Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:18]2[C:19]3[CH:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[C:15]([N+:20]([O-:22])=[O:21])=[CH:16][CH:17]=2)[CH2:12][C@H:11]([NH:23][C:24](=[O:30])[N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:10][N:9]4[CH3:31])[CH2:5]1)(=O)C.N.C(Cl)Cl>Cl>[CH3:31][N:9]1[C@H:8]2[C@@H:13]([C:14]3[C:15]([N+:20]([O-:22])=[O:21])=[CH:16][CH:17]=[C:18]4[C:19]=3[CH:6]([CH2:7]2)[CH2:5][NH:4]4)[CH2:12][C@H:11]([NH:23][C:24](=[O:30])[N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:10]1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c([N+](=O)[O-])ccc4c3C(C[C@H]2N(C)C1)CN4C(C)=O
Agent: Cl
Agent: N
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c([N+](=O)[O-])ccc4c3C(CN4)C[C@H]2N(C)C1
Yield: 56.8 %

Procedure:
One millimole of 3-(1-acetyl-2,3-dihydro-6-methyl-12-nitro-8α-ergolinyl)-1,1-diethylurea, dissolved in 5 ml of 1N hydrochloric acid, is heated for one hour to 95° C. After cooling, the mixture is made alkaline with dilute ammonia solution, combined with methylene chloride, and extracted. After drying the organic phase, the latter is evaporated, thus obtaining 220 mg of 3-(2,3-dihydro-6-methyl-12-nitro-8α-ergolinyl)-1,1-diethylurea.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:5][F:6])=[O:4].[F:7][C:8]1[CH:9]=[CH:10][C:11](O)=[C:12]([C:14](=[O:16])[CH3:15])[CH:13]=1.N1CCCC1>CO>[F:7][C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[O:4][C:3]([CH2:5][F:6])([CH2:2][F:1])[CH2:15][C:14]2=[O:16]
Reactant: O=C(CF)CF
Reactant: CC(=O)c1cc(F)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC(CF)(CF)Oc2ccc(F)cc21
Temperature: 60 °C
Yield: 67.1 %

Procedure:
A solution of 1,3-difluoroacetone (4.90 g, 52.1 mmol), MeOH (100 mL), and 1-(5-fluoro-2-hydroxyphenyl)ethanone (6.69 g, 43.4 mmol, Aldrich Chemical) was stirred at ambient temperature and pyrrolidine (4.31 mL, 52.1 mmol) was added. The reaction was heated at 60° C. for 21 hours, then concentrated and purified by silica gel chromatography (gradient elution, 0-25% EtOAc/hexanes) to provide the title compound (6.70 g, 29.1 mmol, 67%) as a brown oil. MS (DCI) m/z 248 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].ClC1C(C(OO)=[O:32])=CC=CC=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([S:22]([CH3:23])=[O:32])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: O=C(OO)c1ccccc1Cl
Reactant: CSc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reaction time: 48 h
Yield: 110 %

Procedure:
A solution of amide from Example 38 (0.2 g) in chloroform (5 ml) was treated with 70% m chloroperbenzoic acid (0.14 g). The reaction mixture was stirred for two days, calcium hydroxide (0.09 g) added and after stirring for a further 0.5 h the mixture was filtered. The filtrate was concentrated under reduced pressure to yield the sub-title product as a white solid (0.23 g).
Reaction SMILES: [C:1]1([C:7]2[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[C:10](=[O:16])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].C1(P(O[NH2:38])(C2C=CC=CC=2)=O)C=CC=CC=1.CN(C=O)C>C1COCC1.CCOC(C)=O>[NH2:38][N:9]1[C:10](=[O:16])[C:11]2[CH:15]=[CH:14][S:13][C:12]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1
Reactant: O=c1[nH]nc(-c2ccccc2)c2sccc12
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nn1nc(-c2ccccc2)c2sccc2c1=O
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A mixture of Example 9A (69.1 mg, 0.303 mmol) and KOtBu (1 M in THF, 0.35 mL, 0.35 mmol) in THF (1.5 mL) was stirred for 60 min, and O-(diphenylphosphoryl)hydroxylamine (81.0 mg, 0.348 mmol) and DMF (1.5 mL) were added and stirred 1 hour. The mixture was diluted with EtOAc, washed with 1 N NaOH and water, dried (Na2SO4), filtered, and concentrated to give the title compound as a white solid (62.6 mg), which was used without purification. 1H NMR (300 MHz, DMSO-d6) δ 8.16 (d, 1H), 7.89-7.82 (m, 2H), 7.75 (d, 1H), 7.64-7.51 (m, 3H), 6.65 (s, 2H); LC/MS (APCI) M/Z 244.1 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]Br.[S:9]([O-:12])([O-:11])=[O:10].[Na+].[Na+]>O>[CH2:2]([S:9]([OH:12])(=[O:11])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:9]([OH:12])(=[O:11])=[O:10]
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCCBr
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)CCCCCCS(=O)(=O)O
Yield: 100 %

Procedure:
1,6-dibromohexane (25 ml, 0.16 mol) and sodium sulfite (45.5 g, 0.36 mol) in water (85 ml) were heated at reflux for 16 h. The mixture was then filtered whilst hot and the filtrate was concentrated under reduced pressure to yield the hexane 1,6-disulfonic acid (39.3 g, 0.16 mol) which was used without further purification. The diacid was ground into a fine powder and powdered phosphorus pentachloride (84 g, 0.4 mol) was added carefully. After an initial vigorous reaction, the mixture was heated with mechanical stirring at 110° C. for 90 min., yielding a mustard coloured solution. On cooling the mixture was cautiously triturated with ice/water and the resultant solid filtered off. The solid was washed with water and dried under vacuum to afford the disulfonyl chloride hexane compound as a cream yellow solid (38.6 g, 96%). This material was used without purification in the next step.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[C@@:2]1([CH2:12][CH2:11][C@H:7]([C:8]([OH:10])=O)[C:4]1([CH3:6])[CH3:5])[CH3:3].C(Cl)(C)=O.CC(OC(C)=O)=O>>[C:1]1(=[O:13])[O:14][C:8](=[O:10])[CH:7]2[CH2:11][CH2:12][C@@:2]1([C:4]2([CH3:5])[CH3:6])[CH3:3]
Reactant: CC1(C)[C@@H](C(=O)O)CC[C@@]1(C)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Product: CC1(C)C2CC[C@@]1(C)C(=O)OC2=O

Procedure:
A mixture of (1R-cis)-1,2,2-Trimethylcyclopentane-1,3-dicarboxylic acid)[(1R,3S)-camphoric acid](40.0 g), AcCl (23.5 g), and Ac2O (81.6 g) was heated under reflux for 3 hr. The mixture was concentrated in vacuo, dissolved in CHCl3, washed with sat. NaHCO3, brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was triturated with i-Pr2O to give (1R)-1,8,8-Trimethyl-3-oxabicyclo[3.2.1]octane-2,4-dione[(1R)-camphoric anhydride (34.0 g) as crystals.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:25]([O:27][C:28]([N:30]=[C:31]=[S:32])=[O:29])[CH3:26]>O1CCCC1>[NH2:20][C:18]([C:17]1[CH:16]=[N:15][N:14]2[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:4]=3)=[CH:10][CH2:11][N:12]([C:31]([NH:30][C:28](=[O:29])[O:27][CH2:25][CH3:26])=[S:32])[C:13]=12)=[O:19]
Reactant: CCOC(=O)N=C=S
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)N1CC=C(c2cccc(C(F)(F)F)c2)n2ncc(C(N)=O)c21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3.0 g of 4,5-dihydro-7[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared as described in Example 4) in 90 ml of dry tetrahydrofuran, cooled to -78° C. was added 584 mg of sodium hydride (60% dispersion in mineral oil) in one portion. The reaction mixture was stirred at -78° C. for one hour followed by the addition of 2.55 g of ethoxycarbonyl isothiocyanate. The mixture was stirred at -78° C. for 2 hours then was allowed to warm slowly to room temperature. The reaction mixture was stirred at room temperature for 48 hours, then was quenched with water and extracted with ether. The aqueous layer was separated, neutralized with 5% hydrochloric acid and extracted with chloroform. The chloroform extracts were evaporated in vacuo to give the product of the example as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[N:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[NH2:2].[Br:40]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:40][C:23]1[CH:22]=[C:21]([NH:20][C:5]2[C:4]([C:1](=[O:3])[NH2:2])=[N:9][CH:8]=[C:7]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[N:6]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a mixture of tert-butyl 4-(4-{[3-carbamoyl-6-(3-nitrophenoxy)pyrazin-2-yl]amino}phenyl)piperazine-1-carboxylate (1 g) and chloroform (30 mL) was added N-bromosuccinimide (349 mg), followed by stirring at room temperature for 30 minutes. Then, N-bromosuccinimide (100 mg) was added thereto, followed by further stirring at room temperature for 30 minutes. To the reaction mixture was added silica gel, and the solvent was evaporated under reduced pressure and then purified by silica gel column chromatography (eluent; chloroform) to obtain tert-butyl 4-(2-bromo-4-{[3-carbamoyl-6-(3-nitrophenoxy)pyrazin-2-yl]amino}phenyl)piperazine-1-carboxylate (682 mg) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:16][C:17]1[N:21]([CH:22]([CH3:24])[CH3:23])[N:20]=[N:19][N:18]=1.O>CN(C)C=O.ClCCl>[CH:22]([N:21]1[C:17]([CH2:16][N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)=[N:18][N:19]=[N:20]1)([CH3:24])[CH3:23]
Reactant: CC(C)n1nnnc1CCl
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)n1nnnc1Cn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.5 Grams of 5-nitroindole was dissolved in 70 ml of dimethylformamide, then 370 mg of sodium hydride (in oil) was added thereto, the mixture was stirred under nitrogen gas stream at 60° C. for 1 hour. Under cooling at 0° C., 1.63 g of 5-chloromethyl-1-isopropyl-1,2,3,4-tetrazole was added, the reaction mixture was stirred at room temperature for 4.5 hours. After the reaction was finished, water was added to the reaction mixture, then the separated crystals were collected by filtration and washed with water. The crystals were dissolved in dichloromethane, the solution was dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue obtained was subjected to a silica gel column chromatography (eluent: dichloromethane→3% methanol/dichloromethane), there was obtained 2.3 g of 1-(1-isopropyl-1,2,3,4-tetrazol-5-ylmethyl)-5-nitroindole as in the form of yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=1)[CH2:13][CH2:14][CH3:15].Cl>S(Cl)(Cl)=O>[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:6]([C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=2)[C:1]#[N:2])=[O:8])=[C:19]([OH:23])[CH:18]=1)[CH2:13][CH2:14][CH3:15]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: CCCCOc1cccc(OC)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCCCOc1ccc(C(=O)c2cccc(C#N)c2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.5 %

Procedure:
First, 3-cyanobenzoic acid (20 grams) is heated under reflux for 1.5 hours in thionyl chloride (100 ml). The excess thionyl chloride is removed by distillation. The crude acid chloride which remains is diluted with nitrobenzene (200 ml). Anhydrous aluminum chloride (21.75 g) is added and the mixture cooled in an ice bath. Then, 1-butoxy-3-methoxybenzene (20 g, 0.11 mole) is added in one portion. The reaction mixture is stirred at room temperature overnight and then heated to 105° C. for 2 hours. The resulting mixture is cooled and poured into a mixture of ice water (1000 ml) and concentrated hydrochloric acid (100 ml). The product is extracted with ether (3×300 mls). The extract was dried over MgSO4, filtered and evaporated to dryness. The residual dark oil is chromatographed on silica gel (hexane:ether at 80:20) to yield 3-(4-butoxy-2-hydroxybenzoyl)benzonitrile (1.8 g) followed by 3-(2-hydroxy-4-methoxybenzoyl)benzonitrile (2.75 g). The 3-(4-butoxy-2-hydroxybenzoyl)benzonitrile thereby obtained, is heated under reflux in a mixture of acetic acid (18 g) and concentrated hydrochloric acid (18 g) for a hours. The resulting mixture is diluted with water (100 ml) and extracted with methylene chloride (3×50 ml). The extract is dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is recrystallized from heptane/ethanol to yield 3-(4-butoxy-2-hydroxybenzoyl)benzoic acid (1.13 g), m.p. 175° C.
Reaction SMILES: Br[CH:2]1[CH2:20][CH2:19][C:5]2=[CH:6][C:7]3[C:8]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[C:3]1=[O:21].[C:22]([O:26][C:27]([N:29]1[CH2:33][C@@H:32]([CH3:34])[CH2:31][C@H:30]1[C:35]([OH:37])=[O:36])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[CH3:34][C@@H:32]1[CH2:33][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[C@H:30]([C:35]([O:37][CH:2]2[CH2:20][CH2:19][C:5]3=[CH:6][C:7]4[C:8]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:9]=5[CH2:10][O:11][C:12]=4[CH:13]=[C:4]3[C:3]2=[O:21])=[O:36])[CH2:31]1
Reactant: O=C1c2cc3c(cc2CCC1Br)-c1ccc(Cl)cc1CO3
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@@H](C(=O)OC2CCc3cc4c(cc3C2=O)OCc2cc(Cl)ccc2-4)N(C(=O)OC(C)(C)C)C1
Reaction time: 18 h
Yield: 70.5 %

Procedure:
To a solution of 9-bromo-3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (1.32 g, 3.63 mmol) in MeCN (40 mL) was added (2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (1.0 g, 4.36 mmol) and DIPEA (0.7 mL, 3.99 mmol). After stirring for 18 h, the solution was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 40% EtOAc/hexanes) to afford (2S,4S)-1-tert-butyl 2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl) 4-methylpyrrolidine-1,2-dicarboxylate (1.31 g, 70%).
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[N:14]=2)=[CH:4][C:3]=1[CH3:17].[F:18][C:19]1[CH:20]=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[C:23]2[C:27]=1[C@H:26]([O:28][C:29]1[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=1)[CH2:25][CH2:24]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:17][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[N:14]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:22]1[CH:21]=[CH:20][C:19]([F:18])=[C:27]2[C:23]=1[CH2:24][CH2:25][C@H:26]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1
Reactant: Cc1cc(-c2ccc(=O)n(C)n2)cc(C)c1I
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccc(=O)n(C)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 6-(4-iodo-3,5-dimethylphenyl)-2-methylpyridazin-3(2H)-one and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.18 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]1[CH:8]=[C:7]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:6]=[N:5]1>CC(O)=O.[Zn]>[OH:19][CH:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:17](=[O:18])[N:9]1[C:7]1[CH:6]=[N:5][N:4]([CH2:3][C:2]([F:21])([F:20])[F:1])[CH:8]=1
Reactant: O=C1c2cccnc2C(=O)N1c1cnn(CC(F)(F)F)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1c2cccnc2C(O)N1c1cnn(CC(F)(F)F)c1
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 68.9 %

Procedure:
As shown in step 17-i of Scheme 17, to 6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (Compound 2048, 2.32 g, 7.832 mmol) in AcOH (30 mL) at 23° C. was added Zn (2.561 g, 39.16 mmol). After stirring for 20 minutes at 23° C., the reaction mixture was filtered through a glass frit, and the filtrate was concentrated. The residue was dissolved/suspended in hot EtOH (40 mL). The resulting mixture was cooled, treated with Et2O (50 mL). The resulting precipitate was collected by filtration and the mother liquor was concentrated under reduced pressure and the resulting solid recrystallized from hot EtOH (20 mL) and Et2O to give additional 7-hydroxy-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 2055, 1.61 g total) as a yellow solid: ESMS (M+H) 299.26; 1H NMR (DMSO-d6, 300 MHz) δ 8.83 (dd, J=3, 6 Hz, 1H), 8.32 (s, 1H), 8.15 (dd, J=3, 9 Hz, 1H), 7.94 (s, 1H), 7.61 (dd, J=6, 9 Hz, 1H), 7.13 (d, J=9 Hz, 1H), 6.21 (d, J=9 Hz, 1H), 5.20 (q, J=9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[OH:9])=[CH:4][CH:3]=1.[Na].C1(C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O.[I-].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(#N)C>[CH2:41]([N:14]1[CH:13]=[CH:12][N:11]=[C:10]1[C:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[OH:9])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: BrCc1ccccc1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ncc[nH]1
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1nccn1Cc1ccccc1
Reaction time: 4 h

Procedure:
A solution of 19.2 g of α,α-bis(p-chlorophenyl)imidazole-2-methanol (prepared according to Example III B) and 3 g of sodium hydroxyde in 250 ml. of acetonitrile was refluxed for one hour with stirring. Then 500 mg of picric acid, a few crystals of potassium iodide and a solution of 11.3 g of benzyl bromide in 100 ml. of acetonitrile were added. Refluxing was then continued for 4 hours with stirring. The reaction mixture was kept standing overnight. The precipitate formed was filtered off and dissolved in 3 liter of diethyl ether. This solution was washed with a saturated sodium chloride solution, decolorized with active charcoal, dried over sodium sulphate and concentrated. The residue was crystallised from a mixture of methanol and diethyl ether. 1-Benzyl-α,α-bis(p-chlorophenyl)imidazole-2-methanol was obtained. Melting point 167°-168° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:18])([F:17])[C:9]1[S:10][CH:11]=[C:12]([C:14]([O-:16])=O)[N:13]=1.[Li+].[NH2:20][C:21]1[C:26]([Cl:27])=[C:25]([O:28][CH3:29])[CH:24]=[CH:23][C:22]=1[C:30](=[O:32])[CH3:31]>C(Cl)Cl.CN(C=O)C.O1CCOCC1>[C:30]([C:22]1[C:21]([NH:20][C:14]([C:12]2[N:13]=[C:9]([C:8]([F:7])([F:18])[F:17])[S:10][CH:11]=2)=[O:16])=[C:26]([Cl:27])[C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:32])[CH3:31]
Reactant: O=C([O-])c1csc(C(F)(F)F)n1
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(C(C)=O)c(NC(=O)c2csc(C(F)(F)F)n2)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Oxalyl chloride (1.9 mL, 1.4 eq.) was added dropwise under nitrogen at 0° C. to a suspension of compound 252 (4 g, 1.2 eq.) in DCM (120 mL) and DMF (few drops). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for additional 3 hrs. The solid was removed by filtration under nitrogen and the filtrate was evaporated to give a yellow oil. This oil was solubilised in dioxane (30 mL) and added under nitrogen to a solution of 6-acetyl-2-chloro-3-methoxy aniline 201d (3.26 g, 1 eq.) in 1,4-dioxane (60 mL). The reaction mixture was stirred at room temperature for 3 days. The solvent was removed under reduced pressure, the residue was solubilised in dichloromethane, washed with water, dried over Na2SO4 and concentrated in vacuum. The crude oil was triturated in MeOH/Et2O mixture to give the compound 254a as a white solid in 69% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 2.59 (s, 3H), 4 (s, 3H), 6.90 (d, J=8.75 Hz, 1H), 7.70 (d, J=8.75 Hz, 1H), 8.44 (s, 1H), 10.28 (s, 1H); 19F NMR (CDCl3, 376 MHz): δ (ppm) −61.08 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH3:34])=[C:17]([NH:20][C:21](=[O:31])[CH2:22]P(OCC)(OCC)=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:52][N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[CH:58]=O>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH3:34])=[C:17]([NH:20][C:21](=[O:31])/[CH:22]=[CH:58]/[C@@H:54]4[CH2:55][CH2:56][CH2:57][N:53]4[CH3:52])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Reactant: CN1CCC[C@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/[C@@H]1CCCN1C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 63.8 %

Procedure:
N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 7b (100 mg, 0.20 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (400 μL, 0.40 mmol), and the mixture was stirred for 45 minutes, added with (2S)-1-methylpyrrolidine-2-carbaldehyde 1b (100 mg, 0.85 mmol). After stirring for another 1 hour, the reaction mixture was warmed up to room temperature and stirred for 12 hours. The reaction mixture was added with water (1 mL) and methanol (1 mL), extracted with dichloromethane (100 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, then the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enamide 7 (60 mg, yield 65.2%) as a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[N:15][N:16]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:12]([NH:29][C:30]([C:32]2[N:33]=[C:34]([CH2:37]Cl)[S:35][CH:36]=2)=[O:31])[CH:11]=1>C(#N)C>[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[N:15][N:16]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:12]([NH:29][C:30]([C:32]2[N:33]=[C:34]([CH2:37][N:4]3[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]3)[S:35][CH:36]=2)=[O:31])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(NC(=O)c4csc(CCl)n4)cc(Br)cc32)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ncc3c(NC(=O)c4csc(CN5C[C@@H](C)O[C@@H](C)C5)n4)cc(Br)cc32)cc1
Reaction time: 8 h

Procedure:
Acetonitrile (15 mL) and (2R,6S)-2,6-dimethylmorpholine (1.4 ml) were added to N-{6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-yl}-2-(chloromethyl)-1,3-thiazole-4-carboxamide (2 g) and the reaction mixture was refluxed for 3 h. On cooling a solid precipitated. The mixture was diluted with acetonitrile (15 ml) and the solid was collected by filtration, washing with acetonitrile. The solid was dried on the vacuum pump overnight to give title compound (1.86 g).