Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[N:13][N:12]([CH3:15])[C:11]=2[CH2:16][OH:17])=[CH:6][CH:5]=1.Cl[C:19]1[N:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=1>C1COCC1>[CH3:28][O:27][C:25]([C:22]1[CH:21]=[N:20][C:19]([O:17][CH2:16][C:11]2[N:12]([CH3:15])[N:13]=[N:14][C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)=[CH:24][N:23]=1)=[O:26]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OCc2c(-c3ccc(F)cc3)nnn2C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a suspension of NaH (55% in oil, 131 mg, 3.0 mmol) in THF (3.9 mL) was added a solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (622 mg, 3.0 mmol) in THF (7.9 mL) dropwise at 0° C. and the reaction mixture was stirred at room temperature for 30 min. Then a solution of methyl 5-chloropyrazine-2-carboxylate (569 mg, 3.3 mmol) in THF (7.9 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The mixture was then poured into ice water and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane, then 0 to 5% methanol in dichloromethane) afforded the title compound (474 mg, 46%) as an off white gum. MS: m/e=344.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:7][CH2:8][CH2:9][CH2:10][SH:11])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[C:16]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.CO>CN(C)C=O>[CH3:1][C:2]([CH3:12])([CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:16]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)CCCCS
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCCSc1cc(-c2ccccc2)c2ccccc2n1
Reaction time: 2 h

Procedure:
To a solution of 4 g of methyl 2,2-dimethyl-6-mercaptohexanoate in 100 cc of dimethylformamide, is added 0.55 g of sodium hydride (50% w/w dispersion in mineral oil). The mixture is stirred for 2 hours until effervescence has stopped. A solution of 5 g of 2-chloro-4-phenylquinoline in 50 cc of dimethyl-formamide is then added. The obtained mixture is heated to 60 C. for 8 hours. After cooling, 10 cc of methanol is added and the mixture evaporated. The resultant residue is purified by flash chromatography on silica gel (30-60 mm; eluent: 8:2 hexane/ethyl acetate) to give methyl 2,2-dimethyl-6-[(4-phenyl-2-quinolyl)thio]-hexanoate is obtained as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:9])[OH:8])[CH2:3]1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:11]([O:9][C:7]([NH:6][CH:4]1[CH2:5][CH:2]([O:1][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1)=[O:8])([CH3:16])([CH3:12])[CH3:10]
Reactant: O=C(O)NC1CC(O)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CC(OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of (3-hydroxycyclobutyl)carbamic acid tent-butyl ester (180 mg, 0.96 mmol) in pyridine (4 mL) was added benzoyl chloride (116 μL, 1.0 mmol). The reaction mixture was stirred at room temperature for 2 hrs and then concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with 1 N HCl, water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et2O/pentane: gradient 0% to 50%) to give benzoic acid 3-tert-butoxycarbonylaminocyclobutyl ester as a white solid (262 mg, yield: 94%). LCMS (ESI) m/z: 192 [M+H-BOC]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[N:31][CH:32]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[CH3:35][O:36][C:37]([NH:39][C:40](=NC(OC)=O)SC)=[O:38]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:28]=[C:29]6[NH:34][C:40]([NH:39][C:37](=[O:38])[O:36][CH3:35])=[N:33][C:30]6=[N:31][CH:32]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: Cc1ncnc(N2CCOc3ccc(-c4cnc(N)c(N)c4)cc3C2)c1Cc1ccc(F)cc1
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc(C)c3Cc3ccc(F)cc3)CCO4)cc2[nH]1
Temperature: 60 °C
Yield: 4.1 %

Procedure:
To a solution of 5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridine-2,3-diamine (0.21 g, 0.45 mmol) in acetic acid (5 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.09 g, 0.45 mmol). The reaction mixture was heated (60° C.) for 12 h and then concentrated. The resulting residue was dissolved in acetonitrile and purified by preparative reverse phase HPLC to provide methyl [6-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate (0.01 g, 4% yield) as a white solid. 1H NMR (400 MHz, DMSO-D6): δ 11.97 (bs, 1H), 8.51 (d, 1H), 8.28 (s, 1H), 7.79 (s, 1h), 7.42-7.50 (m, 1H), 6.95-7.13 (m, 6H), 4.53 (s, 2H), 4.25-4.32 (m, 2H), 4.00 (s, 2H), 3.74-3.84 (m, 5H), 2.16 (s; 3H); MS (EI) for C29H26FN7O3: 540 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[O:15])[C@@H:10]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@@:9]2([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[F:40])[C:31]#[N:32])[CH:5]=[CH:6][CH:7]=1.N.C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:41])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:44])=[O:22])=[CH:19][CH:18]=3)=[O:15])[C@@H:10]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@@:9]2([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[F:40])[C:31]#[N:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N(CC(=O)Nc2ccc(C(=O)O)cc2)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N(CC(=O)Nc2ccc(C(N)=O)cc2)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 100.1 %

Procedure:
A mixture of rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid (0.33 g, 0.55 mmol), a solution of ammonia (0.5 M in dioxane, Aldrich, 2 mL, 1 mmol), HATU (0.3 g, 0.79 mmol) and iPr2NEt (0.3 g, 2.33 mmol) in CH2Cl2 (20 mL) was stirred at room temperature for 20 h. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by chromatography (EtOAc) to give rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzamide as a white solid (0.33 g, 100%).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.[OH-].[K+].[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1)[CH3:23]
Reactant: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of benzyl bromide 4 (0.05 g, 0.159 mmole) in 5 mL ethanol was added potassium hydroxide (0.350 g, 0.627 mmole). After stirring at R.T. for 1 hour, the solvent was evaporated and the residue was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed on silica gel (hexanes:ethyl acetate, 9:1) to afford 0.039 g (51%) of ethyl ether 7 as a tan solid: Mp=166–168° C.; 1H NMR (DMSO-d6) δ 9.82 (br s, 1 H), 9.12 (bs, 1 H), 7.70 (d, 2 H, J=8.6 Hz), 7.02 (s, 1 H), 6.86 (d, 2 H, J=8.6 Hz), 6.81 (d, 1 H, J=2.1 Hz), 6.69 (d, 1 H, J=2.2 Hz), 4.71 (s, 2 H), 3.56 (q, 2 H, J=7.2 Hz), 1.18 (t, 3 H, J=7.2 Hz); MS 283 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.CO.S(Cl)([Cl:17])(=O)=O.C(=O)(O)[O-].[Na+]>CCCCCCC>[Cl:17][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:11])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1ccc(Cl)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CO
Product: O=C(CCl)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
In a 1 L round bottom flask combine 4′-chloro-2′-fluoroacetophenone (40 g, 231.8 mmol), heptane (120 mL), and methanol (16 mL). Cool to 0° C. and place under nitrogen. Dissolve sulfuryl chloride (21.5 mL, 1.15 equiv.) in heptane (120 mL) and charge to an addition funnel Add drop-wise to the reaction over 60 min. Stir for 2.5 h at 0° C.; a white precipitate forms during this time. Charge the addition funnel with 1 M sodium bicarbonate (400 mL) then add to the reaction drop-wise. After all gas evolution stops, filter the biphasic suspension to collect the title compound (38.18 g, 80%) as white needles. 1H NMR (DMSO-d6) δ 5.00 (d, 2H, J=2.5 Hz), 7.43 (m, 1H), 7.63 (m, 1H), 7.89 (t, 1H, J=8.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].C1(C)C=CC(S(O[C@H:23]2[CH2:30][CH2:29][CH2:28][C@@H:27](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:26][CH2:25][CH2:24]2)(=O)=O)=CC=1>CN(C=O)C>[NH2:1][C:2]1[N:6]([C@H:23]2[CH2:24][CH2:25][CH2:26][C@@H:27]([N:3]3[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]3[NH2:1])[CH2:28][CH2:29][CH2:30]2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCC[C@@H](OS(=O)(=O)c3ccc(C)cc3)CCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2n1[C@H]1CCC[C@@H](n2c(N)nc3ccccc32)CCC1
Reaction time: 0.5 h

Procedure:
To a hot (60° C.) solution of 2-aminobenzimidazole (0.22 g; 1.65 mmol) in DMF (25 ml) was added sodium hydride (70 mg; 60% dispersion in mineral oil), and the mixture was stirred for 30 minutes prior to addition of cis-1,5-bis(p-toluenesulfonyloxy) cyclooctane. The resulting mixture was stirred at 100° C. for four days, cooled and filtered. The filtrate was diluted with water and the precipitate was filtered off, washed with water and dried to yield the desired product (9 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[C:14]([C:17](=O)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)=[O:24]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:32][NH:31][C:29](=[O:30])[C:28]3[CH:27]=[CH:26][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:34][CH:33]=3)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C(C)(C)C)cc3)N=C2C)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
30.5 mg (0.11 mmol) of 1-(1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 23.1 mg (0.11 mmol) of 4-methoxycarbonylbenzhydrazide were dissolved in 3.0 ml of DMF and stirred at 100° C. for 3 hours. After cooling and evaporation of the solvent, the crude product was recrystallized from ethyl acetate/n-hexane to give 32.9 mg of the desired product as a yellow solid (yield 66%).
Reaction SMILES: [C:1]([Si:8]([CH3:16])([CH3:15])[O:9][Si:10]([CH3:14])([CH3:13])[CH:11]=[CH2:12])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C=C[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:1]([Si:8]([CH3:15])([CH3:16])[O:9][Si:10]([CH3:13])([CH3:14])/[CH:11]=[CH:12]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C=Cc1ccccc1
Reactant: C=C[Si](C)(C)O[Si](C)(C)C#CCCCCC
Solvent: Cc1ccccc1
Product: CCCCCC#C[Si](C)(C)O[Si](C)(C)/C=C/c1ccccc1

Procedure:
As in reaction conditions of Example XIX Step 2, to 2.48 mL of toluene, the 0.013 g carbonylchlorohydridebis(tricyclohexylphosphine)ruthenium(II) was added, and the reaction was carried out between the 1-(1-heptynyl)-1,1,3,3-tetramethyl-3-vinyldisiloxane obtained in Step 1 and 0.56 g styrene. Product was separated under the purification conditions of Example XII. The product, 1-(1-heptynyl)-1,1,3,3-tetramethyl-3-[(E)-styryl]disiloxane was obtained with a total yield of 85% pure product in the form of an oily liquid, light yellow in color.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[C:15]([S:24]([CH3:27])(=[O:26])=[O:25])=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][N:37]=[C:36](Cl)[N:35]=3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[O:41]([C:43]1[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=1)[CH3:42]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[C:15]([S:24]([CH3:27])(=[O:26])=[O:25])=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([NH:48][CH2:47][C:46]4[CH:49]=[CH:50][C:43]([O:41][CH3:42])=[CH:44][CH:45]=4)[N:35]=3)=[CH:30][CH:29]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: CS(=O)(=O)c1nn(-c2ccccc2)c2nc(-c3ccc(-c4ccnc(Cl)n4)cc3)n(-c3ccc(Cl)cc3)c(=O)c12
Solvent: CCO
Product: COc1ccc(CNc2nccc(-c3ccc(-c4nc5c(c(S(C)(=O)=O)nn5-c5ccccc5)c(=O)n4-c4ccc(Cl)cc4)cc3)n2)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
To a suspension of crude 5-(4-chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (from example 356) in EtOH (6 mL) is added 4-methoxylbenzylamine (0.4 mL). The mixture is heated at 100° C. for 24 h and then cooled down to room temperature. The precipitate is collected by filtration and washed with EtOH (2×3 mL). The solid is air dried for 14 h to provide the desired 5-(4-chloro-phenyl)-3-methanesulfonyl-6-{4-[2-(4-methoxy-benzylamino)-pyrimidin-4-yl]-phenyl}-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as white solid (230 mg, 80%). HPLC-MS calculated C36H28ClN7O4S (M−H′): 690.2. Found: 690.2.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[CH2:11]([OH:14])[CH2:12][SH:13]>C(#N)C>[OH:14][CH2:11][CH2:12][S:13][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: OCCS
Reactant: Brc1ccc2cnccn12
Solvent: CC#N
Product: OCCSc1ccc2cnccn12
Temperature: 25 °C

Procedure:
2.5 g of 6-bromopyrrolo[1,2-a]pyrazine prepared in Preparation Example 7 was dissolved in 30 ml of acetonitrile; and 1 ml of 2-thioethanol was added thereto. The reaction mixture was refluxed for 12 hours, cooled to room temperature, poured into ice-water and then extracted with ethyl acetate (50 ml×3). The organic layer was concentrated to dryness under a reduced pressure. The residue was chromatographed over silica gel to obtain 1 g of title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:35])=[C:16]([NH:26][C:27](=[O:34])OCC(Cl)(Cl)Cl)[C:17]([CH3:25])=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:36][CH2:37][CH2:38][CH2:39][OH:40]>CCCCCC.C(OCC)(=O)C>[OH:40][CH2:39][CH2:38][CH2:37][NH:36][C:27]([NH:26][C:16]1[C:17]([CH3:25])=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:35])=[O:34]
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Reactant: NCCCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)NCCCO)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 65 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 3-amino-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 65%. Melting point: 145-146° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1.CC(C)([O-])C.[K+:43]>C(O)C.C(O)(C)(C)C>[K+:43].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O-:34])=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)[O-])ccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A stirred suspension of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (179 g, 0.335 mol) in ethanol (2.6 L) was treated with 1 N potassium tert-butoxide in tert-butyl alcohol (350 mL) and stirred at room temperature under N2 for 1 hour. The mixture was then heated to a gentle reflux for 2 hours and was stirred overnight at room temperature. The suspension was filtered, then the filter cake was washed with hexane, combined with 5 g of similarly prepared material and dried at 60° C. in a vacuum oven overnight to yield 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid potassium salt as a beige solid (181 g, 84%). 1H NMR (400 MHz, DMSO-d6): 8.25 (d, J=9 Hz, 1H), 8.18 (d, J=9 Hz, 1H), 8.08 (d, J=2 Hz, 1H), 8.02 (d, J=8 Hz, 1H), 7.94 (dd, J=2, 9 Hz, 1H), 7.68 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.53 (dd, J=7, 9 Hz, 1H), 6.90 (d, J=9 Hz, 2H), 4.86 (s, 2H), 3.46 (m, 1H), 1.32 (d, J=7 Hz, 6H). ES-LCMS m/z 533 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N:7][CH2:6][C:5]1=[O:23])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N+:7]([O-:32])[CH2:6][C:5]1=[O:23])[CH:2]=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCN1C(=O)CN=C(c2ccccc2F)c2cc(Cl)ccc21
Solvent: ClC(Cl)Cl
Product: C=CCN1C(=O)C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6.4 g of 1-allyl-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 50 ml of chloroform are treated with 7 g of m-chloroperbenzoic acid and stirred for 16 hours at room temperature. Then the chloroform solution is washed with 1 N sodium bisulfite solution, with 2 N sodium hydroxide and with water. The organic phase is dried over calcium chloride, filtered and concentrated. The residue is recrystallized from ethanol and there is obtained 1-allyl-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide of melting point 183°C.
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].O>CN(C)C=O>[CH3:27][O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]([CH3:17])=[C:8]1[N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:25]
Reactant: Cc1c(-n2ccnc2)[nH]c2ccccc12
Reactant: COC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCn1c(-n2ccnc2)c(C)c2ccccc21
Reaction time: 48 h

Procedure:
To a suspension of 60% sodium hydride (0.34 g) in dimethylformamide (10 ml), while stirring under nitrogen at 0°-5°, is added dropwise a solution of 2-(1-imidazolyl)-3-methyl-indole (1.50 g) in dimethylformamide (15 ml). Upon complete addition the mixture is stirred at 0°-5° for 1 hour. To the nearly complete solution is added methyl 6-bromohexanoate (1.67 g) dropwise. The mixture is stirred at 0°-5° for 0.5 hour, then for two days at room temperature. The solution is poured into water (100 ml) and extracted with ethyl acetate (3×50 ml), dried (MgSO4), filtered, and concentrated in vacuo to give an amber oil which is stirred with 100 ml of petroleum ether for 15 minutes. The mixture is placed in a separatory funnel and the insoluble amber oil separated and removed. The oil is dried in vacuo to give 1-(5-methoxycarbonylpentyl)-2-(1-imidazolyl)-3-methylindole as an oil; NMR (CDCl3): δ3.60 (3H), 3.90 (2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]=[C:12](SC)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([C:37]([NH:39][NH2:40])=O)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[N:26][CH:27]=1)#[N:21]>C(O)CCC>[Si:1]([O:8][CH2:9][C@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]2[C:37]([C:34]3([C:31]4[CH:32]=[CH:33][C:28]([C:25]5[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][N:26]=5)=[CH:29][CH:30]=4)[CH2:36][CH2:35]3)=[N:39][N:40]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(-c2ccc(C3(C(=O)NN)CC3)cc2)nc1
Reactant: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(-c5ccc(C#N)cn5)cc4)CC3)n2CCS1
Temperature: 140 °C
Reaction time: 5 h
Yield: 53.8 %

Procedure:
The compound (418 mg, 1.31 mmol) obtained in Example 4-1) and the compound (364 mg, 1.31 mmol) obtained in Example 60-3) were dissolved in 1-butanol (5 mL), and the mixture was stirred at 140° C. for 5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 20%) to obtain the title compound (375 mg, 54%) in a white solid form.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:18]([O:37][CH3:38])=[C:19]([NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[C:25]([F:35])[CH:24]=3)[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[OH-].[Pd+2].[OH-]>[C:39]([C:17]1[C:18]([O:37][CH3:38])=[C:19]([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[C:25]([F:35])[CH:24]=2)[CH:20]=[C:15]([C:14]2[C:9](=[O:8])[NH:10][CH:11]=[CH:12][CH:13]=2)[CH:16]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: COc1c(NC(=O)c2ccc(NCC(F)(F)F)c(F)c2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1c(NC(=O)c2ccc(NCC(F)(F)F)c(F)c2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C
Reaction time: 1.5 h

Procedure:
step 4—To a solution of 320 (86 mg, 0.148 mmol) in a mixture of MeOH/EtOAc (2 mL and 1 mL, respectively) at RT was added 20% palladium (II) hydroxide on carbon (moist) (9 mg, 10 wt. %). The reaction mixture was stirred under 1 atm of H2 for 1.5 h. The reaction mixture was filtered through a plug of CELITE and the pad washed with EtOAc. The filtrate was concentrated to afford 72 mg (99%) of I-251 as a light pink solid.