Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[O:22][CH3:23])=[O:10].OS(O)(=O)=O.O=S(=O)=O.[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35]>C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[C:3]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:22][CH3:23])=[O:10])=[C:4](/[CH:35]=[CH:34]/[C:33]([O:37][CH3:38])=[O:36])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1cccc(F)c1NC(=O)Nc1cc(C(F)(F)F)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
N-(2-Fluorophenyl)-N′-[2-methoxy-5-(trifluoromethyl)phenyl]urea (0.225 kg) is dissolved in acetic acid (6.75 l) and treated with palladium acetate (30.3 g). 65% strength oleum (247.5 g) is then metered in and methyl acrylate (90 g) is subsequently added. The solution is stirred at room temperature overnight. Subsequently, acetic acid (3740 g) is distilled off at 30° C. and ca. 30 mbar. The suspension is treated with water (2.25 l) and stirred for ca. 1 hour. The product is filtered off with suction, washed twice with water (0.5 l) and dried at 50° C. overnight in the vacuum drying oven using entraining nitrogen. A total of 210.3 g of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}acrylate are obtained as a solid, corresponding to 72.2% of theory.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:3].CC[O-].[Na+].Cl>C(O)C>[CH3:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:2](=[O:3])[NH:1][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11]2
Reactant: CCOC(=O)C(=O)Nc1cccc(C)c1C(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2cccc(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a suspension of ethyl ((2-(aminocarbonyl)-3-methylphenyl)amino)(oxo)acetate (760 mg, 3.04 mmol) in ethanol (15 mL) was added dropwise sodium ethylate (20% ethanol solution, 1.14 g, 3.34 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was suspended in diisopropyl ether-ethanol, and the insoluble material was collected by filtration to give the title compound as a white powder (450 mg, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17]>CN(C)C=O>[Cl:17][CH2:16][CH2:15][CH2:14][CH2:13][N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9]
Reactant: ClCCCCBr
Reactant: COc1ccc[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccn(CCCCCl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
3-Methoxy-1H-pyridin-2-one (20 mmol, 2.00 g) in 100 ml of N,N-dimethylformamide was added dropwise over the course of 10 minutes to a suspension of sodium hydride (20 mmol, 0.74 g, 60%, deoiled) in N,N-dimethylformamide (100 ml) at 10° C., and the mixture was then stirred at room temperature for 1 hour. Subsequently, 1-bromo-4-chlorobutane (20 mmol, 3.19 g) in 40 ml of N,N-dimethylformamide was added dropwise. The reaction mixture was then stirred at 95° C. After the reaction mixture had been concentrated, the remaining oil was suspended in diethyl ether. The resulting suspension was filtered and the filtrate was washed three times with water and then three times with a saturated aqueous sodium chloride solution. Drying of the organic phase over sodium sulfate was followed by removal of the desiccant by filtration and concentration. The resulting residue contained a mixture of O-alkylated and N-alkylated compound. Chromatography of the residue on silica gel (eluent: CH2Cl2/CH3OH: 0-2%) afforded 1.75 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]3)=[N:21][CH:22]=2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 56.1 %

Procedure:
Following general procedure F, (S)-tert-butyl 1-(5-(6-bromo-3-propionylquinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (80 mg, 0.14 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.17 mmol) to afford the desired product (50 mg, 54%) as an orange solid: ESI MS m/z 636 [C33H35Cl2H5O4+H]+
Reaction SMILES: COC([C:5](=[C:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[OH-].[Na+]>Cl>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[CH:5]=[C:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21]
Reactant: COC(=O)C(=C1CCCN1C)c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C=C2CCCN2C)cc1OC

Procedure:
Boil 12.4 g of 2-(α-methoxycarbonyl-3,4-dimethoxybenzylidene)-1-methylpyrrolidine for 15 minutes with 40 ml of conc. hydrochloric acid. Cool the resulting reaction mixture before rendering it alkaline with sodium hydroxide solution. Filter off the thus-produced precipitate and recrystallize it from ethanol/water 2:1 to obtain 3.2 g (32% of theory) of title compound having a m.p. of 72°.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH3:13].[NH2:14]OS(O)(=O)=O>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH2:14])[CH:8]=[C:7]2[CH3:13]
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: NOS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(N)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of NaH (2.01 g, 50.3 mmol, 60% in mineral oil) in DMF (45 mL) at 0° C. is treated with 5-fluoro-3-methyl-1H-indole (500 mg, 3.55 mmol), and the mixture is stirred at 0° C. for 1 h. NH2OSO3H (1.9 g, 16.75 mmol) is added portion wise, and the mixture is then warmed to rt and stirred for 2 h. The mixture is quenched with MeOH, diluted with water, extracted with EtOAc, dried (Na2SO4), filtered and concentrated to afford 5-fluoro-3-methyl-indol-1-ylamine. MS: 165 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.22 (s, 3H), 6.86 (m, 1H), 6.99 (s, 1H), 7.08 (m, 1H), 7.36 (m, 1H).
Reaction SMILES: CN(C)CCN.[CH3:7][O:8][CH2:9][CH2:10][O:11][N:12]1[C:16](=O)[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2C1=O.C(O)(=O)C.C([C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[NH:42][S:43]([C:46]([F:49])([F:48])[F:47])(=[O:45])=[O:44])(=O)C1C=CC=CC=1>CCO>[Cl:41][C:39]1[CH:40]=[CH:35][C:36]([NH:42][S:43]([C:46]([F:49])([F:47])[F:48])(=[O:45])=[O:44])=[C:37]([C:16](=[N:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[C:15]2[CH:14]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:38]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: COCCON1C(=O)c2ccccc2C1=O
Agent: CN(C)CCN
Solvent: CCO
Solvent: CC(=O)O
Product: COCCON=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 74.2 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-(2-methoxyethoxy)phthalimide (332 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 7 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (364 mg, 1.0 mmol), and the reaction stirred for 15 hours at 30° C. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-{4-chloro-[(2-methoxyethoxyimino)phenylmethyl]phenyl}trifluoromethanesulfonamide 234 (324 mg, 74%), as a colorless oil, 1H n.m.r. (400 MHz, CDCl3) (2:1 mixture of E- and Z-isomers) δ 11.06, br s, 1H, 8.87, br s, 1H, 7.67, d, J=88 Hz, 1H, 7.54-7.31, m, 13H, 7.10, d, J=2.4 Hz, 1H; 6.92, d, J=2.4 Hz, 1H, 4.33, m, 4H, 3.67, m, 4H, 3.46, s, 3H, 3.38, s, 3H. HRMS (M+) 436.0465.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@@:3]([CH2:18][NH:19][C@@H](C1C=CC=CC=1)C)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6]>CCO.[Pd]>[NH2:19][CH2:18][C@:3]([OH:17])([CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6])[C:2]([F:29])([F:28])[F:1]
Reactant: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CN[C@H](C)c1ccccc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CN)C(F)(F)F
Yield: 106.4 %

Procedure:
(2R)-1,1,1-Trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-({[(1R)-1-phenylethyl]amino}methyl)-2-pentanol (Intermediate 20) (200 mg, 0.48 mmol) was dissolved in EtOH (8 mL) and hydrogenated over 10% palladium on charcoal (100 mg) at 53 psi and room temperature for 16 hours. Catalyst was removed by filtration through celite. The celite was washed several times with EtOH. The filtrate was evaporated in vacuo to give the title compound as a pale yellow oil (158 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:16]=[CH:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:10]=3[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[Br:20][C:3]1[CH:4]=[C:5]([C:8]2[C:9]3[N:16]=[CH:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:10]=3[N:11]=[N:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)n1cnc2c(-c3ccc(F)cc3)cnnc21
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Product: CC(C)n1cnc2c(-c3ccc(F)c(Br)c3)cnnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 4-(4-fluorophenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine (Preparation 86, 770 mg, 3.00 mmol) in concentrated sulfuric acid (7.00 mL) at 0° C. was added 1,3-dibromo-5,5-dimethyl hydantoin (687 mg, 2.40 mmol) portionwise over 1.5 hours and the reaction stirred at 0° C. for 1 hour. The reaction mixture was added dropwise into a solution of saturated aqueous sodium thiosulfate solution (20 mL) at 0° C. Following complete addition the reaction mixture was basified to pH=9 with solid potassium carbonate. The reaction mixture was filtered through celite, washed with CH2Cl2 (20 mL) and extracted into CH2Cl2 (3×40 mL), dried over Na2SO4, filtered and concentrated under vacuum to yield a pale yellow solid. Purification by silica gel column chromatography eluting with EtOAc:CH2Cl2 1:1 afforded the title compound as a pale yellow solid (558 mg, 55%).
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][C:36](B(O)O)=[C:35]([O:43][CH3:44])[CH:34]=1>CCCCCCC.CCOC(C)=O>[F:32][C:33]1[C:38]([F:39])=[CH:37][C:36]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:2][CH3:3])=[C:35]([O:43][CH3:44])[CH:34]=1
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1cc(F)c(F)cc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic separation. Light brown solid (91%). MS (ESI): m/z=251.099 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13](B4OC(C)(C)C(C)(C)O4)[CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=2)[CH:4]=[N:3]1.[CH2:33]([SH:36])[CH2:34][CH3:35].N1C=CC=CC=1>CN(C=O)C.CCOC(C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([S:36][CH2:33][CH2:34][CH3:35])[CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)cn1
Reactant: CCCS
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCSc1cnc2c(c1)c(-c1cnn(C)c1)cn2COCC[Si](C)(C)C
Temperature: 110 °C
Reaction time: 20.5 h
Yield: 12.6 %

Procedure:
A mixture of 25 (60 mg, 0.132 mmol), n-propanethiol (21.1 mg, 0.264 mmol), copper (II) acetate (36 mg, 0.198 mmol), pyridine (32 μL, 0.396 mmol) and 4A molecular sieves (50 mg) in DMF (1.5 mL) were heated at 110° C. for 25 h. More n-propanethiol (21.1 mg, 0.264 mmol), copper (II) acetate (36 mg, 0.198 mmol) and pyridine (32 μL, 0.396 mmol) were added and heating continued for 20.5 h. More n-propanethiol (21.1 mg, 0.264 mmol), copper (II) acetate (36 mg, 0.198 mmol), pyridine (32 μL, 0.396 mmol) and 4A sieves were added again and the heating continued at 130° C. overnight. The reaction mixture was cooled, diluted with AcOEt, filtered and washed with brine. The aqueous layer was extracted with AcOEt (2×), and the combined organic extracts dried (MgSO4) and concentrated. The residue was purified by preparative LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give 26 as an orange oil (6.7 mg, 13%); 1H NMR (400 MHz, CDCl3) δ-0.056 (s, 9H), 0.93 (t, J=8.3 Hz, 2H), 1.00 (t, J=7.3 Hz, 3H), 1.61 (sextet, J=7.4 Hz, 2H), 2.84 (t, J=7.3 Hz, 2H), 3.57 (t, J=8.3 Hz, 2H), 4.00 (s, 3H), 5.68 (s, 2H), 7.43 (s, 1H), 7.64 (s, 1H), 7.76 (s, 1H), 8.15 (d, J=2.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H).
Reaction SMILES: Br[CH:2]([CH3:6])[C:3]([NH2:5])=[O:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]([C:26]3[C:34]4[CH:33]=[N:32][CH:31]=[N:30][C:29]=4[NH:28][CH:27]=3)=[O:25])[CH:23]=2)=[O:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([C:26]3[C:34]4[CH:33]=[N:32][CH:31]=[N:30][C:29]=4[N:28]([CH:2]([CH3:6])[C:3]([NH2:5])=[O:4])[CH:27]=3)=[O:25])[CH:21]=[N:20][CH:19]=2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Nc1cncc(C(=O)c2c[nH]c3ncncc23)c1
Reactant: CC(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(N)=O)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
2-bromopropionamide (46.5 mg, 0.31 mmol) was added to a mixture of 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308, 100 mg, 0.26 mmol) and cesium carbonate (150 mg, 0.46 mmol) in DMF (1.3 mL). The mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled and water (10 mL) was added. The mixture was extracted with EtOAc (3×10 mL) and the combined organic phases were passed through a phase separator and evaporated in vacuo. Purification by preparative HPLC gave the title compound as a white solid in 34% yield, 15 mg.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[CH2:17][CH:16]2[C:18](=O)[CH:12]([CH2:13][N:14]([CH:20]([CH3:22])[CH3:21])[CH2:15]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.NN.C1C2C(=CC=CC=2)CCC1>C(O)COCCOCCO.O>[CH2:3]([N:10]1[CH2:11][CH:12]2[CH2:18][CH:16]([CH2:15][N:14]([CH:20]([CH3:22])[CH3:21])[CH2:13]2)[CH2:17]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)N1CC2CN(Cc3ccccc3)CC(C1)C2=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Solvent: c1ccc2c(c1)CCCC2
Product: CC(C)N1CC2CC(CN(Cc3ccccc3)C2)C1
Temperature: 25 °C

Procedure:
To a mixture of KOH pellets (85%, 11.62 g, 176 mmol) and the ketone (21) (6.0 g, 22 mmol) in triethylene glycol (100 mL) was added hydrazine (95%, 2.97 g, 88 mmol) in one portion in a 200-mL, jacketed flask equipped with a magnetic stirrer, a heating mantle, a standard condenser, a lower take-off condenser with a N2 inlet, and two glass stoppers. A heating temperature of 200°-210° C. for 4 h under N2 was produced by boiling tetralin (bp 207° C.) in the jacket. Cooling of the solution to RT was followed by the addition of chilled water (125 mL). Combined extracts (ether, 4×50 mL) of the suspension were washed with 10% NaOH (50 mL) and saturated NaCl (50 mL), dried (Na2SO4, 1 h), filtered, and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to a yellow oil (5.53 g, 97.3%). Analysis of the very slight crude amine (30) showed no carbonyl stretch in the IR spectrum, and thus it was used without further purification.
Reaction SMILES: O.[OH-].[Li+].BrC1C=CC(C([O:11][C@H:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]4)[C:15]=3[C@H:14]([CH3:34])[CH2:13]2)=O)=CC=1.O>C1COCC1>[OH:11][C@H:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[C:15]=2[C@H:14]([CH3:34])[CH2:13]1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc(Br)cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
Lithium hydroxide hydrate (0.779 mL, 28.0 mmol) was added to a solution of tert-butyl 4-((5R,7R)-7-(4-bromobenzoyloxy)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (5.8 g, 11.2 mmol) in THF:H2O (150 mL, 2:1) at 0° C. The mixture was allowed to warm to room temperature and stirred at for 1 hour. The mixture was concentrated in vacuo, taken up into saturated sodium bicarbonate (100 mL) and extracted into EtOAc (2×200 mL). The reaction was dried over Na2SO4 and concentrated in vacuo to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (3.8 g, 11.4 mmol, 100% yield) as a foam. Similarly, tert-butyl 4-05R,7S)-7-(4-bromobenzoyloxy)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.29 g, 2.49 mmol) was dissolved in THF:H2O (10 mL, 2:1), cooled to 0° C. and then treated with solid lithium hydroxide hydrate. The solution was stirred at ambient temperature for 16 hours. The reaction was quenched with saturated NH4Cl and concentrated in vacuo. The resulting residue was diluted with ethyl acetate and a small amount of water. The layers were separated, and the aqueous layer was washed with ethyl acetate. The combined organic layers were washed with saturated NaHCO3 (2×), saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The resulting residue was dried under high vacuum to give tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate as a foam (0.843 g, 100%).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.[Br:22][C:23]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:24]=1[C:25](Cl)=[O:26].Cl>C(#N)C>[Br:22][C:23]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:24]=1[C:25]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])=[O:26]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1Br
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
15.9 g (0.167 mol) of magnesium chloride in 150 ml of anhydrous acetonitrile (dried over zeolite) are initially introduced into the reaction vessel and 26.9 g (0.167 mol) of diethyl malonate are added dropwise, while cooling. The mixture is cooled to 0° C., 46 ml (33.7 g=0.33 mol) of triethylamine are added dropwise and the mixture is subsequently stirred for 30 minutes. 48.9 g (0.168 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoyl chloride are then added dropwise and the mixture is subsequently stirred at 0° C. for a further hour and brought to room temperature overnight. 100 ml of 5N hydrochloric acid are added, the mixture is extracted three times with methylene chloride and the extract is dried with Na2SO4 and concentrated in vacuo.
Reaction SMILES: C([O-])(=O)C.[K+].C(O)C.[NH2:9][NH:10][C:11]([NH2:13])=[S:12].Cl[CH2:15][C:16](=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>O>[NH:10]([C:11]1[S:12][CH:15]=[C:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:13]=1)[NH2:9]
Reactant: NNC(N)=S
Reactant: CCOC(=O)CC(=O)CCl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1csc(NN)n1

Procedure:
Potassium acetate (1.3 g., 12.5 mmoles) was dissolved in 40 ml. of an aqueous ethanol mixture (1:1). With stirring, thiosemicarbazide (1.1 g., 12.5 mmoles) and ethyl 4-chloroacetoacetate (2.0 g., 12.5 mmoles) were introduced. After 3 hours of stirring at room temperature a red oil settled out. The reaction mixture was diluted with water and extracted several times with methylene chloride (total 100 ml.). Combined extracts were dried (calcium chloride), filtered, and concentrated under reduced pressure to approximately 2.0 g. of oily residue. Thin layer chromatography (chloroform) revealed the presence of two compounds. This oil was then chromatographed on a silica gel column using methylene chloride as the eluent. Compound IVA (see Example 12) was in the first few fractions while the latter fractions contained a single component (0.6 g.) characterized as Compound IIA by pmr. Although Compound IIA was chromatographically pure, it would not crystallize; ir (mull): 3450-3200 (N--H), 1725 (C=O), 1620, 1580 (C=N) cm-1 : pmr (deuteriochloroform): δ1.20 (t, 3H, CH3), 3.55 (s, 2H, CH2CO), 4.15 (q, 2H, OCH2), 5.80-6.20 (s-broad, 3H, NH), 6.30 (s, 1H, vinyl); ms: (m/e)201(M+).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([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.[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][S:57](Cl)(=[O:59])=[O:58])=[C:52]([N+:61]([O-:63])=[O:62])[CH:51]=1>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:57]([CH2:56][C:53]1[CH:54]=[CH:55][C:50]([Cl:49])=[CH:51][C:52]=1[N+:61]([O-:63])=[O:62])(=[O:59])=[O:58])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CS(=O)(=O)Cl
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)cc3[N+](=O)[O-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 74 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added (4-chloro-2-nitro-phenyl)-methanesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 74% yield.