Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:14][C:13]2[C:12]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[CH:20][CH:19]=3)=[N:11][CH:10]=[N:9][C:8]=2[CH:7]=1.CS(Cl)(=O)=O.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[N:42]1([CH2:2][CH2:3][C:4]#[C:5][C:6]2[S:14][C:13]3[C:12]([NH:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:36])[C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=5)=[CH:20][CH:19]=4)=[N:11][CH:10]=[N:9][C:8]=3[CH:7]=2)[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: O=C(Nc1ccc(CCNc2ncnc3cc(C#CCCO)sc23)cc1)c1cccc(C(F)(F)F)c1
Reactant: C1CCNC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(CCNc2ncnc3cc(C#CCCN4CCCC4)sc23)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 23.1 (0.27 mmol) in dichloromethane was added sequentially TEA (3.0 equiv.) and methanesulfonyl chloride (2.5 equivalents). After stirring at room temperature for 2 hours, excess pyrrolidine (−5.0 equivalent) was added and the reaction was heated at 40° C. until starting material is consumed. The reaction was cooled, concentrated to dryness and purified by flash column chromatography on silica gel to provide N-(4-{2-[6-(4-pyrrolidin-1-yl-but-1-ynyl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethyl}-phenyl)-3-trifluoromethyl-benzamide (compound 23.2).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1.C1C2CCC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:9]2[CH:8]=[CH:7][C:6]3[CH:19]=[C:2]([SH:1])[CH:3]=[CH:4][C:5]=3[S:11][C:10]=2[CH:12]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(S)cc1C=C2
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Product: OCc1ccc2c(c1)Sc1ccc(S)cc1C=C2

Procedure:
Repeat the process of Example 1, substituting an equivalent quantity of 8-mercaptodibenzo[b,f]thiepin-3-carboxylic acid for the 10,11-dihydro-dibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:23])[C:11]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[F:8][C:7]1[C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH:24]=[O:25])[CH:27]=2)=[CH:3][C:4]([CH2:9][N:10]([CH3:23])[C:11]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:12])=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(Br)c2)c1
Reactant: O=Cc1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Temperature: 130 °C
Yield: 86.3 %

Procedure:
To a solution of methyl 3-{[[(3-bromo-4-fluorophenyl)methyl]-(methyl)amino]carbonyl}benzoate (0.20 g, 0.526 mmol) in p-dioxane/H2O (4.5/1.5 mL) was added (4-formylphenyl)boronic acid (0.118 g, 0.789 mmol), Pd(PPh3)4 (0.030 g, 0.026 mmol), and K2CO3 (0.29 mL, 2.1 mmol). The mixture was heated in a microwave at 130° C. for 15 min. It was then filtered, concentrated and the concentrate purified by CombiFlash chromatograph to afford the title compound 0.184 g (86%). LC-MS m/z 406 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]1)#[CH:2].Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])=[CH:29][CH:28]=2)[N:17]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:12]([C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[C:2][C:20]2[C:21]([C:22]([F:23])([F:25])[F:24])=[CH:16][N:17]=[C:18]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])=[CH:31][CH:32]=3)[N:19]=2)[CH2:11][CH2:10]1)(=[O:13])[NH2:14]
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cc1
Temperature: 120 °C

Procedure:
A solution of 1-(2-ethynylphenyl)cyclopropanecarboxamide K6 (0.15 g, 0.81 mmol) in DMF (3 mL) was added to a reaction vessel containing tert-butyl 1-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate A80 (0.34 g, 0.81 mmol), PdCl2(PPh3)2 (0.028 g, 0.040 mmol) tri-tert-butylphosphonium tetrafluoroborate (0.023 g, 0.081 mmol) and copper(I)iodide (0.015 g, 0.081 mmol). The mixture was bubbled with nitrogen for 10 minutes before Et3N (1.5 mL) was added. The mixture was heated at 120° C. under microwave irradiation for 15 minutes. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Combiflash Rf, 0-100% EtOAc in cyclohexane) to give the title compound A81 as a yellow oil (0.26 g, 56%). LCMS-C: rt 5.80 min; m/z 566 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:5])[CH3:2].[CH:17]1([C:21]2[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]3[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=3)[S:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28](/[CH:27]=[CH:26]/[C:23]2[S:24][CH:25]=[C:21]([CH:17]3[CH2:20][CH2:19][CH2:18]3)[N:22]=2)[CH:29]=1)=[O:16])[CH3:2]
Reactant: CCOC(=O)c1ccccc1CCC(=O)O
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1CCC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reaction time: 16 h
Yield: 95.4 %

Procedure:
A solution composed of 0.44 g of 2-(ethoxycarbonyl)benzenepropanoic acid and 25 ml of methylene chloride was added to a solution composed of 0.51 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 0.4 g of N-ethyl-N-(dimethylaminopropyl)carbodiimide, 1.0 g of 4-dimethylaminopyridine and 25 ml of methylene chloride at 0° C. After 16 hr., the reaction mixture was washed with 30 ml of water, dried (MgSO4) and the solvents removed by rotary evaporation. The residual materials were recrystallized from ethyl ether to yield 0.87 g of (E)-2-[3-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-3-oxopropyl]benzoic acid ethyl ester; m.p.110°-111° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[CH:27][C:28]=4[F:30])[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[C:5]([O:41][CH3:42])[CH:4]=1)#[N:2].[OH:43]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[CH:27][C:28]=4[F:30])[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[C:5]([O:41][CH3:42])[CH:4]=1)(=[O:43])[NH2:2]
Reactant: OO
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)cc(F)c32)C1c1cccc(Cl)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)cc(F)c32)C1c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.3 g, 0.49 mmol) prepared in Example 75 in DMSO (15 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (1.1 g, 9.7 mmol), then aqueous solution (1N) of NaOH (4.9 mL, 4.9 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a white solid (Yield 0.2 g, 64%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH3:10].C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CO)ccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)ccc1Br
Yield: 93 %

Procedure:
To a solution of 2-bromo-5-hydroxymethyltoluene (87.4 g) in methylene chloride (350 ml) were added, under ice-cooling with stirring, trietylamine (72.7 ml) and 4-dimethylaminopyridine (DMAP)(500 mg), and then thereto was added t-butyldimethylsilyl chloride (65.5 g). The mixture was stirred at 0° C. for 15 minutes, and stirred at room temperature for 3 hours. The reaction mixture is filtrated, and the filtrate was concentrated under reduced pressure. To the residure was added water (100 ml), and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous hydrochloric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled away. The residue was purified by a reduced pressure distillation (110° C. to 115° C./0.4 mmHg) to give the title compound (127.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[C:9](=O)[CH3:10])=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])([O-])=O.[K+].[K+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[C:9](=[N:29][OH:30])[CH3:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCC(C(C)=O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC(C(C)=NO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 130 °C
Reaction time: 2 h

Procedure:
To a solution of N-(1-(3-(4-chlorophenyl)-2-oxopentan-3-yl)-1H-indol-4-yl)methanesulfonamide (200 mg, 0.49 mmol), as described in Example 23 Step A, in EtOH (5 mL) was added hydroxylamine hydrochloride (68 mg, 0.99 mmol) and K2CO3 (137 mg, 0.99 mmol). The mixture was stirred at 130° C. under microwave for 2 h. After removing the solvent, the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (10 mL) and brine (10 mL), dried over sodium sulfate, and then filtered. After removing the organic solvent, the residue was purified by silica gel chromatography eluting with PE/EA (10/1 to 5/1, v/v) to afford the title compound as a white solid. LC/MS m/z=441.9 [M+Na]+.
Reaction SMILES: O.NN.C([O:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:27][C@@H:26]1[O:39][N:40]1C(=O)C2=CC=CC=C2C1=O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)C.ClCCl.[Cl-].[Zn+2].[Cl-]>[NH2:40][O:39][C@@H:26]1[C@@H:25]([CH2:24][OH:23])[O:29][C@@H:28]([N:30]2[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:27]1
Reactant: Cc1cn([C@H]2C[C@H](ON3C(=O)c4ccccc4C3=O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Agent: NN
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](ON)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 0.5 h

Procedure:
Hydrazine monohydrate (7 mL) is added to a suspension of 5′-O-trityl-3′-O-phthalimido-thymidine (2.9 g; ca. 3 mmol nucleoside, contaminated with some Ph3P═O) in ethanol (30 mL), and the solution is heated under reflux for 2 h. The ethanol is removed in vacuo and the resulting mixture is partitioned between CH2Cl2 (100 mL) and aqueous NaCl (50% sat.; 100 mL). The organic phase is separated and concentrated in vacuo to give a colorless foam, which is redissolved in anhydrous dichloromethane (20 mL). A solution of zinc chloride etherate (1 M in Et2O; 30 mL; 30 mmol) is then added. After a few minutes, the product starts to precipitate. After 30 minutes, the solution is diluted with CH2Cl2 (100 mL) and the precipitate removed by filtration. The solids are partitioned between water (20 mL) and CH2Cl2 (20 mL). The aqueous phase is separated and lyophilized. The crude product is purified by reverse phase HPLC(C18, gradient 0-5% acetonitrile in water over 20 minutes) to give 3′-O-amino-thymidine (expected 340 mg; 44% overall) as a colorless foam. 1H-NMR (DMSO-d6; 300 MHz): δ(ppm)=1.77 (d, J=0.7 Hz, 3H); 1.97-2.07 (m, 1H); 2.29 (ddd, J=0.7, 5.9, 13.7 Hz, 1H); 3.50-3.66 (m, 2H); 3.99-4.03 (m, 1H); 4.16-4.20 (m, 1H); 5.08 (t, J=5.1 Hz, 1H); 6.10-6.16 (m, 3H); 7.73 (d, J=1.0 Hz, 1H); 11.27 (br s, 1H). 13C-NMR (DMSO-d6; 75 MHz): a (ppm)=12.3, 35.7, 62.1, 83.7, 83.7, 83.9, 109.5, 136.0, 150.5, 163.7.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1.CO.[OH-].[K+]>O>[F:1][C:2]([F:15])([F:16])[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(NCC(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(NCC(F)(F)F)cc1
Yield: 84.7 %

Procedure:
step d—To a solution of 124 (0.349 g, 1.497 mmol), MeOH (3 mL), H2O (1 mL) was added KOH (0.420 g, 7.48 mmol) and the resulting solution was heated at reflux for 1 h. The MeOH was evaporated and the residue diluted with H2O (15 mL) and acidified to pH of 2 with 6N HCl. The white precipitate was filtered, washed with H2O and air dried to afford 0.278 g (85%) of 126.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]1[N:25]=[C:24]2[C:20]([NH:21][C:22](=[O:34])[N:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:19]([C:35]([O:37]CC)=O)[N:18]=1)(C(C)(C)C)(C)C.[NH2:40]C1C(C(OCC)=O)=NC(NC2C=CC=C(CO[Si](C(C)(C)C)(C)C)C=2)=NC=1NC1C=CC=CC=1OC>ClCCl>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]1[N:25]=[C:24]2[C:20]([NH:21][C:22](=[O:34])[N:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:19]([C:35]([NH2:40])=[O:37])[N:18]=1
Reactant: CCOC(=O)c1nc(Nc2ccccc2CO[Si](C)(C)C(C)(C)C)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(Nc2cccc(CO[Si](C)(C)C(C)(C)C)c2)nc(Nc2ccccc2OC)c1N
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccccc3CO)nc21
Yield: 91 %

Procedure:
Ethyl 2-(2-((tert-butyldimethylsilyloxy)methyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-2-(3-((tert-butyldimethylsilyloxy)methyl)phenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.200 g, 0.382 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.433 g, 2.67 mmol) in dichloromethane (20 mL) were reacted according to General Procedure F and purified using biotage chromatography (10 to 90% EtOAc in hexanes) to afford the title compound (0.190 g, 91%). MS (ESI) m/z 550.5 [M+1]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[CH:20]12[CH2:26][CH:23]([NH:24][CH2:25]1)[CH2:22][NH:21]2>CC#N>[CH:20]12[CH2:26][CH:23]([NH:24][CH2:25]1)[CH2:22][N:21]2[C:11]1[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:19]=[C:9]2[N:10]=1
Reactant: C1NC2CNC1C2
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Solvent: CC#N
Product: Nc1nc(N2CC3CC2CN3)nc2nc(-c3ccco3)nn12
Temperature: 25 °C

Procedure:
2-Furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.7 mmol, 1 eq.; see J. Chem. Soc. Perkin Trans. 1, 801 (1995)) and 2,5-diaza-bicyclo[2.2.1]heptane (5 eq.) were suspended in 10 mL of CH3CN. The mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with water, brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (95% CH2Cl2, 4% MEOH, 1% Et3N) to afford 5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].C(N(CC)CC)C>ClCCl>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NCc1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e, 0.060 g, 0.202 mmol) in dichloromethane (2 mL) is added butyryl chloride (0.024 g, 0.222 mmol) and triethylamine (0.056 mL, 0.405 mmol), and the reaction is stirred at room temperature for 30 min. The reaction mixture is diluted with dichloromethane and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-butyramide as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 0.98 (t, J=7.5 Hz, 3H), 1.65-1.77 (m, 2H), 2.29 (t, J=7.5 Hz, 2H), 3.82 (s, 3H), 4.57 (s, 2H), 7.38 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.09 (t, J=2.1 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 367.1327 [(M+H)+ Calcd for C20H20N4OCl: 367.1326].
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@H:3]([OH:5])[CH3:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.O>N1C=CC=CC=1>[OH:5][C@H:3]([CH3:4])[CH2:2][CH2:1][O:6][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](O)CCO
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC[C@@H](C)O)cc1
Temperature: -25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
After adding pyridine (100 ml) to (R)-1,3-butanediol (86.0 g), the solution was cooled to −25° C. under nitrogen atmosphere. A solution of p-toluenesulfonyl chloride (200 g) in pyridine (200 ml) was slowly added dropwise thereto at a temperature ranging from −20 to −10° C. The mixture was stirred for 1 hour at a temperature ranging from −20 to −10° C. A small amount of water was added to the reaction mixture to stop the reaction and the solution was extracted with toluene and water. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain (R)-3-hydroxy-1-(p-toluenesulfonyloxy)butane (209 g) as light brown oil. The oil thus obtained was used in the next step as such without purification.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7]/[C:6](=[N:8]\[C:9](=[O:11])[CH3:10])/[N:5]([C:12]2[CH:22]=[CH:21][C:15]3[O:16][C:17]([F:20])([F:19])[O:18][C:14]=3[CH:13]=2)[CH:4]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[F:19][C:17]1([F:20])[O:16][C:15]2[CH:21]=[CH:22][C:12]([N:5]3[CH:4]=[C:3]([CH2:2][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[S:7]/[C:6]/3=[N:8]\[C:9](=[O:11])[CH3:10])=[CH:13][C:14]=2[O:18]1
Reactant: C1CCNC1
Reactant: CC(=O)/N=c1\sc(CCl)cn1-c1ccc2c(c1)OC(F)(F)O2
Product: CC(=O)/N=c1\sc(CN2CCCC2)cn1-c1ccc2c(c1)OC(F)(F)O2
Reaction time: 0.17 h

Procedure:
The allyl chloride (Example 24A, 16 mg, 46 μmol) was dissolved into pyrrolidine (200 μL) and stirred 10 minutes. Then the mixture was twice diluted with and concentrated from EtOAc, and partitioned between 2:1 EtOAc/hexanes (1.5 mL) and water (1 mL). The organic phase was separated and washed with water, dried (Na2SO4), and chromatographed on silica (2 to 5% MeOH/CH2Cl2) to give the titled compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.81 (4 H), 2.22 (3 H), 2.60 (4 H), 3.66 (2 H), 6.91 (1 H), 7.17 (2 H), 7.36 (1 H); MS (ESI) 382 (M+H)+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.C(O[C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34]#[N:35])=[CH:31][CH:32]=2)[NH:27][C:26]=1[C:36]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([Br:47])[CH:40]=1)([CH3:38])[CH3:37])=[O:24])C.O>CC#N>[Br:47][C:41]1[C:42]([O:45][CH3:46])=[CH:43][C:44]2[C:23](=[O:24])[C:25]3[C:33]4[C:28](=[CH:29][C:30]([C:34]#[N:35])=[CH:31][CH:32]=4)[NH:27][C:26]=3[C:36]([CH3:38])([CH3:37])[C:39]=2[CH:40]=1
Reactant: CCOC(=O)c1c(C(C)(C)c2ccc(OC)c(Br)c2)[nH]c2cc(C#N)ccc12
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1Br)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
Phosphorus pentoxide-methanesulfonic acid (12 mL) was added with 2-[1-(3-bromo-4-methoxy-phenyl)-1-methyl-ethyl]-6-cyano-1H-indole-3-carboxylic acid ethyl ester (Compound K5, 1.0 g, 2.27 mmol), and the mixture was stirred at room temperature for 20 min. The reaction solution was diluted with MeCN (20 mL), poured into water (20 mL), and the precipitated solid was filtered to obtain the title compound (yellow solid, 763 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(NCC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(CNC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3Br)cc2)c2ccc3ccccc3c2N1
Yield: 21 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-bromobenzoyl chloride (0.143 mmol), the title compound (10 mg, yield 21%) was obtained in the same manner as that of Example 1, (4).