CH:19]=[C:18]([C:39]([F:41])([F:42])[F:40])[N:17]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NCC4CN(Cc5ccccc5)CCO4)ncn3)cccc2s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NCC4CN(Cc5ccccc5)CCO4)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(6-(2((4-benzylmorpholin-2-yl)methylamino)-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine, Example 1(c), (110 mg, 0.18 mmol) and DMAP (10 mg, 0.08 mmol, Aldrich) in DCM (8 mL) was added acetic anhydride (90 μL, 0.9 mmol, Aldrich). The mixture was stirred at room temperature for 18 h and evaporated under reduced pressure. The residue was dissolved in EtOAc and the solution was washed with a sat. aqueous solution of NaHCO3, H2O and brine, dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography [2% (2N NH3 in MeOH)/DCM] to give the title compound as a light-yellow solid. MS (ESI, pos. ion.) m/z: 636 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:21][CH:22]1[CH2:24][CH2:23]1
Reactant: ClCC1CC1
Reactant: CCOC(=O)c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC2CC2)c1
Temperature: 80 °C
Yield: 31.4 %

Procedure:
Ethyl 4-bromo-3-hydroxybenzoate (2.0 g, 8.2 mmol), potassium carbonate (3.4 g, 24.48 mmol and (chloromethyl)cyclopropane (1.13 mL, 12.24 mmol) were placed in 50 mL DMF and the reaction was heated at 80° C. for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated to an oil. Purification by column chromatography on silica gel using 0-50% EtOAc/hexane gave the product (0.77 g, 31%) as a clear oil.
Reaction SMILES: [Na].CO.[OH:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1.Br[CH:17]([CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CS(C)=O>[CH2:21]([O:20][C:18]([CH:17]([O:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)[CH2:23][CH2:24][CH3:25])=[O:19])[CH3:22]
Reactant: Oc1ncn(-c2ccccc2)n1
Reactant: CCCC(Br)C(=O)OCC
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCCC(Oc1ncn(-c2ccccc2)n1)C(=O)OCC

Procedure:
The synthesis was carried out substantially as shown above in Example 7, except that it was necessary to chromatograph the product as described in Example 8. The reactants were 0.7 g of sodium, 20 ml of methanol, 5 g of 3-hydroxy-1-phenyl-1,2,4-lH-triazole and 6.5 g of ethyl 2-bromopentanoate. The solvent was 80 ml of dimethylsulfoxide. Five g of the desired product, an oil, was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(#N)C>[C:10]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1)(=[O:12])[CH3:11]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(=O)Nc1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension containing 80 g (0.56 mole) of 5-amino-2-chlorophenol, 70 ml (0.74 mole) of acetic anhydride, and 200 ml of acetonitrile was refluxed with stirring for 2 hours. This suspension was cooled to room temperature and the resulting crystalline precipitate was collected by filtration and washed with 200 ml of acetonitrile.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:13]2[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:20][N:21]1[C:30](=[O:31])[C:29]2[C:24](=[C:25]([C:32](Cl)=[O:33])[CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1.Cl>O1CCOCC1>[CH3:20][N:21]1[C:30](=[O:31])[C:29]2[C:24](=[C:25]([C:32]([NH:19][C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([N:8]4[CH2:9][CH2:10][CH2:11][CH2:12]4)[N:18]=3)=[O:33])[CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:42])[F:44])[CH:36]=1
Reactant: Nc1cccc(N2CCCC2)n1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)Cl)cccc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)Nc3cccc(N4CCCC4)n3)cccc2c1=O
Temperature: 70 °C
Reaction time: 48 h
Yield: 59.6 %

Procedure:
Triethylamine (100 μL) and 6-pyrollidin-1-ylpyridin-2-amine 35 (0.136 mmol) was added to a solution of 3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazoline-8-carbonyl chloride 34 (50 mg, 0.136 mmol) in dioxane (1 mL). The reaction was stirred at 70° C. for 2 d, after which 1N HCl (4 mL) was added. The resulting precipitate was collected by filtration, rinsed with 5 mL H2O, 5 mL pentane, and dried under vacuum to give Compound 350 (40 mg, 56% yield). MS (ESI) calc. for C26H22F3N5O2: 493.17. found: 494 [M+H].
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1>CCO>[CH3:8][N:7]1[CH:2]([CH3:1])[CH2:3][NH:4][CH2:5][C:6]1=[O:9]
Reactant: CC1CN(C(=O)OCc2ccccc2)CC(=O)N1C
Solvent: CCO
Product: CC1CNCC(=O)N1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of benzyl 3,4-dimethyl-5-oxopiperazine-1-carboxylate (780 mg, 2.97 mmol) in EtOH was degassed and purged with nitrogen and treated with 10% palladium on carbon (78 mg). The mixture was degassed and purged with nitrogen again and placed under a balloon atmosphere of hydrogen. The reaction was stirred for 3 h at room temperature and filtered through a pad of Celite, washing with MeOH. The resulting filtrate was concentrated to an oil which was dissolved in toluene. The solution was again filtered through Celite, and the resulting filtrate was concentrated in vacuo to afford the product.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[Br:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[NH2:22]>>[Br:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[NH:22][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: Nc1c(F)cccc1Br
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2c(F)cccc2Br)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-bromo-6-fluoro-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.26 (br, 1H), 7.72 (br, 1H), 7.57 (brd, 1H), 7.34 (br, 2H), 7.05-6.95 (2H), 6.37 (br, 1H), 3.94 (t, 2H), 3.84 (s, 3H) and 2.96 (t, 2H); MS (ESI) (M+H)+ 416, 418.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Fc1ccccc1C1CCCN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccccc1F

Procedure:
The title compound, white solid, m.p. 134° C. and MS: m/e=340.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(2-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: C([O:3][C:4]([C@@:6]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[C:15]([O:14][C:12]([NH:11][C@:6]1([C:4]([OH:5])=[O:3])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with 1N HCl until pH 4 and extracted with ethyl acetate (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87%). 1H NMR: (DMSO-d6) 1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); MS m/z 228 (M++H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([CH:17]([OH:26])[CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([C:17](=[O:26])[CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH3:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(c1ccccn1)C(O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)c1ccccc1)c1ccccn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
A solution of DMSO (5.5 mL, 77.5 mmol) in dichloromethane (10 mL) is added drop wise to a solution of oxalyl chloride (3.3 mL, 39.0 mmol) in dichloromethane (100 mL) with the internal temperature under −60° C. The reaction mixture is stirred for 15 minutes and then a solution of 1-phenyl-2-(pyridin-2-yl) propan-1-ol (2) (7.0 g, 32.8 mmol) in dichloromethane (10 mL) is added slowly to keep the internal temperature under −60° C. After 30 minutes, triethylamine (22.3 mL, 0.16 mol) is added slowly at −78° C. After 15 minutes, the reaction is allowed to warm up to 0° C. for 30 minutes and then quenched with water. The mixture is separated and the aqueous phase is extracted with dichloromethane (2×50 mL). The extracts are combined, washed with brine, dried, concentrated and purified by column chromatography (hexane/ethyl acetate 10:1 to 4:1) to give 3 (6.4 g, 91%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 1.51-1.54 (m, 3H), 4.84-4.92 (m, 1H), 7.03-708 (m, 1H), 7.18-7.20 (m, 2H), 7.30-7.35 (m, 1H), 7.40-7.43 (m, 1H), 7.52-7.57 (m, 1H), 7.95-7.98 (m, 2H), 8.47-8.48 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1.[S].C(=S)=[S:19]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][C:9]1[S:8][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: c1ccc2scnc2c1
Reactant: S=C=S
Agent: [S]
Solvent: Nc1ccccc1
Product: Sc1nc2ccccc2s1

Procedure:
The distillates containing aniline and benzothiazole, can be reacted with carbon disulphide and sulphur, if appropriate together with fresh aniline and/or benzothizole, in a known manner to give highly pure 2-mercaptobenzothiazole.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:22]([NH:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:28]2[C:29]([O:31][C:32](=O)[C:27]=12)=[O:30])(=[O:24])[CH3:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:22]([NH:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:28]2[C:27]=1[C:32](=[O:31])[N:1]([CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])[C:29]2=[O:30])(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: NC(CC(=O)O)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Reaction time: 2 h
Yield: 147.4 %

Procedure:
To a solution of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (500 mg, 1.0 mmol) in acetic acid (10 ml) was added 3-acetamido-phthalic anhydride (390 mg, 1.9 mmol) and sodium acetate (160 mg, 1.9 mmol). The mixture was heated at reflux temperature overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with water (30 ml×4), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was slurried with ether for 2 hours. The suspension was filtered to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid as a white solid (720 mg, 85%). 1HNMR (CDCl3): δ 0.35-0.39 (m, 2H), 0.64-0.68 (m, 2H), 1.15-1.36 (m, 1H), 2.27 (s, 3H), 3.24 (dd, J=5.8, 17 Hz, 1H), 3.82 (dd, J=10, 17 Hz, 1H), 3.88 (d, J=8.3 Hz, 2H), 5.70 (dd, J=5.8, 10 Hz, 1H), 6.59 (t, JH-F75 Hz, 1H), 7.06-7.14 (m, 3H), 7.48 (d, J=7.3 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 8.76 (d, J=8.3 Hz, 1H), 9.47 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:18][C:19]1[S:23][N:22]=[C:21]([CH3:24])[CH:20]=1)#[N:2].C([O-])([O-])=[O:26].[K+].[K+].OO>CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:26])=[C:4]([NH:18][C:19]2[S:23][N:22]=[C:21]([CH3:24])[CH:20]=2)[CH:5]=1)[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C#N)sn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C(N)=O)sn1
Reaction time: 0.08 h
Yield: 29.8 %

Procedure:
To a solution of (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-4-methylpentanamide (102 mg, 0.297 mmol) in DMSO (2 mL), K2CO3 (200 mg, 1.45 mmol) and H2O2 (50% aq., 1.00 mL) were added. After being stirred at 100 C for 5 min, the mixture was purified by HPLC to give the titled compound (32 mg). MS 362.4 (M+H); UV 226.6, 275.5, 303.2 nm