Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][CH2:15]Cl.[CH3:17][NH:18][CH3:19].C1COCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][N:18]([CH3:19])[CH3:17])[CH:6]=1
Reactant: CNC
Reactant: ClCCBr
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(Br)cn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-bromopyrazole (100 mg, 0.680 mmol, available from Aldrich), cesium carbonate (333 mg, 1.021 mmol) and 1-bromo-2-chloroethane (0.085 mL, 1.021 mmol, available from Aldrich) were suspended in N,N-Dimethylformamide (DMF) (2 mL) and heated to 60° C. under microwave conditions in a Biotage Initiator for 1 hour. 2M dimethylamine in THF (1.701 mL, 3.40 mmol) added and the mixture allowed to stand over the weekend. The mixture was heated to 60° C. under microwave conditions in a Biotage Initiator for 1 hour, then to 100° C. under microwave conditions in a Biotage Initiator for 2 hours. The mixture was filtered, evaporated to 13 mbar, loaded on to a 5 g SCX cartridge and eluted with MeOH (25 ml) followed by 2M methanolic ammonia (25 ml). The basic fraction was evaporated to a colourless oil (99 mg). LCMS (Method C): Rt=0.43, MH+=218
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10]Br.[C-:12]#[N:13].[Na+]>CO.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:12]#[N:13]
Reactant: Clc1cc(Cl)c(Cl)c(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CCc1cc(Cl)cc(Cl)c1Cl
Temperature: 35 °C
Reaction time: 4.5 h
Yield: 70 %

Procedure:
A solution of 19.2 grams (0.070 mole) of 2,3,5-trichlorophenylmethyl bromide in 50 mL of methanol was stirred, and a solution of 4.1 grams (0.084 mole) of sodium cyanide in 10 mL of water was added dropwise during a 10 minute period. The addition caused an exothermic reaction which raised the reaction mixture temperature to about 35° C. Upon completion of the addition the reaction mixture was warmed to reflux, where it was stirred for 4.5 hours. The reaction mixture was allowed to cool to ambient temperature, where it was stirred for about 60 hours. After this time the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with two portions of water, two 25 mL portions of aqueous 10% hydrochloric acid, and then with three portions of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 10.8 grams of 2,3,5-trichlorophenylacetonitrile. The infrared spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[C:39]([C:41]1[CH:42]=[C:43]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:44]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:46]=1)#[N:40].C(=O)([O-])[O-].[Na+].[Na+]>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>[C:39]([C:41]1[CH:42]=[C:43]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:44]=[C:45]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:46]=1)#[N:40]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(C#N)cc(NS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(C#N)cc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 88.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (138 mg, 0.23 mmol) was treated with N-(3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (545 mg, 0.62 mmol, prepared from N-(3-bromo-5-cyanophenyl)methanesulfonamide, described at WO 2009015369 A2 20090129, and bis(pinacolato)diboron according to Preparation 119b), sodium carbonate (58 mg, 0.55 mmols) and bis(triphenylphosphine)palladium(II) dichloride (61 mg, 0.07 mmol) according to the method described in Preparation 62. The residue was purified by reverse phase chromatography using SP1® Purification System (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 145 mg (88% yield) of the title compound. Purity 100%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[C:7]2[C:3]=1[C:4]1[CH:17]=[C:16](C(OCC)=O)[N:15]=[CH:14][C:5]=1[NH:6]2.Cl.[C:24]([O-])(O)=O.[Na+].[CH2:29]1[CH2:33][O:32]CC1>CCOCC>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([NH2:12])=[O:13])=[C:7]2[C:3]=1[C:4]1[CH:17]=[C:16]([C:33]([OH:32])([CH3:29])[CH3:24])[N:15]=[CH:14][C:5]=1[NH:6]2
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(O)c1cc2c(cn1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 33 %

Procedure:
A solution of ethyl 5-bromo-8-carbamoyl-9H-pyrido[3,4-b]indole-3-carboxylate (0.4 g, 1.104 mmol) in THF (31.6 mL) was cooled in a salt-ice bath slowly treated with methylithium (1.6 M in ether, 3.80 mL, 6.07 mmol). The solution was stirred at −5° C. for 1.5 h, then was treated with ice and 1 M aqueous HCl (7 mL). The mixture was made basic with NaHCO3 (aq) and extracted with chloroform-isopropanol (3:1). The organic phase was washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (40 g), eluting with Methanol-CH2Cl2 (gradient from 2:98 to 10:90) to provide the desired product as a yellow solid (128 mg, 33% yield). LCMS (M+H)+ m/z 347.9, 349.9.
Reaction SMILES: [Mg].II.[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][Cl:8].[CH3:13][N:14]1[CH2:23][C:22](=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1>CCOCC>[ClH:8].[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][C:22]1([OH:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][N:14]([CH3:13])[CH2:23]1
Reactant: Fc1ccccc1CCl
Reactant: CN1CC(=O)c2ccccc2C1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CN1Cc2ccccc2C(O)(Cc2ccccc2F)C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium shavings (3.96 g) and a crystal of iodine in anhydrous ether (50 ml) is added several milliliters of 2-fluorobenzyl chloride. After initiation of the reaction with a hot air gun, the remainder of the 2-fluorobenzyl chloride for a total of 27.2 g is added dropwise as a solution in ether (50 ml). After the addition is complete, the reaction mixture is refluxed for 2 hours. A solution of 2-methyl-2,3-dihydro-4(1H)-isoquinolone (24.2 g) in ether (100 ml) is added dropwise at room temperature. The granular precipitate which forms is stirred at room temperature for one hour, filtered and washed with ether. The solid is hydrolyzed by stirring at room temperature for one hour with an ammonium chloride solution, followed by ether extraction. The ether extract is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the ether yields 28.6 g of an oil. A portion of the oil (5 g) is dissolved in ether, filtered, and ethereal hydrogen chloride is added to give product as a white powder (5.5 g, 97%), mp 105°.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH3:21])[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.BrC1C=CC2N=C(/C=C/C3C=CC(C(F)(F)F)=CC=3)N(C)C=2C=1.[CH3:47][S:48]([NH:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1B(O)O)(=[O:50])=[O:49]>>[CH3:21][N:6]1[C:5]2[CH:22]=[C:23]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=3[NH:51][S:48]([CH3:47])(=[O:50])=[O:49])[CH:2]=[CH:3][C:4]=2[N:8]=[C:7]1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)Nc1ccccc1B(O)O
Reactant: Cn1c(/C=C/c2ccc(C(F)(F)F)cc2)nc2cc(Br)ccc21
Agent: Cn1c(/C=C/c2ccc(C(F)(F)F)cc2)nc2ccc(Br)cc21
Product: Cn1c(/C=C/c2ccc(C(F)(F)F)cc2)nc2ccc(-c3ccccc3NS(C)(=O)=O)cc21

Procedure:
Using the procedure of Example 1, Step B, the title compounds were prepared from a mixture of (E)-5-bromo-1-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole and (E)-6-bromo-1-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole and 2-methylsulfonylaminophenyl boronic acid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:27])(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(Cl)(=O)OCC.[C:34](O)(=[O:42])[C:35]1[C:36](=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH2:37]>C(Cl)Cl>[CH2:9]([C:8]1[O:27][C:34](=[O:42])[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Nc1ccccc1C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2c(=O)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Triethylamine (0.46 ml) was added to a suspension of stearic acid (853 mg) in methylene chloride (8.5 ml). Then, ethyl chlorocarbonate (0.32 ml) was dropwise added to the mixture while being cooled with ice. After being stirred for 1 hour at 0° C., the mixture, with a mixed solution of anthranilic acid (411 mg) and triethylamine (0.42 ml) in methylene chloride (2 ml) dropwise added thereto, was stirred for 16 hours at 45C and cooled with ice. The reaction mixture, with triethylamine (0.46 ml) and ethyl chlorocarbonate (0.32 ml) dropwise added thereto, was stirred for 1 hour at 0° C. and for 1.5 hours at room temperature successively, and then concentrated. The residue, with ethyl acetate added thereto, was washed with water, neutralized with diluted hydrochloric acid, and washed with saturated brine. The organic layer was dried over magnesium sulfate anhydride and then concentrated. The residue was purified by silica gel column chromatography (silica gel 35 g, chloroform-methanol), thereby yielding 966 mg of the aimed compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]([C:18]1[NH:22][N:21]=[C:20](C(O)=O)[CH:19]=1)=[O:17].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[N:10]2)=[CH:7][CH:8]=1.[CH3:14][O:15][C:16]([C:18]1[NH:22][N:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: COc1ccc(-n2cccn2)cc1
Reactant: COC(=O)c1cc(C(=O)O)n[nH]1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccn[nH]1
Product: COc1ccc(-n2ccc(CO)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-1H-pyrazole-5-(methoxycarbonyl)pyrazole-3-carboxylic acid (2.4 g, 8.69 mmol) in 50 mL of tetrahydrofuran at -20° C. was added triethylamine (1.21 mL, 8.69 mmol) and ethyl chloroformate (0.83 mL, 8.69 mmol). This mixture was stirred for 30 min and then there was added sodium borohydride (0.66 g, 17.4 mmol) in a minimal amount of water. The reaction mixture was stirred with slow warming to room temperature for 1 h and then was quenched with 10% aq HCl. After diluting with ethyl acetate, the organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:2 ethyl acetate/hexane) to afford 1.4 g (61%) of the title compound. LRMS (DCI): 263.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([NH:15][C:16](=[O:47])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[N:29]=[C:28]([NH:30][C:31]3([C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:33][CH2:32]3)[N:27]=[C:26]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])[N:25]=2)=[CH:19][CH:18]=1)[C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([NH:15][C:16](=[O:47])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[N:29]=[C:28]([NH:30][C:31]3([C:34]4[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=4)[CH2:32][CH2:33]3)[N:27]=[C:26]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])[N:25]=2)=[CH:19][CH:18]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3].[NH2:8][CH2:9][C@H:10]([NH:15][C:16](=[O:47])[C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]2[N:29]=[C:28]([NH:30][C:31]3([C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:32][CH2:33]3)[N:27]=[C:26]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])[N:25]=2)=[CH:21][CH:22]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H](NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1)C(=O)O
Product: NC[C@H](NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate (25 mg) and K2CO3 (25.4 mg) in acetone and water (1:1, 4 mL) was stirred at room temperature for 16 hours. The mixture was acidified to pH1. Solvents were removed under vacuum and the residue was purified by preparative HPLC to give (S)-3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoic acid (15.6 mg) and (S)-3-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoic acid (3.9 mg).
Reaction SMILES: CNS(CC[C:8]1[CH:9]=[CH:10][C:11]2[NH:16][CH:15]=[C:14](C3CCN(C)CC3)[C:12]=2[CH:13]=1)(=O)=O.Br[C:25]1[CH:26]=C2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=C2.CN1CCC(=[O:41])CC1.[OH-].[K+]>CO>[OH:41][CH:31]1[CH2:32][CH:33]([C:13]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12]=2[CH:14]=[CH:15][NH:16]3)[CH2:25][CH2:26][N:30]1[CH3:29]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Reactant: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(c2cccc3[nH]ccc23)CC1O

Procedure:
U.S. Pat. No. 4,997,841 discloses naratriptan, its salts and several processes for its preparation. One of the processes comprises reacting 5-bromoindole with 1-methylpiperidin-4-one by means of KOH in methanol at room temperature to give 5-bromo-3-(4-(hydroxy-1-methylpiperidin-4-yl)-1H-indole, which is condensed with N-methylvinylsulfonamide by means of palladium acetate and tri-p-tolyl phosphine in hot DMF to afford (E)-N-methyl-2-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]vinylsulfonamide. Finally, this compound is hydrogenated with H2 over Pd/C to obtain naratriptan.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([N:37]2[C:42](=[O:43])[C:41]([CH2:44]OS(C)(=O)=O)=[CH:40][C:39]([C:50]3[CH:55]=[CH:54][C:53]([S:56]([CH3:58])=[O:57])=[CH:52][CH:51]=3)=[N:38]2)[CH2:36][CH2:35]1.[CH3:59]N1CCNCC1>>[CH:35]1([CH2:34][N:37]2[C:42](=[O:43])[C:41]([CH2:44][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:40][C:39]([C:50]3[CH:55]=[CH:54][C:53]([S:56]([CH3:58])=[O:57])=[CH:52][CH:51]=3)=[N:38]2)[CH2:59][CH2:36]1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CS(=O)c1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(C3CC3)n2)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2cc(-c3ccc(S(C)=O)cc3)nn(CC3CC3)c2=O)CC1
Yield: 60.6 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropyl-4-methanesulfonyloxymethyl-6-[4-(methyl-sulfinyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 60.6%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][C:35]2[CH:40]=[CH:39][C:38](SC)=[CH:37][CH:36]=2)=[CH:4][N:3]=1.[CH:43]1C=C(Cl)C=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].[S:59]([O-:63])([O-])(=[O:61])=S.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([S:59]([CH3:43])(=[O:63])=[O:61])=[CH:39][CH:40]=2)=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(SC)cc4)cnc3F)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 75 %

Procedure:
4-(2-Fluoro-5-(4-(methylthio)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (624.5 mg, 1.074 mmol) was dissolved in DCM (11 mL) and the flask was cooled in an ice water bath. Then, mCPBA (557 mg, 3.23 mmol) was added as a solution in DCM (17.5 mL) and the reaction was warmed to room temperature and stirred under nitrogen. After 35 min, the reaction was treated with a mixture of saturated sodium bicarbonate (25 mL) and saturated sodium thiosulfate (6 mL), and stirring was continued at room temperature. After 50 minutes, the layers were separated, and the aqueous phase was extracted with DCM. The organic phase was dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (30 mL fritted filter with about 1 inch of silica gel; DCM to 50:1 DCM/MeOH) to give 4-(2-fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (539.6 mg, 75% yield based on 91% purity). 1H NMR (CDCl3, 400 MHz) δ 8.34 (dd, J=8.90 Hz, 2.45 Hz, 1H), 8.16 (d, J=1.76 Hz, 1H), 7.89 (d, J=8.41 Hz, 2H), 7.40 (d, J=8.22 Hz, 2H), 7.21 (d, J=8.61 Hz, 4H), 6.90-6.82 (m, 4H), 4.82 (s, 2H), 4.79 (s, 2H), 4.13 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.03 (s, 3H), 2.54 (s, 3H). m/z (ESI, +ve ion) m/z 614 (M+H)+.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]3=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.NC1C=CC([F:31])=CC=1C(O)=O.C(O)(=O)[C:33]1[C:34](=CC=CC=1)[NH2:35]>>[F:31][C:3]1[CH:2]=[CH:10][C:9]2[NH:8][C:7]3[C:34]([CH3:33])=[N:35][C:12]4[CH2:13][C:14]([CH3:19])([CH3:18])[CH2:15][C:16](=[O:17])[C:11]=4[C:6]=3[C:5]=2[CH:4]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: CC1(C)CC(=O)C(c2c[nH]c3cc(F)ccc23)C(=O)C1
Reactant: Nc1ccc(F)cc1C(=O)O
Product: Cc1nc2c(c3c1[nH]c1ccc(F)cc13)C(=O)CC(C)(C)C2

Procedure:
Utilizing the procedures described in Example 3 a-c except substituting 2-(5-fluoro-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione for 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione in step 3a, and 2-amino-5-fluorobenzoic acid for anthranilic acid in step 1a of Example 1, the title compound was prepared and crystallized from toluene; m.p. 229-230° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]([CH3:25])[CH:16]([CH:26]=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.[C:36]([O:40][C:41](=[O:55])[NH:42][S:43]([CH2:46][CH2:47][CH2:48][N:49]([CH3:54])[CH2:50][CH2:51][NH:52][CH3:53])(=[O:45])=[O:44])([CH3:39])([CH3:38])[CH3:37].[BH3-]C#N.[Na+]>CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:18]=[CH:24][CH:23]=[CH:22][C:21]=2[N:17]([CH3:25])[CH:16]([CH2:26][N:52]([CH3:53])[CH2:51][CH2:50][N:49]([CH3:54])[CH2:48][CH2:47][CH2:46][S:43](=[O:44])(=[O:45])[NH:42][C:41](=[O:55])[O:40][C:36]([CH3:39])([CH3:37])[CH3:38])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNCCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C=O)N(C)c1ccccc1-3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C)N(C)c1ccccc1-3
Reaction time: 0.08 h

Procedure:
Methyl 13-cyclohexyl-6-formyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate was dissolved in MeOH (0.08 M) and HOAc was added. Tert-butyl[(3-{methyl[2(methylamino)ethyl]amino}propyl)sulfonyl]carbamate (1.5 eq. prepared as described in Example 15, Steps 1-3) was added and the mixture was stirred for 5 min. NaCNBH3 (1.5 eq.) was added and the mixture was stirred for 6 h. All volatiles were evaporated and the residual material was dissolved in EtOAc. The solution was extracted with sat. aq. NH4Cl, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. A yellow amorphous solid was obtained which was used without further purification in the next reaction (60%). (ES+) m/z 711 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[C:31]1(/[CH:37]=[CH:38]/B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:11][C:10]1[C:5]2[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][C:2](/[CH:38]=[CH:37]/[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:7][C:6]=2[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Reactant: OB(O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(/C=C/c2ccccc2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
(see, e.g., Greig, I. R., et al., J Med Chem 2006, 49, 7487-92; Li, X., et al., J Med Chem 2003, 46, 5663-73). To a mixture of 50 (205 mg, 0.49 mmol), Pd(PPh3)4 (27 mg, 0.02 mmol) and (E)-2-phenylvinylboronic acid (112 mg, 0.74 mmol) in 1,4-dioxane: H2O (3 mL/2 mL) was added Na2CO3 (153 mg, 1.45 mmol), followed by stirring at 90° C. overnight. To the reaction mixture was added H2O (10 mL) and the aqueous layer was extracted with EtOAc (10 mL×2). The combined organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Crude was subjected to flash column chromatography on silica gel to provide the title compound (216 mg, 90%) as a light yellow oil which solidified upon standing. 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J=16.1 Hz, 1H), 7.74 (s, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.41 (t, J=7.6 Hz, 2H), 7.39-7.33 (m, 3H), 7.30 (t, J=7.7 Hz, 3H), 7.07 (t, J=7.4 Hz, 1H), 6.98 (d, J=8.6 Hz, 2H), 6.95 (d, J=8.3 Hz, 2H), 5.69 (s, 2H), 4.51 (q, J=7.1 Hz, 2H), 2.71 (s, 3H), 1.49 (t, J=7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.76, 157.04, 156.79, 154.93, 152.39, 141.19, 136.28, 134.74, 133.60, 132.13, 129.69, 129.50, 128.81, 127.69, 127.33, 123.28, 118.94, 118.82, 116.48, 110.28, 61.93, 49.80, 16.30, 14.30.