Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][OH:22])=[CH:25][CH:26]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Yield: 87.6 %

Procedure:
Methyl 4-[(2-phenyl-1H-indol-1-yl)methyl]benzoate (2.8 g, 8.20 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and the solution was ice-cooled. To this solution was added dropwise a solution (13.5 mL, 20.3 mmol) of 1.5 mol/L diisobutylaluminum hydride in toluene. This solution was stirred under ice-cooling for 4 hr. An aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4-1:2) to give the title compound (2.25 g, yield 88%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.CN1CCCC1=O.[OH-].[K+].[C:44]1([SH:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O>[C:44]1([S:50][C:2]2[CH:34]=[CH:33][C:5]3=[N:6][N:7]([C:9]4[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)([CH3:25])[CH3:24])[C:10]=4[OH:32])[N:8]=[C:4]3[CH:3]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 90 °C
Yield: 94.7 %

Procedure:
To a stirred mixture of 75 g of 5-chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octyl-phenyl)-2H-benzotriazole and 105 g of N-methylpyrrolidone heated at 90° C. is added first 44.3 g of 45% aqueous potassium hydroxide solution over a 15-minute period then 20.4 g of thiophenol over another 15 minutes. The reaction mixture is then heated at 170-175° C. for four hours with water being removed by distillation. After cooling to 100° C., xylene and water are added and the resultant mixture is made acidic with 15% aqueous hydrogen chloride solution. The organic layer is separated and washed with water and then concentrated. The crude product residue is recrystallized from methanol to yield 82 g of the title compound as a pale yellow solid melting at 124-125° C.
Reaction SMILES: [OH:1][C@@H:2]([C:21]([CH3:27])([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])/[CH:3]=[CH:4]/[C@H:5]1[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][C@H:6]1[CH3:20].[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:28]([O:1][C@@H:2]([C:21]([CH3:26])([CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25])/[CH:3]=[CH:4]/[C@H:5]1[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][C@H:6]1[CH3:20])(=[O:30])[CH3:29]
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCC(C)(C)[C@@H](/C=C/[C@@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
A mixture of 156 mg of (8R,11R,12S,15R,5Z,13E)-15-hydroxy-11,16,16-trimethyl-9-oxoprosta-5,13-dien-1-oic acid, 100 mg of acetic, anhydride, 21 mg of 4-(dimethylamino)pyridine, and 2 ml of triethylamine was stirred at room temperature under a positive nitrogen atmosphere. After 16 hr, the reaction mixture was partitioned between ethyl acetate-water and the organic layer separated, dried (MgSO4), and condensed by rotary evaporation. The residual material was purified by chromatography over Sephadex LH-20 (hydroxypropylated beaded dextran) using chloroform/hexane (3:2) as the eluant to yield 112 mg (65%) of (8R,11R,12S,15R,5Z,13E)-15-acetyloxy-11,16,16-trimethyl-9-oxoprosta-5,13-dien-1-oic acid. [α]D25 -78.52 (CHCl3, c 1.02).
Reaction SMILES: [NH2:1][C:2]1[C:19]([C:20]#[C:21][Si](C)(C)C)=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[NH2:1][C:2]1[C:19]([C:20]#[CH:21])=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Yield: 77.7 %

Procedure:
To a solution of (S)-6-amino-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (308 mg, 0.83 mmol) in 20 mL THF/methanol (1:1 ratio) at 0° C. was added K2CO3 (344 mg, 2.5 mmol) added. After 7 minutes the solution was decanted from the solids and partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown oil was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a white solid (193 mg, 78%).
Reaction SMILES: O.[F:2][C:3]([F:20])([F:19])[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][N:8]1[N:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10]>[Zn].C(O)(=O)C>[F:19][C:3]([F:2])([F:20])[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][N:8]1[C:9](=[O:10])[NH:11][C:12](=[O:13])[CH2:14][NH:15]1
Reactant: O=c1cnn(Cc2cccc(C(F)(F)F)c2)c(=O)[nH]1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CNN(Cc2cccc(C(F)(F)F)c2)C(=O)N1
Yield: 49.6 %

Procedure:
A 1 liter three-necked flask equipped with a mechanical stirrer was charged with 300 ml of water and 60 ml of glacial acetic acid. 3 g of 1-(3'-trifluoromethylbenzyl)-6-aza uracil was added in one portion followed by the addition of 3.3 g of zinc powder in small portions. After the addition was terminated the mixture was stirred vigorously and refluxed for 36 hours after which the mixture was cooled in ice and filtered. The crystals obtained were recrystallized from iso-propanol to give 1.5 g (50%) of 2-(3'-trifluoromethylbenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 152°.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26]Br)[CH3:21])[C:14]=3[Cl:30])[C:5]2=[N:4][C:3]=1[CH3:31].[CH3:32][NH2:33]>CO>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][NH:33][CH3:32])[CH3:21])[C:14]=3[Cl:30])[C:5]2=[N:4][C:3]=1[CH3:31]
Reactant: CN
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CBr)c3Cl)cccn2c1Br
Solvent: CO
Product: CNCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-[N-(bromoacetylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg) and 30% solution of methylamine in methanol (2 ml) was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(sarcosylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (103 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C:35]1([O:38]C(=O)C)[CH2:37][CH2:36]1)=[O:34]>>[OH:38][C:35]1([C:33]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:34])[CH2:37][CH2:36]1
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: O=C(N[C@H]1CC[C@@H](NC(=O)C2(O)CC2)CC1)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A156) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][CH2:8][C:9]([OH:11])=O)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.C(N)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C=O)C.CO>[O:11]=[C:9]1[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:12][C:13]2[S:14][CH:15]=[CH:16][C:17]1=2
Reactant: CCOC(=O)N(CCC(=O)O)Cc1cccs1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: ClCCl
Solvent: NCc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(=O)c2ccsc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
To a solution of Compound 1042 (5.0 g, 19.43 mmol) in methylene chloride (200 mL) containing one drop of DMF at 0° C. was added oxalyl chloride (2.03 mL, 23.32 mmol). The reaction mixture was stirred at RT until LCMS analysis (after a benzyl amine quench of the aliquot to be analyzed) indicated complete conversion to the intermediate acyl chloride. The reaction was concentrated by 50%, at which point solid aluminum chloride (5.18 g, 38.86 mmol) was added. The reaction was then stirred at room temperature overnight. The reaction was cooled to 0° C. and methanol (50 mL) carefully added. After gas evolution had ceased, 100 mL of saturated sodium bicarbonate was added carefully. After gas evolution had ceased the reaction was extracted with 10% n-BuOH in chloroform, concentrated, and the residue purified by silica chromatography (0-50% ethyl acetate/hexanes) to give ethyl 4-oxo-5,6-dihydro-4H-thieno[2,3-c]azepine-7(8H)-carboxylate (Compound 1043) as a pale tan oil (1.27 g, 27%).
Reaction SMILES: [F:1][CH:2]([F:15])[C:3](=[N:13]O)[NH:4][C:5]1[C:10]([CH3:11])=[N:9][CH:8]=[C:7]([CH3:12])[N:6]=1.[OH-].[NH4+]>OP(O)(O)=O>[F:1][CH:2]([F:15])[C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[N:9][CH:8]=[C:7]([CH3:12])[N:6]2[N:13]=1
Reactant: Cc1cnc(C)c(NC(=NO)C(F)F)n1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ncc(C)n2nc(C(F)F)nc12
Temperature: 130 °C
Reaction time: 18 h

Procedure:
A mixture of 2,2-difluoro-N′-hydroxy-N-(3,6-dimethylpyrazin-2-yl)ethanimidamide (3.05 g, 14.1 mmol, from Step D) and superphosphoric acid (100 mL) was heated to 130° C. with stirring for 18 h. The solution was added to ice and neutralized by addition of ammonium hydroxide. The dark aqueous solution was extracted three times with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography (35% ethyl acetate/hexane) afforded the title compound as a yellow solid. LC/MS 199 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:29]=[CH:28][N:27]([CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[N:26]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=[N:12]2)[C:8]([NH:24][C:25]2[CH:29]=[CH:28][N:27]([CH2:30][C:31]([OH:33])([CH3:32])[CH3:34])[N:26]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(OC2CCCC2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(OC3CCCC3)cc2=O)n1
Yield: 23 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-(4-cyclopentyloxy-6-oxo-6H-pyridazin-1-yl)-propionic acid (Intermediate 61) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-(4-cyclopentyloxy-6-oxo-6H-pyridazin-1-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (49.8 mg, 23%) as a white solid; ES+-HRMS m/e calcd for C24H35N5O4 [M+Na+] 480.2581, found 480.2582. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.05 (m, 1H), 1.25-1.80 (m, 14H), 1.83-2.00 (m, 3H), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 4.86 (m, 1H), 5.45 (dd, J=4.3, J=11.1 Hz, 1H), 6.24 (d, J=2.8 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.76 (d, J=2.8 Hz, 1H), 10.74 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:24])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([Cl:23])=[CH:12][CH:11]=3)[O:4][N:3]=1.[CH3:25][S:26]([CH2:29][CH2:30][O:31][C:32](=O)[O:33]N1C(=O)CCC1=O)(=[O:28])=[O:27]>>[CH3:25][S:26]([CH2:29][CH2:30][O:31][C:32](=[O:33])[NH:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:24])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([Cl:23])=[CH:12][CH:11]=3)[O:4][N:3]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)CCOC(=O)ON1C(=O)CCC1=O
Reactant: Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Product: CS(=O)(=O)CCOC(=O)Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1

Procedure:
This was prepared according to Example 64 from 3-(3-amino-isoxazol-5-yl)-6-chloro-4-phenyl-1H-quinolin-2-one and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 2-methanesulfonyl-ethyl ester. 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 10.78 (s, 1H), 7.66 (dd, 1H), 7.48 (m, 4H), 7.32 (m, 2H), 6.96 (d, 1H), 6.89 (s, 1H), 4.42 (t, 2H), 3.56 (t, 2H), 3.12 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C22H18ClN3O6S 487.0, found 488.0 (M+H).
Reaction SMILES: C([O-])(O)=O.[Na+].Cl.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Cl)[CH:8]=1.[CH2:15]([O:17][P:18]([O:22]CC)[O:19][CH2:20][CH3:21])[CH3:16]>>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][P:18](=[O:22])([O:19][CH2:20][CH3:21])[O:17][CH2:15][CH3:16])[CH:8]=1
Reactant: CCOP(OCC)OCC
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOP(=O)(Cc1cccnc1)OCC
Temperature: 85 °C
Yield: 26.2 %

Procedure:
To a stirred solution of saturated NaHCO3 was added 3-picolyl chloride hydrochloride (8.2 g, 50 mmol). After gas evolution ended, the mixture was extracted with CH2Cl2. The organic phase was dried (MgSO4) and concentrated in vacuo. To the resulting residue was added triethylphosphite (8.3 g, 50 mmol) and the neat mixture was stirred and heated at 85° C. overnight. The mixture was cooled and purified by flash column chromotography on silica gel eluting with 5% MeOH--CH2Cl2 to afford 3.0 g of diethyl 3-pyridylmethylphosphonate as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH:29]1([N:32]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37](B4OC(C)(C)C(C)(C)O4)[CH:38]=3)[C:33]2=[O:50])[CH2:31][CH2:30]1>>[CH:29]1([N:32]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:19]4[C:16]5[CH:17]=[N:18][C:13]([C:3]6[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=6[F:12])=[CH:14][C:15]=5[NH:21][N:20]=4)[CH:38]=3)[C:33]2=[O:50])[CH2:31][CH2:30]1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(C4CC4)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (Example 21, Step 2) LCMS (M+H)+=463.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[CH:27][C:28](I)=[C:29]([CH3:31])[CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:28]1[CH:27]=[CH:26][C:25]([Br:24])=[CH:30][C:29]=1[CH3:31])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Br)ccc1I
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: Cc1cc(Br)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 5-bromo-2-iodotoluene in analogy to Example 1a): MS (ISP): 473.9 (M+H)+ and 373.9 ((M-Boc)+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:21]=1[C:22](N(OC)C)=[O:23]>>[CH3:18][O:19][C:20]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:21]=1[C:22]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:23]
Reactant: COc1ccc(C(=O)N(C)OC)c(OC)c1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)c(OC)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 2,4-dimethoxy-N-methoxy-N-methylbenzamide. It is used in crude form in the following reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[N:7]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:25][CH3:26]>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[N:7]3[CH2:16][CH2:15][N:14]([CH2:25][CH3:26])[CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CCNCC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCN1CCc2nc3cc(Br)ccc3c(=O)n2CC1

Procedure:
A solution of 8-bromo-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one (100 mg, 0.34 mmol), K2CO3 (188 mg, 1.36 mmol) and excess iodoethane in acetone (20 mL) was stirred at room temperature overnight. Then the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3×70 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give 100 mg of the desired product. MS (ESI): 322, 324 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:15]C(=O)C(F)(F)F)=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[BH4-].[Na+].O>C(O)C>[NH2:15][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:14][C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: Cc1ccc(NC(=O)C(F)(F)F)c(C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)c(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a suspension of tert-butyl 5-methyl-2-(2,2,2-trifluoroacetamido)benzoate (19.78 mmol, 6.0 g) in ethanol (19 ml) was cooled with a water-iced bath. NaBH4 (39.57 mmol, 1.50 g) was added in portions and the mixture was stirred at room temperature for 3 hours. Water (40 ml) was added slowly and evaporated. The solid was dissolved with CHCl3 and washed with water and brine. The organic phase was evaporated affording 3.73 g (yield 91%) of the expected product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:6]([CH3:16])[CH:5]=[CH:4][C:3]=1[S:17](Cl)(=[O:19])=[O:18].[CH3:21][NH:22][CH3:23]>O1CCCC1>[CH3:21][N:22]([CH3:23])[S:17]([C:3]1[CH:4]=[CH:5][C:6]([CH3:16])=[C:7]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[C:2]=1[CH3:1])(=[O:19])=[O:18]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)Cl)c(C)c1NS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(C)C)c(C)c1NS(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 69.7 %

Procedure:
2,4-Dimethyl-3-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.4 g) was added to tetrahydrofuran (20 ml) containing dimethylamine (0.6 g), and the resultant mixture was allowed to stand overnight at room temperature. The reaction mixture was concentrated, admixed with 5% hydrochloric acid and extracted with chloroform. The extract was washed with 5% hydrochloric acid and water in order, dried over anhydrous magnesium sulfate and concentrated to give an oily substance, which was purified by column chromatography with silica gel (150 ml) to give 1.0 g of N,N-dimethyl-2,4-dimethyl-3-(trifluoromethanesulfonamido)benzenesulfonamide. M.P., 70.5°-72° C.
Reaction SMILES: [OH-].[K+].Br[CH2:4][CH:5]([CH3:7])[CH3:6].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1.O>CS(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][CH2:4][CH:5]([CH3:7])[CH3:6])=[CH:11][CH:10]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(C)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)COCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Potassium hydroxide (1.32 g) and 1-bromo-2-methylpropane (1.04 mL) were added to a solution of 2-(4-bromophenyl)ethylalcohol (140 μL) in dimethyl sulfoxide (2 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was filtered through diatomaceous earth and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give the title compound as a colorless oil (180 mg, 70%).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:40]=[CH:39][O:38][CH:37]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:40]=[CH:39][O:38][CH:37]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccoc1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccoc1
Reaction time: 2 h
Yield: 92 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)furan-3-sulfonamide (20 mg, 0.036 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 16 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)furan-3-sulfonamide (percentage yield: 92%), was obtained.