Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH2:21][C:22]1[C:23]([C:29]([NH:31][CH3:32])=[O:30])=[N:24][C:25](Br)=[CH:26][N:27]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:21][C:22]1[N:27]=[CH:26][C:25]([C:9]2[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])=[N:24][C:23]=1[C:29]([NH:31][CH3:32])=[O:30]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Reactant: CNC(=O)c1nc(Br)cnc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)c1nc(-c2ccc(Cl)c(C(=O)OC)c2)cnc1N
Temperature: 95 °C
Yield: 54.4 %

Procedure:
To a solution of methyl 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.16 g, 0.55 mmol) in toluene (2 mL)) were added 3-amino-6-bromo-N-methyl-2-pyrazincarboxamide (0.13 g, 0.58 mmol), tetralds(triphenylphosphin)palladium(0) (64 mg, 0.06 mmol), ethanol (2 mL), and 2.0 N sodium carbonate (0.42 g, 4.00 mmol). The solution was degassed with nitrogen gas for 3-5 min and heated at 90-100° C. for 2 h. Reaction cooled to room temperature and diluted with ethyl acetate (200 mL). The organic layer was washed water (50 mL) and saturated aqueous sodium chloride (40 mL), dried over magnesium sulfate, filtered, and concentrated to afford crude product. Trituration with methanol (1 mL), filtration and drying gave methyl 5-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}-2-chlorobenzoate (96 mg, 56% yield) as yellow solid. 1H NMR (400 MHz, CDCl3): 8.62 (br s, 1H), 8.28 (d, 1H), 7.92 (dd, 2H), 7.52 (d, 1H), 4.02 (s, 3H), 3.02 (s, 3H); MS (EI) for C14H13N4O2Cl: 321 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH2:16][NH:17][O:18][CH3:19]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:17]([CH2:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[F:13])[O:18][CH3:19])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccccc1F
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccccc1F)C(=O)C=C1OC(C)(C)OC1=O
Yield: 84 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as a white solid (84% yield): mp 109–111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.72 (3H, s, OCH3), 4.92 (2H, s, NCH2), 6.40 (1H, s, CH), 7.03–7.12 (2H, m, aromatics), 7.24–7.30 (1H, m, aromatic), 7.4 (1H, m, aromatic). Anal. calcd. for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52. Found: C, 58.47; H, 5.16; N, 4.66.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@:16]12[CH2:51][C:50](=[O:52])[C:49]([CH:53]([CH3:55])[CH3:54])=[C:17]1[C@@H:18]1[C@@:31]([CH3:34])([CH2:32][CH2:33]2)[C@@:30]2([CH3:35])[C@@H:21]([C@:22]3([CH3:48])[C@@H:27]([CH2:28][CH2:29]2)[C:26]([CH3:37])([CH3:36])[C@@H:25]([O:38][C:39](=[O:47])[CH2:40][C:41]([CH3:46])([CH3:45])[C:42]([OH:44])=[O:43])[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)(=[O:3])[CH3:2].C=O.[BH3-][C:59]#N.[Na+]>CO>[C:1]([O:4][C@@H:5]([C@:16]12[CH2:51][C:50](=[O:52])[C:49]([CH:53]([CH3:55])[CH3:54])=[C:17]1[C@@H:18]1[C@@:31]([CH3:34])([CH2:32][CH2:33]2)[C@@:30]2([CH3:35])[C@@H:21]([C@:22]3([CH3:48])[C@@H:27]([CH2:28][CH2:29]2)[C:26]([CH3:37])([CH3:36])[C@@H:25]([O:38][C:39](=[O:47])[CH2:40][C:41]([CH3:45])([CH3:46])[C:42]([OH:44])=[O:43])[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[CH3:59])(=[O:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)O[C@H](CNCc1ccc(Cl)cc1)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(=O)O[C@H](CN(C)Cc1ccc(Cl)cc1)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((4-chlorobenzyl)amino)ethyl)-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)oxy)-2,2-dimethyl-4-oxobutanoic acid (50) (150 mg, 0.192 mmol) in MeOH (6 mL) stirred in air at rt was added formaldehyde (31.2 mg, 0.384 mmol). The reaction mixture was stirred at rt for 2 h. Then it was added NaCNBH3 (85 mg, 1.345 mmol) portionwise and stirred for overnight. The solvent was evaporated and the residue diluted with DCM and washed with water and brine. The dried organics were filtered and concentrated to give 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((4-chlorobenzyl)(methyl)amino)ethyl)-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)oxy)-2,2-dimethyl-4-oxobutanoic acid (68) (120 mg, 65% yield) as a white solid. This material was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.31-7.26 (m, 2H), 7.24-7.16 (m, 2H), 5.65 (d, J=8.5 Hz, 1H), 4.50 (br. s., 1H), 3.66-3.51 (m, 1H), 3.49-3.36 (m, 1H), 3.27-3.06 (m, 2H), 2.73-2.32 (m, 5H), 2.26 (s, 3H), 2.08-0.73 (m, 49H); LC/MS: m/z calculated 793.5. found 794.3 (M+1)+.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24].[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 54.9 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), isoamylamine (0.234 g, 2.69 mmol) and 3 Å molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, and dissolve it in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate to give the title compound (0.484 g, 54.9%): TOF MS ES+ 345.2 (M+H)+, HRMS calcd for C18H25N4O3 345.1927 (M+H)+, found 345.1938, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=10.1 min, 95.4% purity.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Cl.[C:17]1([P:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:24]C)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC>[C:10]1([P:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:2]2[CH:7]=[C:6]([P:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:24])[N:5]=[CH:4][N:3]=2)=[O:24])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: Clc1ccccc1Cl
Solvent: CCCCCC
Product: O=P(c1ccccc1)(c1ccccc1)c1cc(P(=O)(c2ccccc2)c2ccccc2)ncn1

Procedure:
To a stirred, refluxing mixture of 5.00 g 4,6-dichloropyrimidine in 100 of o-dichlorobenzene under nitrogen was added dropwise 17.00 g of methyl diphenylphosphinite. After the addition was completed, the mixture was refluxed for 6.5 hours and then allowed to cool. The cooled mixture was added to 750 ml of n-hexane, and the white solid that formed was separated by filtration, washed with n-hexane, recrystallized from 150 ml of toluene, and dried at 100° C./0.1 mm (13 Pa) to give 13.64 g of 4,6-bis(diphenylphosphinyl)pyrimidine (shown by formula in Claim 9) as cream-colored crystals, mp 213°-215° C. Anal. Calcd for C28H22N2O2P2 : C, 70.00; H, 4.62; N, 5.83; P, 12.89. Found: C, 69.80; H, 4.65; N, 5.65; P, 12.89.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]3[N:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][C:11]3=[N:12][C:13]=2[CH:14]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(O)C.O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]3[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][C:11]3=[N:12][C:13]=2[CH:14]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc3cc(NC(C)=O)ccc3c(=O)n2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1ccc2c(=O)n3nc(C(=O)O)ccc3nc2c1

Procedure:
A mixture of methyl 7-acetylamino-10-oxo-10H-pyridazino [6, 1-b]-quinazoline-2-carboxylate (0.38 g, 1.22 mmol, Example 4, Step B) and 0.5M sodium carbonate solution (6.0 mL, 3.0 mmol), Example 4, Step B) and 0.5M sodium carbonate solution (6.0 mL, 3.0 mmol) in 100 mL of THF:ethanol:water (1:1:2) was gently refluxed for 3 h. The resultant solution was filtered through a pad of Celite, concentrated, redissolved into water, acidified to a pH~ 1.5-2.0 with 10% hydrochloric acid and cooled. Solid formed, the mixture was filtered and washed with water, acetone and diethyl ether to give the titled compound as a dark yellow solid, mp 272°-275° C. dec
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=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>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:21]1[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reactant: OB(O)c1cc(F)cc(F)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: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 100 °C
Yield: 38 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.318 mmol) and (3,5-difluorophenyl)boronic acid (60.3 mg, 0.382 mmol) in 1,4-dioxane (2 mL) was added a 1M solution of sodium carbonate (40.5 mg, 0.382 mmol) in water (0.38 mL) and tetrakis(triphenylphosphine)palladium (0) (18.4 mg, 0.0159 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to provide the desired product (42 mg, 38.0%). LCMS calculated for C15H12F2N5OS (M+H)+: m/z=348.1. Found: 348.2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].O1CCCC1>O>[C:26]([O:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:5][C:4]=1[C:1]([OH:3])=[O:2])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)ccc1O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1C(=O)O

Procedure:
A mixture of 25.0 g. (0.075 mole) of 1-(3-carboxy-4-hydroxyphenyl)-2-phenyl-4,5,6,7-tetrahydroindole and 225 g. (2.25 mole) of acetic anhydride was heated under reflux for 3 hours, diluted with 200 ml. of tetrahydrofuran, and poured into 3 l. of water. An oil separated and slowly solidified. Recrystallization from acetic acid gave a tan solid, m.p. 155°-162°.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][NH:13]1.Br[CH2:27][C:28](Br)=[O:29].[CH2:31]([NH:38][CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:27][C:28]([N:38]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:39])=[O:29]
Reactant: CNCc1ccccc1
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)N(CC(=O)N(C)Cc1ccccc1)CC2

Procedure:
prepared by reaction of 1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with N-benzyl-N-methyl-amine
Reaction SMILES: C(O[C:5]1([C:26](=[O:29])[CH2:27]O)[C@:21]2([CH3:22])[CH:8]([CH:9]3[C:18](=[CH:19][CH2:20]2)[C@:17]2([CH3:23])[C:12](=[CH:13][C:14](=[O:24])[CH:15]=[CH:16]2)[C@@H:11]([CH3:25])[CH2:10]3)[CH2:7][CH2:6]1)(=O)C.[C:30](=[O:33])([O-])[O-:31].[CH3:34]N(C)C=O>>[C:30]([O:31][CH2:27][C:26](=[O:29])[C:5]1[C@:21]2([CH3:22])[CH:8]([CH:9]3[C:18](=[CH:19][CH2:20]2)[C@:17]2([CH3:23])[C:12](=[CH:13][C:14](=[O:24])[CH:15]=[CH:16]2)[C@@H:11]([CH3:25])[CH2:10]3)[CH2:7][CH:6]=1)(=[O:33])[CH3:34]
Reactant: CC(=O)OC1(C(=O)CO)CCC2C3C[C@H](C)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Product: CC(=O)OCC(=O)C1=CCC2C3C[C@H](C)C4=CC(=O)C=C[C@]4(C)C3=CC[C@]12C

Procedure:
(6S,10R,13S)-17-(2-hydroxyacetyl)-6,10,13-trimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl acetate is heated with 2 equivalents of postassium carbonate in dimethyl formamide. Standard aqueous workup yields the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[NH:5][C:4](=[O:12])[CH:3]=1.[H-].[Na+].[H][H].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4](=[O:12])[CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)CBr
Reactant: CCCn1c(N)cc(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCn1c(N)cc(=O)n(CC(=O)OCC)c1=O
Temperature: 40 °C

Procedure:
6-Amino-1-propyluracil (10 g, 59.1 mmol) was dissolved by warming gently in 60 mL of dimethylsufoxide. 2.0 g (66 mmol) of an 80% dispersion of sodium hydride in mineral oil was added in portions to the solution while stirring under argon. After the evolution of hydrogen ceased, the mixture was heated to 40° C. until a solution resulted. To this solution at 25° C. was added ethyl bromoacetate (7.1 mL, 62 mmol), with the mixture maintained under argon at room temperature for 44 hours. The mixture was then diluted with 200 mL of water and extracted with hexane to remove the mineral oil. The aqueous layer was adjusted to pH 10 with 3N sodium hydroxide and extracted with dichloromethane. The extracts were dried over anhydrous sodium sulfate and concentrated to a brown liquid, which was purified by flash chromatography (silica gel, 9:1/chloroform:ethanol) to yield a crystalline product.
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:14]C[C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1.[CH:22]1C=CC=CC=1>>[Cl-:14].[CH3:21][C:18]1[S:19][CH:20]=[C:16]([CH:10]([P+:5]([CH3:22])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13])[N:17]=1
Reactant: Cc1nc(CCl)cs1
Reactant: c1ccccc1
Reactant: CCCCP(CCCC)CCCC
Product: CCCC[P+](C)(CCCC)C(CCC)c1csc(C)n1
Product: [Cl-]
Reaction time: 8 h
Yield: 97 %

Procedure:
Tri-n-butylphosphane (38 ml, 0.156 mol) was added to a solution of 4-chloromethyl-2-methylthiazole (23 g, 0.156 mol) in anhydrous benzene (200 ml) under argon, and the solution was heated to boiling for 8 hours. Then, it was concentrated by evaporation in a vacuum, the residue was dried for 30 more minutes at 0.01 Torr, and the phosphonium salt was brought to crystallization by trituration with dry diethyl ether. 53 g (97%) of the title compound was obtained as colorless, hygroscopic crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[C:16]2[N:15]=[C:14]([S:17][C:18]3[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=3)[NH:13][C:12]=2[CH:11]=[C:10]([F:25])[CH:9]=1.[C:26]1(=O)[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[CH2:27]1>C(O)CCC>[F:25][C:10]1[CH:9]=[C:8]([F:7])[C:16]2[NH:15][C:14]([S:17][C:18]3[O:22][C:21]([CH:23]4[C:27]5[C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:26]=5[NH:1][C:2]5=[N:3][NH:4][CH:5]=[C:6]45)=[CH:20][CH:19]=3)=[N:13][C:12]=2[CH:11]=1
Reactant: O=Cc1ccc(Sc2nc3c(F)cc(F)cc3[nH]2)o1
Reactant: Nc1cc[nH]n1
Reactant: O=C1CCCC(=O)C1
Solvent: CCCCO
Product: O=C1CCCC2=C1C(c1ccc(Sc3nc4cc(F)cc(F)c4[nH]3)o1)c1c[nH]nc1N2
Yield: 68.7 %

Procedure:
A mixture of 3-aminopyrazole (0.089 g, 1.07 mmol), 5-(4,6-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (described in example 142, 0.30 g, 1.07 mmol) and 1,3-cyclohexanedione (0.12 g, 1.07 mmol) in 5 ml of 1-butanol is heated at reflux temperature for 3 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified on a silica gel column (40 g) eluted with a mixture of cyclohexane and ethyl acetate (2/8, v/v). The fractions containing the expected product are concentrated under reduced pressure and the obtained solid is washed with pentane (25 ml) and diisopropylether (25 ml) and dried under vacuum to yield 323 mg of 4-[5-(5,7-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-2,4,6,7,8,9-hexahydro-pyrazolo[3,4-b]quinolin-5-one as a white powder. Yield=69%. Analytical LC/MS (method C): m/z=438 (negative ion mode [M−H]−), m/z=440 (positive ion mode [M+H]+)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C@@H:14]1[CH2:23][CH2:22][C:21]2[C:16](=[C:17]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH:18]=[CH:19][CH:20]=2)[CH2:15]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH2:15][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:23][CH2:22]3)[CH2:25][CH2:26]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)CCCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)CCCc2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Phenylbutyric acid (1.0 g, 6.1 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (86 mg, 0.47 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine (93 μL, 0.68 mmol) in methylene chloride (15 mL) . After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 150 mg (82%) of the title compound as white crystals: mp 137-139° C.; [α]21D +8.4° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 391 (23, M+).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[NH2:17][C@@H:18]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20].C(O)(=O)C.[O-]S([O-])(=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O1CCCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:17][C@@H:18]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: CN(C)C(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C(=O)[C@H](Cc1c[nH]c2ccccc12)NC1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(dimethylamino)-4-phenylcyclohexanone (1.1 g, 5.41 mmol) was dissolved in a mixture of 1,2-dichloroethane (30 ml) and tetrahydrofuran (40 ml) in argon, mixed with (S)-2-amino-3-(1H-indol-3-yl)-N,N-dimethylpropanamide (1 g, 4.3 mmol), acetic acid (0.31 ml, 5.41 mmol) and Na2SO4 (2.7 g). The mixture was stirred for 15 min at RT and then mixed with sodium triacetoxyboron hydride (1.65 g, 7.57 mmol) and stirred for 48 hours. For work up of the batch the mixture was mixed with saturated NaHCO3 solution (60 ml) and stirred for 15 min. The aqueous phase was extracted with dichloromethane (2×40 ml). The combined organic phases were concentrated to low volume after drying and a light brown oil was obtained. The chromatographic separation of the substance mixture on silica gel 60 (100 g) was conducted with ethyl acetate/methanol (1:1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][S-:16].[Na+]>CC(C)=O>[CH3:15][S:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(SC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (28 g) in acetone (250 mL) is treated portionwise with sodium thiomethoxide (10 g) and the mixture is stirred overnight at room temperature. After filtration, the solution is concentrated and water (300 mL) is added to the residue. The yellow solid is filtered off and subjected to flash chromatography eluting with a mixture of diethyl ether and pentane (1:4 v/v), to give methyl 4-methylthio-3-nitrobenzoate (18.5 g), in the form of a yellow solid, m.p. 118-120° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH:8](O)[C:7]=2[CH:18]=1.[ClH:19]>O1CCOCC1>[Cl:19][CH:8]1[C:7]2[CH:18]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH:12]=[CH:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=2
Reactant: Cl
Reactant: CSc1ccc2c(c1)C(O)c1ccccc1C=C2
Solvent: C1COCCO1
Product: CSc1ccc2c(c1)C(Cl)c1ccccc1C=C2

Procedure:
A solution of 18 g. (0.071 mole) of 3-methylmercapto-5H-dibenzo[a,d]cyclohepten-5-ol in 90 ml. of dry dioxane is cooled in an ice-bath and saturated with dry hydrogen chloride. A solid separates and when precipitation appears to be complete, the mixture is stirred with 150 ml. of petroleum ether and the product collected, washed with petroleum ether, and dried in a vacuum desiccator over potassium hydroxide. The yield of 5-chlor-3-methylmercapto- 5H-dibenzo[a,d]cycloheptene is 16 g. (84%), m.p. 135°-138°C. The melting point is unchanged by recrystallization from cyclohexane.