Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].[NH2:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(OCC)C.C(OCC)(=O)C>[CH2:29]([O:28][C:26]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:10]([OH:17])[C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)OC(=O)C(O)[C@@H](N)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)C(O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Water (10 ml) and sodium carbonate (763 mg) are added to a solution of isopropyl (2RS,3S)-3-amino-2-hydroxy-4-phenylbutyrate (800 mg, Reference compound No. 4-1) in diethyl ether (10 ml). Benzyl chloroformate (691 mg) is added to the mixture, and the whole is stirred for two hours. Ethyl acetate is added to the reaction mixture, and the whole is washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine successively and dried over anhydrous magnesium sulfate. The organic layer is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (1.02 g).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].C(=O)=O.[OH:31][CH2:32][CH2:33][S:34][S:35][CH2:36]CO>>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH2:36][S:35][S:34][CH2:33][CH2:32][OH:31])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: OCCSSCCO
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Product: COC12C(CO)C3=C(C(=O)C(C)=C(OCCSSCCO)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 44 %

Procedure:
A solution of mitomycin A (100 mg or 0.286 mmole) in 4 ml of 2-hydroxyethyldisulphide was stirred at room temperature and under nitrogen for 45 minutes with 240 mg of a 1.6% solution of KOH in 2-hydroxyethyldisulphide. The reaction mixture was decomposed with excess dry ice while immersing the flask into a water bath at room temperature. The reaction mixture was chromatographed on a silica gel column using CHCl3 -acetone 1:1 and the CHCl3 -MeOH 9:1 as solvent systems. The product was further purified by preparative thin layer chromatography on silica gel using CHCl3 -acetone 3:7. Thus, there was obtained 23 mg (44%) of the desired product, having a melting point of 87°-95° C. (decomposition) and providing the following analysis:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])([O-:19])=[O:18].S(Cl)(Cl)(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N+:17]([O-:19])=[O:18])(=[O:27])=[O:28])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer, charged with p-anisidine (13.0 mmol), followed by dichloromethane (75 mL). The flask was then placed in an ice bath to chill the contents. Triethylamine was added and an addition funnel was installed. The addition funnel was charged with 2-nitrobenzenesulfonyl chloride (32.4 mmol) in dichloromethane (75 mL). The sulfonyl chloride was added dropwise very slowly and the reaction monitored by TLC (dichloromethane/silica) several times during the addition. The reaction was complete after addition of 50 mL (21.6 mmol) of the sulfonyl chloride solution. The reaction solvent was removed at 0° C. and immediately loaded onto a 600 mL sintered glass funnel charged with silica gel (400 g), eluted with dichloromethane collecting 100 mL fractions. Fractions containing the desired product were combined and evaporated under diminished pressure to yield the title compound as a yellow powder in excellent yield. 3.67 g, (92%). 1H-NMR (CDCl3): δ 3.20 (s, 3H); 6.78-6.79 (d, 2H, J=8.9 Hz); 7.07-7.10 (d, 3H, J=8.9 Hz); 7.53-7.58 (t, 1H, J=7.7 Hz); 7.66-7.71 (t, 1H, J=7.8 Hz); 7.73-7.76 (d, 1H, J=7.8 Hz); 7.84-7.87 (d, 1H, J=7.9 Hz).
Reaction SMILES: CS(OCC[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:17]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:20][C:9]1=2)(=O)=O.[C-]#N.[Na+].CS(C)=O.S([O-])(=O)(=O)C>O.C(N(CC)CC)C>[N:21]1([C:19]2[N:18]=[C:17]([N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]=3[N:20]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CS(=O)(=O)OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Agent: CS(=O)(=O)[O-]
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)[nH]c1nc(N3CCCC3)nc(N3CCCC3)c12

Procedure:
A stirred mixture of 9-[2-(methanesulfonyloxy)ethyl]-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (II, EXAMPLE 1 and WO/9626941-A1, 165 g), sodium cyanide (180 g), water (360 mL) and DMSO (3000 mL) are heated at 100° for 18 hr. It is important that the starting mesylate contain traces of triethylamine either left over from its preparation, or added intentionally. The mixture is cooled to 20-25°, diluted with water (approximately 6,000 mL) and filtered. The solid is washed with water to remove excess cyanide, then triturated with acetone. Filtration and drying gives 2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (III), mp 209-211°; NMR (CDCl3) 7.88, 7.22, 7.09, 3.95, 3.67 and 1.98 δ; MS (m/z, FAB, M+H) 308.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH:10]2[O:15][C:14]3[CH:16]=[CH:17][C:18]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:19][C:13]=3[O:12][CH2:11]2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].C(C1C=CC(OCC2OC3C=CC(CC(OC)=O)=CC=3C2)=C(CCC)C=1O)(=O)C>>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH:10]2[O:15][C:14]3[CH:16]=[CH:17][C:18]([CH2:20][C:21]([OH:23])=[O:22])=[CH:19][C:13]=3[O:12][CH2:11]2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC2COc3cc(CC(=O)OC)ccc3O2)ccc(C(C)=O)c1O
Agent: CCCc1c(OCC2Cc3cc(CC(=O)OC)ccc3O2)ccc(C(C)=O)c1O
Product: CCCc1c(OCC2COc3cc(CC(=O)O)ccc3O2)ccc(C(C)=O)c1O

Procedure:
Following the procedure of Example 26, but substituting the compound of Example 46 for the compound of Example 25, there was obtained the title compound as a solid, m.p. 143°-146°.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].C(N([CH2:16][CH3:17])CC)C.[C:18]1([C:23](Cl)=[O:24])[S:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[C:18]1([C:23]([NH:10][C:8](=[N:9][C:23](=[O:24])[C:18]2[S:22][CH:17]=[CH:16][CH:19]=2)[S:7][CH3:6])=[O:24])[S:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCN(CC)CC
Reactant: CSC(=N)N
Reactant: O=C(Cl)c1cccs1
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: CSC(=NC(=O)c1cccs1)NC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5.56 g. (0.02 mole) of 2-methylthiopseudourea sulfate, 4.0 g. (0.04 mole) triethylamine and 50 ml. of dimethylformamide is cooled to 0° C. and treated with a solution of 5.88 g. (0.04 mole) of 2-thenoyl chloride in 15 ml. of dimethylformamide. The reaction mixture is allowed to warm to room temperature, stirred for 2 hours and is then poured onto 500 g. of an ice-water mixture. The colorless solid product is separated by filtration and washed with water. This solid is recrystallized from ethanol to give 1,3-dithenoyl-2-methylthio-pseudourea, m.p. 166°-167° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:18]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:19][C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:21][C:10]1=2.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:1][S:2]([O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:18]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:19][C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:21][C:10]1=2)(=[O:4])=[O:3]
Reactant: OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21

Procedure:
A mixture of methanesulfonyl chloride (0.38 mL) in methylene chloride (20 mL) is added dropwise to a mixture of 9-(2-hydroxyethyl)-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (VIII, EXAMPLE3, 1.05 g) and triethylamine (0.5 mL) in methylene chloride (25 mL). After a few minutes, the reaction mixture is diluted with water and extracted with methylene chloride. The organic layer is dried (sodium sulfate) and concentrated, to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.[N:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:14]=[O:15].[H-].[Na+].Cl>O.O1CCCC1>[CH2:16]([N:13]1[C:7](=[O:9])[C:6]2[CH:5]=[C:4]([CH2:11][CH3:12])[S:3][C:2]=2[NH:1][C:14]1=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: O=C=NCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc2c(=O)n(Cc3ccccc3)c(=O)[nH]c2s1
Temperature: 60 °C
Reaction time: 5 h
Yield: 25 %

Procedure:
To a mixture of methyl 2-amino-5-ethylthiophene-3-carboxylate (5 g), (isocyanatomethyl)benzene (3.33 mL) and tetrahydrofuran (50 mL) was added sodium hydride (1.18 g), and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was diluted with water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound as colorless crystals (2.1 g, 25%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7]O)[CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[CH:26]12[CH2:32][CH:29]([NH:30][CH2:31]1)[CH2:28][N:27]2[C:33]1[N:38]=[C:37]([NH2:39])[N:36]2[N:40]=[C:41]([C:43]3[O:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[C:35]2[N:34]=1>C(Cl)Cl.CC#N>[O:44]1[CH:45]=[CH:46][CH:47]=[C:43]1[C:41]1[N:42]=[C:35]2[N:34]=[C:33]([N:27]3[CH2:28][CH:29]4[CH2:32][CH:26]3[CH2:31][N:30]4[CH2:7][C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)[N:38]=[C:37]([NH2:39])[N:36]2[N:40]=1
Reactant: Nc1nc(N2CC3CC2CN3)nc2nc(-c3ccco3)nn12
Reactant: Cc1cc(CO)no1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(CN2CC3CC2CN3c2nc(N)n3nc(-c4ccco4)nc3n2)no1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a separate flask, (5-methyl-isoxazol-3-yl)-methanol (32 mg, 0.28 mmol) was dissolved in 4 mL of CH2Cl2 along with 1.3 eq. of Et3N. The solution was cooled in an ice bath and methanesulfonyl chloride (1.2 eq) was added. The reaction mixture was warmed to room temperature and stirred for 45 minutes. It was then quenched with brine and the two layers were separated. The organic layer was dried with Na2SO4 and concentrated under reduced pressure to afford the mesylated derivative. This mesylate was then added to a solution containing 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 (0.14 mmol; see subpart (a) above), and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temperature for 18 hours. It was then concentrated and purified by preparative HPLC to afford 2-furan-2-yl-5-[5-(5-methyl-isoxazol-3-ylmethyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine. 1H NMR (400 Hz, DMSO-d6) δ 8.20 (brs, 1H), 7.80 (d, J=1.0 Hz, 1H), 7.00 (d, J=3.6 Hz, 1H), 6.60 (dd, J=3.6, 1.0 Hz, 1H), 6.30 (s, 1H), 4.80 (brs, 2H), 4.20-4.30 (m, 8H), 2.35 (s, 3H), 2.30 (m, 1H). MS m/z: 394 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([Cl:15])[N:7]=[C:6]2[NH:16][NH2:17].[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1.COC(OC)OC>>[Cl:15][C:8]1[N:7]2[CH:18]=[N:17][N:16]=[C:6]2[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][C:10]=2[N:9]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc2nc(Cl)nc(NN)c2cc1OC
Solvent: COC(OC)OC
Product: COc1cc2nc(Cl)n3cnnc3c2cc1OC
Reaction time: 19 h

Procedure:
A mixture of 10.0 g. of 6,7-dimethoxy-2-chloro-4-hydrazinoquinazoline, 1.0 g. of p-toluenesulfonic acid and 150 ml. of trimethoxy methane is refluxed with stirring for 19 hours and then stirred for 24 hours at room temperature. The resulting mixture is evaporated in vacuo to dryness and the residue dissolved in 1500 ml. of methylene chloride. This solution is extracted twice with sodium carbonate solution, washed neutral with water, dried and evaporated in vacuo to dryness. The residue is twice crystallized from methylene chloride/ diethyl ether and then from ethanol to obtain 5-chloro-8,9-dimethoxy-1,2,4-triazolo[4,3-c]quinazoline, m.p. 269°-271° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][OH:10].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][O:10][C:30]1[CH:29]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:26][CH:31]=1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: Cc1cccc(Cl)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(OCc2c(C)cccc2Cl)c1
Reaction time: 4 h

Procedure:
A solution of (2-chloro-6-methylphenyl)methanol (Step A, 3 g, 19.1 mmol) and diisopropyl azodicarboxylate (DIAD, 4.13 ml, 21 mmol) in THF (20 ml) was added drop wise to a solution of ethyl 2-(3-hydroxyphenyl)acetate (3.79 g, 21 mmol) and triphenylphosphine (5.48 g, 21 mmol) in THF (30 ml) at 0° C. under argon. The reaction mixture was stirred at the same temperature for 4 hours, diluted with ether and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 2:1) to give the title compound.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=O)C.[CH3:35][CH:36]1[NH:40][C:39](=[O:41])[CH2:38][CH2:37]1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:10]4[CH:11]=[CH:12][C:13]([N:40]5[C:39](=[O:41])[CH2:38][CH2:37][CH:36]5[CH3:35])=[CH:14][C:9]=4[N:6]4[CH2:7][CH2:8][NH:4][C:5]4=[O:34])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Reactant: CC1CCC(=O)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)CCC3C)cc2N2CCNC2=O)CC1
Yield: 26.9 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (239 mg) described in Preparation Example 236 and 5-methylpyrrolidin-2-one (74 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (67 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COc1ccc2c(-c3ccc(Cl)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-chloro-phenylboronic acid to give [1-(4-Chloro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 351(MH+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]([CH3:21])[C:14]1=[O:22]>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]([CH3:21])[C:14]1=[O:22]
Reactant: Cn1c(=O)[nH]c(=O)n(-c2ccc(F)cc2Cl)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(=O)[nH]c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
Nitric acid (70% real, 8.3 mL, 0.131 mol) is added to a solution of 1-(2-chloro-4-fluorophenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (32.4 g, 0.119 mol) in concentrated sulfuric acid while maintaining the reaction mixture temperature below 10° C. After the addition is complete, the reaction mixture is stirred at room temperature for 30 minutes, cooled to 10° C. and diluted with ice-water. The resultant aqueous mixture is filtered to obtain a solid which is washed with water and air-dried to give the title product as a white solid (28.5 g, mp 135°-139° C.)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:11]([O:10][CH2:9][CH2:8][NH2:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCOCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Dissolve (2-benzyloxyethyl)-carbamic acid tert-butyl ester (15 g) in DCM (50 mL), add trifluoroacetic acid (20 mL) and stir at 0° C. for 3 h. Concentrate and dissolve the residue in a minimal amount of DCM. Purify by chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1 and 1:1), EtOAc and 2M ammonia in methanol to give the title compound (8.3 g, 85%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].I[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH3:42])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:42][CH2:41][CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=3)[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: CCCCc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCCc4ccccc4)CC3)C2=O)c1
Yield: 91.4 %

Procedure:
tert-Butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.593 mmol), 1-iodo-4-butylbenzene (0.15 g, 0.593 mmol), and potassium carbonate (0.12 g, 0.890 mmol) in N,N-dimethylformamide (8 mL) were stirred at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.30 g, 90%); MS for C35H43N3O3 m/z 554 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[S:24]([C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=1)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl.O>[CH:1]1([CH2:4][CH2:5][N:6]([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[S:24]([C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=2)(=[O:26])=[O:25])[CH2:3][CH2:2]1
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Reactant: FC(F)(F)c1ccc(-c2cccc(NCCC3CC3)c2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(S(=O)(=O)N(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Yield: 54.5 %

Procedure:
To a solution of N-(2-cyclopropylethyl)-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (155 mg, 0.51 mmol) in anhydrous CH2Cl2 (10 mL) under nitrogen at room temperature was added ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (223 mg, 0.76 mmol) and triethylamine (0.213 mL, 1.53 mmol). The resultant mixture was stirred for 40 h at room temperature. The reaction mixture was diluted with water (15 mL) and extracted with CH2Cl2 (30 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by Biotage™ chromatography (40 g Silica column) eluted with 1:19–1:9 EtOAc:cyclohexane afforded the title compound as a white crystalline solid (156 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Na].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>CS(C)=O.O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: Brc1cccc(-n2ccnc2)n1
Temperature: 25 °C
Yield: 9.7 %

Procedure:
A stirred solution of 2,6-dibromopyridine (2.0 g, 8.3 mmol) and imidazole sodium salt (1.0 g, 10.5 mmol) in dimethylsulfoxide (10 ml) was heated at 100° C. for 36 h. After cooling to ambient temperature the reaction was diluted with water and extracted into dichloromethane. Combined organic extracts were washed with water and saturated brine then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel eluting with dichloromethane, then dichloromethane containing 5% methanol, gave 2-bromo-6-(1H-imidazol-1-yl)pyridine (0.18 g) as an off-white solid: δH (400 MHz, CDCl3) 7.20 (1H, m), 7.32 (1H, d, J 8), 7.47 (1H, d, J 8), 7.62 (1H, m), 7.68 (1H, dd, J 8 and 8), 8.35 (1H, s); m/z (ES+) 224/226 (M++H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:27]5[CH:28]=[CH:29][C:24]([S:23][CH3:22])=[CH:25][CH:26]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Product: CSc1ccc(-c2ccc(N3CCCN(c4ccc(-c5ccc(SC)cc5)cn4)CC3)nc2)cc1
Yield: 43.7 %

Procedure:
Following the procedure of Example 1, crude crystals were obtained from the 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol) synthesized in Reference Example 1 and 4-methylthiophenylboronic acid (202.0 mg, 1.20 mmol). The crude crystals were recrystallized from chloroform-hexane to yield the title compound as pale yellow needles (melting point: 252.0–255.0° C.) (109.0 mg, yield: 43%).