Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17]([C:18]4[CH:19]=[N:20][C:21]5[C:26]([CH:27]=4)=[CH:25][CH:24]=[CH:23][CH:22]=5)=[C:12]3[C:11]([CH:28]([CH3:30])[CH3:29])=[N:10]2)=[CH:5][C:4]=1[NH:31][CH:32]1[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]1)#[N:2].C(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH:28]([C:11]1[C:12]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([NH:31][CH:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]3)[CH:5]=2)[N:10]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NC3CCN(C(=O)OC(C)(C)C)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nn(-c2ccc(C#N)c(NC3CCNCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Tert-butyl 4-{2-cyano-5-(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenylamino}piperidine-1-carboxylate obtained in Example 76 was dissolved in trifluoroacetic acid, followed by stirring at room temperature for 1 hr. The reaction solution was distributed between chloroform and saturated sodium bicarbonate water, and the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain (77a) (the second stage yield: 56%) as a white solid.
Reaction SMILES: [S:1]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[NH2:19])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[S:1]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[NH:19][C:20](=[O:22])[CH3:21])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: NC1CCCCC1S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC1CCCCC1S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
Alternatively, compound 9 is reductively aminated with ammonium acetate and sodium cyanoborohydride to provide for intermediate 11 which, upon removal of the lauroyl groups, affords 2-aminocyclohexyl 1-thio-β-D-galactopyranoside, B2. Compound B2 can then be acylated with acetic anhydride to give 2-acetamidocyclohexyl 1-thio-β-D-galactopyranoside, C2. Alternatively, intermediate 11 can be acylated with phthalic anhydride to provide for intermediate 12 which affords 2-(2-carboxybenzamidocyclohexyl 1-thio-β-D-galactopyranoside, D2, by removal of the lauroyl groups using the conditions described above.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][C:20]#[N:21].O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]2[CH2:19][C:20]#[N:21])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(Br)cc2n1CC#N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95.3 %

Procedure:
A solution of ethyl 6-bromoindole-2-carboxylate (4.4 g, 16.4 mmol) in DMF (20 mL) was added dropwise over ˜2-3 min to a stirred suspension of sodium hydride (60%, 1.0 g, 25 mmol) in DMF (20 mL) at 0° C. under Ar. The reaction was stirred at 0° C. for 45 min then chloroacetonitrile (2.1 mL, 33 mmol) was added in one portion. The reaction was then heated to 75° C. and stirred for 1 h. After allowing to cool to room temperature the mixture was poured into water (150 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with brine (75 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude solid which was purified by flash column chromatography (SiO2; ethyl acetate) to give the product as a yellow solid (4.8 g, 95%). IR νmax (Nujol)/cm−1 3320, 3089, 2925, 2855, 1898, 1705, 1609, 1530, 1521, 1470, 1449, 1427, 1400, 1394, 1377, 1367, 1336, 1308, 1265, 1205, 1151, 1134,1108, 1054, 1027, 993, 950, 90, 873, 841, 832, 802, 792, 762, 736, 663, 615 and 589; NMR OH (400 MHz; CDCl3) 7.61 (1H, s), 7.57 (1H, d, J.8.5 Hz), 7.37 (1H, d, J 1.5 Hz), 7.35 (1H, dd, J 8.5 Hz, 1.5 Hz), 5.57 (2H, s), 4.45 (2H, q, J 7.2 Hz), 1.42 (3H, t, J 7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20](Cl)=[O:21])=[CH:9]2)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]([F:32])([F:31])[S:27]([NH2:30])(=[O:29])=[O:28].C(Cl)Cl.N1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([NH:30][S:27]([C:26]([F:32])([F:31])[F:25])(=[O:29])=[O:28])=[O:21])=[CH:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: COc1ccc2c(c1)c(CC(=O)Cl)cn2C(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(c1)c(CC(=O)NS(=O)(=O)C(F)(F)F)cn2C(=O)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
80 mg (0.22 mmol) 2-(1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetyl chloride and 49.4 mg (0.33 mmol) trifluoromethanesulfonamide were dissolved in 1.8 mL 1,2-dichloro ethane (or CH2Cl2) under stirring. Then 17.5 mg (0.22 mmol) pyridine were added and the reaction was allowed to run at ambient temperature until the starting material was consumed (˜4 h). After the addition of 13 μL of AcOH the organic solution was washed with H2O (3×2 mL), dried over Na2SO4, filtered and the concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, ethyl acetate/hexane, 0.5% AcOH gradient) to afford the title compound in 70% yield (73 mg). C19H14ClF3N2O5S, Mr=474.84; 1H NMR (400 MHz, DMSO-d6) d: 3.44 (s, 2H), 3.79 (s, 3H), 6.95 (dd, J=2.6/9.0 Hz, 1H), 7.14 9d, J=2.4 Hz, 1H), 7.23 (s, 1H), 7.64-7.66 (m, 2H), 7.72-7.74 (m, 2H), 8.15 (d, J=8.8 Hz, 1H, C7′-H); 19F NMR (282 MHz, DMSO-d6) d: −75.58 (s, —CF3); LCMS (ESI) tR: 2.37 min (>99%, UV254, ELSD), m/z: 475.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1.[Li+].[OH-].[H][H]>C1COCC1.O>[CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Reactant: [H][H]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
A solution of 24.0 mg (0.06 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71) and 6.5 mg (0.16 mmol) of LiOH-H2 0 in 3 mL THF/water (3:1, v/v) was stirred overnight (22 hours) at room temperature. The reaction mixture was extracted with Et2O and the layers were separated. The aqueous layer was acidified with HCl (1M aqueous solution) and then extracted with EtOAc. The organic phase was dried over Na2 SO4 and concentrated in vacuo to give the title compound as a colorless solid.
Reaction SMILES: S(Cl)(Cl)=[O:2].[CH3:5][C:6]1([CH3:25])[CH2:10][O:9][CH2:8][N:7]1[C:11]([N:13]1[C:17]2[CH:18]=[C:19](C(O)=O)[CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1)=[O:12].[N:26]1[CH:31]=CC=CC=1.N>ClCCl.C(O)C.O>[CH3:25][C:6]1([CH3:5])[CH2:10][O:9][CH2:8][N:7]1[C:11]([N:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:31]([NH2:26])=[O:2])=[CH:21][C:16]=2[N:15]=[N:14]1)=[O:12]
Reactant: CC1(C)COCN1C(=O)n1nnc2ccc(C(=O)O)cc21
Reactant: c1ccncc1
Reactant: O=S(Cl)Cl
Agent: N
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)COCN1C(=O)n1nnc2cc(C(N)=O)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.8 %

Procedure:
Thionyl chloride (0.633 mL, 8.67 mmol) was added dropwise to a stirred solution of 1-(4,4-dimethyloxazolidine-3-carbonyl)-1H-benzo[d][1,2,3]triazole-6-carboxylic acid (0.763 g, 2.63 mmol) and pyridine (0.702 mL, 8.67 mmol) in dichloromethane (17 mL) at room temperature. The yellow solution was allowed to stir at room temperature for 15 minutes. This solution was then added dropwise to a 1.75 N solution of ammonia (15.02 mL, 26.3 mmol) in ethanol at 0° C., whereupon a white suspension formed. The reaction mixture was allowed to stir at room temperature for a further 30 minutes. Water was added and the ethanol was evaporated. Then the residue was diluted with dichloromethane, and the organic layer was separated and washed with 1 N HCl solution. The organic layer was dried (MgSO4), filtered and evaporated to give a yellow solid. The solid was recrystallised from a dichloromethane/ethanol mixture to give the product as a beige solid (151 mg, 20%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2)([O-:3])=[O:2].[H-].[Na+].I[CH3:17].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH3:17][C:6]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[NH:8][C:7]1=[O:13]
Reactant: O=C1Cc2c(cccc2[N+](=O)[O-])N1
Reactant: CI
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C)C(=O)Nc2cccc([N+](=O)[O-])c21
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-nitro-1,3-dihydro-2H-indol-2-one (6.95 g, 39.0 mmol, described in Intermediate 44) in DMF (180 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil; 1.72 g, 42.9 mmol) and the resulting mixture was stirred for 30 min. Iodomethane (2.43 mL, 39.0 mmol) in DMF (20 mL) was added dropwise over 20 min, and the mixture was stirred at 0° C. for 1 h. A further equivalent of sodium hydride (60% dispersion in mineral oil; 1.56 g, 39.0 mmol) was added and stirring was continued for 1 h. Ethyl bromoacetate (3.46 mL, 31.2 mmol) in DMF (20 mL) was added dropwise over 20 min The reaction mixture was stirred at 0° C. for 1 h, then quenched with saturated aqueous NH4Cl (500 mL). The mixture was extracted with EtOAc (3×500 mL) and the combined organic extracts were washed with brine (100 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: n2/z=279 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[NH:11][C:10]([C:18]([OH:20])=O)=[CH:9]2.[CH2:21]([S:28][CH:29]([CH:32]([O:35][CH3:36])[O:33][CH3:34])[CH2:30][NH2:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CCCCCC.C(OCC)(=O)C.CN(C)C=O>[CH2:21]([S:28][CH:29]([CH:32]([O:33][CH3:34])[O:35][CH3:36])[CH2:30][NH:31][C:18]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N+:15]([O-:17])=[O:16])=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(OC)C(CN)SCc1ccccc1
Reactant: COCCOc1cc([N+](=O)[O-])c2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COCCOc1cc([N+](=O)[O-])c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.5 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-nitro-1H-indole-2-carboxylic acid (4.7 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (4.9 g), 1H-1,2,3-benzotriazol-1-ol (3.4 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (4.9 g) and N,N-dimethylformamide (150 mL) was stirred at room temperature for 15 hr. The reaction solution was concentrated under reduced pressure, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=20:80-80:20) to give the title compound (6.8 g, yield 97%) as a orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:17](Cl)(=O)/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[C:15]([C:13]1[CH:12]=[CH:11][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[C:17](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:1][C:2]=2[CH:14]=1)#[N:16]
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: N#Cc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: N#Cc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
(E)-5-Cyano-1-(2-pyridyl)-2-styryl-1H-benzimidazole was prepared from 2-amino-4-Cyano-N-(2-pyridyl)aniline and (E)-cinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 322.37; mp: 172.0-172.7° C.; 1H-NMR (CDCl3) δ: 8.80 (1H. ddd, J=4.8, 1.8, 0.7 Hz), 8.15-8.02 (2H, m), 8.05 (1H, d, J=16.0 Hz), 7.57-7.48 (6H, m), 7.42-7.33 (3H, m), 7.07 (1H, d, J=16.0 Hz).
Reaction SMILES: [SH2:1].[Na].Cl[C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][S:7][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C=O)C.O>[CH2:22]([S:1][C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][S:7][N:8]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCBr
Reactant: Clc1nsnc1-c1cccnc1
Reactant: S
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCSc1nsnc1-c1cccnc1
Reaction time: 0.5 h

Procedure:
Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added to a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3 mmol) in DMF (20 ml) at room temperature and the reaction mixture was stirred for 30 min. Potassium carbonate (1.24 g, 9 mmol) and 1-bromooctane (0.80 ml, 4.5 mmol) were added and the reaction mixture was stirred for additionally 10 min. Water (50 ml) was added and extracted with ether. The combined ether phases were dried and evaporated to give the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:36]=[CH:35][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][N:27]([CH2:26][C:25]2[CH:35]=[CH:36][C:22]([NH:20][C:18]3[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[N:16]4[N:17]=3)=[CH:23][CH:24]=2)[CH2:28][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccc3nc(Nc4ccc(CN5CCS(=O)(=O)CC5)cc4)nn23)cc1

Procedure:
N-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-5-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(4-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale orange foam (0.040 g, 30%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.25 (d, J=7.9 Hz, 2H), 8.14 (d, J=7.4 Hz, 2H), 7.59-7.56 (m, 2H), 7.52 (d, J=7.8 Hz, 2H), 7.29-7.25 (m, 2H), 7.08-7.03 (m, 1H), 6.94 (s, 1H), 3.61 (s, 2H), 3.16 (s, 3H), 3.08-3.03 (m, 4H), 3.01-2.96 (m, 4H). MS=512 (MH)+.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.CC(O)=O.C(O[Na])(C)=O.[Br:19]Br>CO.C1COCC1.C([O-])(=O)C>[Br:19][C:6]1[NH:7][C:8]2[C:4](=[N:3][CH:2]=[N:1][CH:9]=2)[N:5]=1
Reactant: BrBr
Reactant: c1ncc2[nH]cnc2n1
Agent: CC(=O)O[Na]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Brc1nc2ncncc2[nH]1

Procedure:
A solution of purine in MeOH/THF/acetate buffer (1N in each AcOH and AcONa) was treated with Br2 (1.3-equiv. 1M in CHCl3) at room temperature (r.t.) for 16 h. Evaporation, work-up (EtOAc), drying (MgSO4) and flash chromatography afforded the desired 8-bromopurine.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23](OB(C2C=CC=CC=2)O)=[CH:22][CH:21]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[N:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: COc1ccc(OB(O)c2ccccc2)cn1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: COc1ccc(-c2cc(Cl)cc3c(C)c4n(c23)CCNC4=O)cn1

Procedure:
The title compound, off-white solid (68 mg, 80%), MS (ISP) m/z=342.5 [(M+H)+], mp 196° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 6-methoxy-pyridin-3-ylphenylboronic acid (49.7 mg, 0.325 mmol).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[OH:8].ClCCl.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(N(CC)CC)C>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[O:8][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OC1CC2C=CC1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1CC2C=CC1C2
Reaction time: 3 h

Procedure:
To a solution of bicyclo[2.2.1]hept-5-en-2-ol (25 g) in 200 mL of anhydrous, dichloromethane is added triethylamine (30 mL) and 4-N,N-dimethylaminopyridine (30 mg). With stirring at room temperature and under an inert atmosphere, of acetic anhydride (35 mL) was added neat and dropwise to the above reaction mixture while maintaining the reaction at room temperature over 1.5 h. Upon complete addition of the anhydride the reaction is left for 3 h, the solvents were stripped and the crude mixture was purified by silica gel chromatography eluting with 25% ethyl acetate/hexanes to afford the title compound in a quantitative yield. 1H NMR (CDCl3, 400 MHz) δ 6.21 (m, 1H), 5.83 (m, 1H), 5.18 (m, 1H), 3.12 (d, 1H), 2.72 (d, 1H), 2.16 (s, 3H), 2.00 (m, 1H), 1.35 (m, 1H), 1.21 (m, 1H), 0.83 (m, 1H), APCl MS m/z 153.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O)[CH2:2][CH2:3][CH3:4].[NH2:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1.O=[C:21]([CH2:28][CH2:29][CH3:30])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH2:28][CH2:29][CH3:30])[NH:14][C:15]2=[N:16][NH:17][CH:18]=[C:19]12)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccccc1C=O
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCCOc1ccccc1C1C(C(=O)OCC)=C(CCC)Nc2n[nH]cc21

Procedure:
The title compound was prepared from 2-butoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:13]([CH2:15][NH2:16])[OH:14]>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:16][CH2:15][CH2:13][OH:14])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Clc1c(Br)cnc2ccccc12
Reactant: NCCO
Solvent: O
Product: OCCNc1c(Br)cnc2ccccc12
Temperature: 150 °C

Procedure:
A mixture of 9.1 g of 3-bromo-4-chloro-quinoline and 2.0 g of ethanolamine was heated at 150° C. for 30 minutes. The reaction mixture was cooled, 60 ml of water was added and the precipitate was collected by filtration and recrystallized from isopropanol. The yield was 9.5 g, mp 163°-165° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18]N4C5C=CC=CC=5N=C4C)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:29]=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[OH:37].[CH3:38][C:39]1[O:43][N:42]=[C:41]([C@:44]([OH:48])([C:46]#[CH:47])[CH3:45])[CH:40]=1>CS(C)=O.BrC1C=CC2OCCN3C(COC4C=CC=CC=4Cl)=C(C(N)=O)N=C3C=2C=1.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>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:18][C:12]1[N:8]2[CH2:9][CH2:10][O:11][C:5]3[CH:4]=[CH:3][C:2]([C:47]#[C:46][C@@:44]([OH:48])([C:41]4[CH:40]=[C:39]([CH3:38])[O:43][N:42]=4)[CH3:45])=[CH:29][C:6]=3[C:7]2=[N:14][C:13]=1[C:15]([NH2:17])=[O:16]
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: Oc1ccccc1Cl
Reactant: Cc1nc2ccccc2n1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: NC(=O)c1nc2n(c1COc1ccccc1Cl)CCOc1ccc(Br)cc1-2
Solvent: CS(C)=O
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(COc4ccccc4Cl)n2CCO3)no1
Yield: 28 %

Procedure:
Similar to as in General Procedure E with the exceptions of using Pd(PPh3)4 in DMSO, 10-bromo-3-((2-chlorophenoxy)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly to 10-bromo-3-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylbenzimidazole with 2-chlorophenol) was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound as a colorless solid (39 mg, 28%).
Reaction SMILES: [Cl:1][CH:2](P(OCC)(OCC)=O)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[OH-].[Ca+2].[OH-].[CH3:21][O:22][C:23]1[N:27]([C:28]2[CH:32]=[CH:31][S:30][C:29]=2[CH:33]=O)[C:26](=[O:35])[N:25]([CH3:36])[N:24]=1>C(OCC)(=O)C>[Cl:1][C:2](=[CH:33][C:29]1[S:30][CH:31]=[CH:32][C:28]=1[N:27]1[C:26](=[O:35])[N:25]([CH3:36])[N:24]=[C:23]1[O:22][CH3:21])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4]
Reactant: COc1nn(C)c(=O)n1-c1ccsc1C=O
Reactant: CCOP(=O)(OCC)C(Cl)C(=O)OC(C)(C)C
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1nn(C)c(=O)n1-c1ccsc1C=C(Cl)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
A solution of the title compound of Step C (0.026 g, 0.0009 mol) in ethyl acetate (2 mL) was added to a mixture of calcium hydroxide (0.068 g, 0.0009 mol) and the title compound of Step A (0.220 g, 0.0009 mol) in ethyl acetate (5 mL). The resulting mixture was stirred at 60° C. overnight. Three additional 0.026 g (0.0009 mol) portions of the title compound of Step C were added at 3 h intervals and then the temperature of the mixture was increased to 70° C. and heating was continued overnight. After 40 h of total reaction time, the reaction mixture was poured into ice water and extracted three times with ethyl acetate. The combined organic phase was washed successively with saturated aqueous NaCl and then with a 1/1 mixture of saturated aqueous NaCl and saturated aqueous sodium hydrogen carbonate, dried (Na2SO4), filtered and concentrated to a pale yellow oil. The crude product was purified by flash column chromatography on silica gel to give a preliminary fraction of 0.170 g of the title compound of Step D, a compound of the invention, as a white solid (m.p. 105-115° C.) consisting of a 7:3 ratio of Z- and E-isomers, respectively, followed by a final fraction of 0.04 g of the title compound of Step D, a compound of the invention, as a white solid (m.p. 104° C.) consisting of a 5:1 ratio of Z- and E-isomers, respectively. 1H NMR (300 MHz, CDCl3 : for the Z/E mixture): δ 7.77 and 7.00 (2d,1H total, J=0.8 Hz), 7.62 and 7.46 (2dd,1H total, J=0.8, 5.4 Hz), 7.09 and 6.98 (2dd,1H total, J=0.9, 5.4 Hz), 3.97 (s,3H), 3.45 (s,3H), 1.54 (s,9H).