Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCC/C=C/C=[CH:7]/[C:8]([O:10][C@@H:11]1[C@@:49]2([OH:51])[O:50][C@H:19]([CH2:20][CH:21]([C@H:62]([OH:64])[CH3:63])[O:22][C:23]([CH2:25][C@H:26]([OH:61])[CH2:27][C@H:28]3[O:33][C@@:32]([OH:54])([CH2:34][C@H:35]4[O:45][C@@H:44]([CH:46]=[CH:47][C:48]2([CH3:53])[CH3:52])[CH2:43]/[C:37](=[CH:38]\[C:39]([O:41][CH3:42])=[O:40])/[CH2:36]4)[C:31]([CH3:56])([CH3:55])[C@@H:30]([O:57][C:58]([CH3:60])=[O:59])[CH2:29]3)=[O:24])[CH2:18]/[C:12]/1=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[O:9].[CH3:65][CH2:66][CH2:67]CCC.CC(C)=O>C(OCC)(=O)C>[CH3:63][C@@H:62]([OH:64])[C@@H:21]1[O:22][C:23](=[O:24])[CH2:25][C@H:26]([OH:61])[CH2:27][C@H:28]2[O:33][C@:32]([OH:54])([C:31]([CH3:55])([CH3:56])[C@@H:30]([O:57][C:58]([CH2:60][CH:66]([CH3:67])[CH3:65])=[O:59])[CH2:29]2)[CH2:34][C@H:35]2[O:45][C@H:44]([CH2:43]/[C:37](/[CH2:36]2)=[CH:38]\[C:39]([O:41][CH3:42])=[O:40])[CH:46]=[CH:47][C:48]([CH3:52])([CH3:53])[C@:49]2([OH:51])[O:50][C@H:19]([CH2:18]/[C:12](/[C@@H:11]2[O:10][C:8]([CH3:7])=[O:9])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])[CH2:20]1
Reactant: CCCCCC
Reactant: CCC/C=C/C=C/C(=O)O[C@H]1/C(=C/C(=O)OC)C[C@H]2CC([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H]3C[C@H](OC(C)=O)C(C)(C)[C@](O)(C[C@@H]4C/C(=C/C(=O)OC)C[C@H](C=CC(C)(C)[C@]1(O)O2)O4)O3
Agent: CCC/C=C/C=C/C(=O)O[C@H]1/C(=C/C(=O)OC)C[C@H]2CC([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H]3C[C@H](OC(C)=O)C(C)(C)[C@](O)(C[C@@H]4C/C(=C/C(=O)OC)C[C@H](/C=C/C(C)(C)[C@]1(O)O2)O4)O3
Agent: COC(=O)/C=C1/C[C@H]2C[C@]3(O)O[C@H](C[C@@H](O)CC(=O)O[C@@H]([C@@H](C)O)C[C@H]4C/C(=C\C(=O)OC)[C@H](OC(C)=O)[C@@](O)(O4)C(C)(C)/C=C/[C@@H](C1)O2)C[C@H](OC(=O)CC(C)C)C3(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)/C=C1/C[C@H]2C[C@]3(O)O[C@H](C[C@@H](O)CC(=O)O[C@@H]([C@@H](C)O)C[C@H]4C/C(=C\C(=O)OC)[C@H](OC(C)=O)[C@@](O)(O4)C(C)(C)C=C[C@@H](C1)O2)C[C@H](OC(=O)CC(C)C)C3(C)C

Procedure:
From a succession of silica gel column chromatographies and gel permeation (Sephadex LH-20) chromatography, an active fraction (0.38 g) was isolated as a white amorphous powder with PS ED50 =1.6×10-3 μg/ml and which contained bryostatins 4-7 by TLC (7:3 n-hexane:acetone and 2:3 n-hexane:ethyl acetate). By using dry column (2×60 cm) silica gel chromatographic methods with n-hexane:acetone (5:1→1:1) and n-hexane:ethyl acetate (2:1→1:2), six fractions were selected for further purification. The first fraction contained bryostatin 4. The second, third and fifth fractions were subjected to HPLC using Partisil-10M-9-ODS-2 (C-18 reversed phase) with a 1:1→9:1 methanol:water gradient (flow rate of 2 ml/min). The second fraction (15 mg) yielded pure bryostatin 5 (14.1 mg), melting at 169°-172° C. (needles from CH2Cl2 --CH3OH); FAB MS m/z 866 for C44H66O17 :[α]27D+106.92 (c=0.028, CH3OH); uv (CH3OH) λmax 226 nm (ε 36,300); and ir (KBr) 3465, 2980-2935, 1740, 1725, 1660-1640, 1440, 1385, 1370, 1290, 1230, 1165, 1100, 1080, 1060, and 1000 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[CH:25]N(C)C)[C:20](OCC)=[O:21])=[CH:15][CH:14]=1)#[N:12].Cl.CCN(C(C)C)C(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([N:8]2[C:20]([OH:21])=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:18][CH:17]=3)[CH:25]=[N:9]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1
Reactant: Cc1cc(NN)ncc1Br
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Combined 5-bromo-2-hydrazinyl-4-methylpyridine (6.0 g, 29.85 mmol) and isopropanol (100 mL) and added ethyl 2-(4-cyanophenyl)-3-(dimethylamino)acrylate (8.02 g, 32.84 mmol) and HCl solution (aqueous, 1.85%, 49.75 mL) and stirred at room temperature for 2 h, then DIEA (19.40 g, 149.25 mmol) was added. After about 30 minutes the reaction was evaporated to give a residue which was extracted with EtOAc (50 mL×2) and water (50 mL×2), the EtOAc layers were combined and washed with brine, dried over Na2SO4 to give a residue which was purified by flash chromatography (petroleum ether:EtOAc 5:1-1:8) to give the title compound (8.67 g, 82.04%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:22]#[N:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.OCCC(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1>>[OH:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:22]#[N:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Agent: N#Cc1c[nH]c2cccc(C(CCO)c3ccccc3)c12
Product: N#Cc1c[nH]c2ccc(C(CCO)c3ccccc3)cc12

Procedure:
5-(3-Hydroxy-1-phenyl-propyl)-1H-indole-3-carbonitrile LXV (1.24 g, 79%) was prepared from 3-(3-cyano-1H-Indol-5-yl)-3-phenyl-propionic acid ethyl ester using the procedure described for 4-(3-hydroxy-1-phenyl-propyl)-1H-indole-3-carbonitrile LX (see Example 14).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH2:7][C:8]#[N:9].[C:10]([C:18]1C=CC=CC=1)(=O)[C:11]1C=CC=C[CH:12]=1.[CH3:24]CN(C(C)C)C(C)C>ClCCl>[N:9]1[C:8]2[CH:18]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][CH:24]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: N#CCN
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: c1ccc2[nH]cnc2c1
Reaction time: 18 h
Yield: 156273.7 %

Procedure:
To a stirred solution of 2-aminoacetonitrile bisulfate (2.9 g, 0.013 mmol) in dichloromethane (50 mL) was added benzophenone (3.48 mL, 0.0208 mmol) followed by DIEA (4.53 mL, 0.026 mmol). After stirring 18 h, the dichloromethane solution was washed with water (50 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified on a flash silica gel column (hexanes:EtOAc, 1:1) to give 3 (2.40 g, 82%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>>[ClH:16].[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:16])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2ncccc2c1
Product: Cl
Product: O=C(Cl)c1ccc2ncccc2c1

Procedure:
6-Quinolinecarboxylic acid was refluxed in thionyl chloride for 30 min. The excess thionyl chloride was then removed by rotary evaporation (90° C.) to provide 6-quinolinecarbonyl chloride hydrochloride.
Reaction SMILES: [ClH:1].[NH2:2][OH:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][CH2:27][N:28]3[S:31]([C:34]3[CH:39]=[C:38](Cl)[CH:37]=[CH:36][C:35]=3[O:41][CH3:42])(=[O:33])=[O:32])=[CH:24][CH:23]=2)=[O:21])=[CH:15][CH:14]=1)#[N:12]>CS(C)=O.O>[OH:3][NH:2][C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][CH2:27][N:28]3[S:31]([C:34]3[CH:39]=[C:38]([Cl:1])[CH:37]=[CH:36][C:35]=3[O:41][CH3:42])(=[O:33])=[O:32])=[CH:24][CH:23]=2)=[O:21])=[CH:15][CH:14]=1)=[NH:12]
Reactant: Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C#N)cc3)cc21
Reactant: NO
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C(=N)NO)cc3)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of hydroxylamine hydrochloride (223 mg, 3.21 mmol, 5 equiv.) in dimethyl sulfoxide (3 ml) was treated with triethylamine (0.45 ml, 3.21 mmol, 5 equiv.) and stirred at room temperature for 5 min. The white precipitate was filtered off and to the filtrate, 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-phenyl)-amide (300 mg, 0.64 mmol, 1 equiv.) (prepared as illustrated in example 37, steps 1 to 3) was added. The mixture was stirred at 75° C. for 1 hour and 15 min. The reaction mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic phase was extracted three times with 0.5 N HCl. The combined aqueous phase was adjusted to pH 9-10 with NaOH 1N and extracted three times with ethyl acetate. The combined organic phases were dried with Na2SO4 and the solvent was evaporated. Crude 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(N-hydroxycarbamimidoyl)-phenyl]-amide was obtained as a white solid, 261 mg (81%), which was used as such in the following reaction. MS (ISP): m/e=501.3 (M+H+.), δH (300 MHz; d6-DMSO) 10.25 (1H, s), 9.50 (1H, s), 7.80 (1H, s), 7.55-7.71 (7H, m), 7.28 (1H, d), 7.16 (1H, d), 5.69 (2H, s), 4.04 (2H, t), 3.60 (3H, s), 3.06 (2H, t).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][C:12]=2[CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23].[CH2:24]=[O:25].Cl>C(O)C>[CH3:21][N:22]([CH2:4][C:3]1[C:24]([OH:25])=[C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][C:12]=2[CH3:20])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=1)[CH3:23]
Reactant: CNC
Reactant: C=O
Reactant: Cc1cc(S(N)(=O)=O)sc1S(=O)(=O)c1ccc(O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1cc(S(N)(=O)=O)sc1S(=O)(=O)c1cccc(CN(C)C)c1O
Temperature: 98 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To 5-(4-hydroxyphenylsulfonyl)-4-methylthiophene-2-sulfonamide (2.0 g, 0.006 mol) in ethanol (10 ml) was added 40% aqueous dimethylamine (2.7 g, 0.024 mol) followed by 37% aqueous formaldehyde (0.59, 0.0072 mol). The solution was stirred in an oil bath (98° C.) for 161/2 hours. The solvent was removed in vacuo. The residual oil was taken up in ethyl acetate and extracted with dilute HCl. The HCl extract was basified with NaHCO3 and the product was extracted into ethyl acetate. The extract was washed with water, dried, filtered and concentrated in vacuo. This procedure gave a solid foam in 44% yield which was converted to the hydrochloride salt with ethanolic HCl. The white solid HCl salt melted at 262°-263° C. Purity and structure were confirmed by C, H, N analyses, HPLC and NMR.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.[CH3:21][N:22]([CH3:36])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](N(OC)C)=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:30](=[O:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([N:22]([CH3:36])[CH3:21])=[CH:24][CH:25]=2)[C:17]([F:20])=[N:18][CH:19]=1
Reactant: CON(C)C(=O)Cc1ccc(N(C)C)cc1
Reactant: Fc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN(C)c1ccc(CC(=O)c2cc(Br)cnc2F)cc1
Temperature: -20 °C
Yield: 42.5 %

Procedure:
Diisopropylamine (1.93 ml, 13.66 mmol) and tetrahydrofuran (80 ml) were combined and cooled to −20° C. with stirring. n-Butyl lithium (2.5 M in hexanes, 5.2 ml, 13.00 mmol) was slowly added and stirred at this temperature for 30 minutes. The temperature was decreased to −78° C. and neat 5-bromo-2-fluoropyridine (1.34 ml, 13.02 mmol) was added (internal temperature was not allowed to exceed −68° C.). The reaction mixture was stirred at −78° C. for 40 minutes. The reaction mixture was added to a solution of 2-(4-dimethylamino-phenyl)-N-methoxy-N-methyl-acetamide (2.76 g, 12.42 mmol) in tetrahydrofuran (10 ml). The combined reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was slowly warmed to room temperature, and quenched with saturate aqueous ammonium chloride. The reaction mixture was extracted with methylene chloride, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (0 to 40% ethyl acetate in hexanes) to give 1.78 g (43%) of 1-(5-bromo-2-fluoro-pyridin-3-yl)-2-(4-dimethylamino-phenyl)-ethanone. MS m/z 337.1+339.1 (M+H+).
Reaction SMILES: [CH3:1]I.[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5]C=1.C([O:11][CH2:12][CH3:13])C>>[CH2:8]([CH:7]([CH2:6][CH3:5])[CH2:1][C:12](=[O:11])[CH3:13])[CH3:3]
Reactant: CI
Reactant: c1ccccc1
Reactant: CCOCC
Product: CCC(CC)CC(C)=O

Procedure:
85.2 g methyl iodide in 50 ml of diethyl ether are added dropwise. Thereafter, 100 ml of benzene are added, and a part of the diethylether is distilled off. After addition of 33.3 g of ethyl-2-butyl-carbonitrile 19b, the mixture is heated under reflux for 5 hours. The reaction mixture is hydrolyzed with NH4Cl-solution, extracted with diethyl ether, washed with water, dried over sodium sulfate, concentrated, and distilled in vacuo over a Vigreux column. Obtained are:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:22].[OH-:28].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)(=[O:22])=[O:28])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: ClCCl
Product: O=Cc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A mixture of 4-(4-chlorophenylthio)benzaldehyde (3.63 mmol, 900 mg), 3-chloroperoxybenzoic acid (max 77%, 10.9 mmol, 2.44 g) in CH2Cl2 (5.00 mL) was stirred at room temperature for 60 min and poured into a separatory funnel with 5% aqueous KOH solution (20 mL). The phases were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with water (10 mL), brine (50 mL) and dried over MgSO4. Removal of solvents in vacuo gave a light yellow liquid. Purification by flash column chromatography (eluent: 5% EtOAc in Hexane) provided 4-[(4-chlorophenyl)sulfonyl]benzaldehyde (700 mg, 68.9% yield) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:22][NH2:23].C([O-])(=O)/C=C/C([O-])=O>C(O)(C)C>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([N:10]1[CH2:9][CH2:8][C:5]2[N:6]=[N:7][C:2]([NH:22][NH2:23])=[CH:3][C:4]=2[CH2:11]1)=[O:20]
Reactant: O=C(c1cccc(Cl)c1)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: O
Solvent: CC(C)O
Product: NNc1cc2c(nn1)CCN(C(=O)c1cccc(Cl)c1)C2

Procedure:
10.8 g of 3-chloro-6-(m-chlorobenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 50 cc of hydrazine hydrate are stirred at a bath temperature of 100° for 4 hours with the addition of 25 cc of isopropanol, and the mixture is worked up to a crude base as described in Example 17, and this crude base is converted into the fumarate in a manner analogous to that described in Example 4. The fumarate of the title compound has a M.P. of 178°-180° (decomp., from absolute ethanol).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH:2]([CH2:4][OH:5])[OH:3].[Br:9][CH:10](O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:7][CH2:8][CH2:10][Br:9])(=[O:6])[CH:2]([CH2:4][OH:5])[OH:3]
Reactant: CC(O)Br
Reactant: COC(=O)C(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(OCCBr)C(O)CO
Yield: 92 %

Procedure:
A mixture of methyl glycerate (2 g, 0.17 moles) and bromoethanol (5.28 g, 0.42 moles was heated at 60° C. under nitrogen in the presence of a catalytic amount of p-toluene sulfonic acid for 10 h. The excess bromoethanol was removed on rotary evaporator under reduced pressure. The crude mixture was diluted with large volume of chloroform (100 mL) and the free acid was neutralized by adding anhydrous sodium carbonate. Filtration and removal of the solvent gave the crude product which was purified by chromatography on a silica gel column eluting with chloroform:methanol (9:1). Removal of the solvent on a rotary evaporator gave bromoethyl glycerate (3.26 g, 92% yield) which showed the following characteristics: 1H NMR (200 MHz, CDCl3), δ 3.52 (m, 2H, CH2Br), 3.90 (m, 2H,CO2CH2), 4.27 (s, 2H, OH), 4.36 (m, 2H, CH2OH), 4.52 (m, 1 H, CH), 13C NMR (50 MHz, CDCl3) δ 28.42, 63.76, 64.50, 71.58, 172.13.
Reaction SMILES: [NH3:1].[Br:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11].BrCC1C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1>[Br:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:1])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1ccccc1CBr
Reactant: N
Agent: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1CBr

Procedure:
A solution of ammonia (1.0 ml) in tetrahydrofuran (50 ml) at -78° was contacted dropwise with a solution of a 60/40 mixture of 2-(bromomethyl)benzenesulfonyl chloride/4-(bromomethyl)benzenesulfonyl chloride (4.52 g) in tetrahydrofuran (20 ml). The stirred mixture was allowed to warm to 0° and volatiles were removed in vacuo. The residue was contacted with water (50 ml) and extracted three times with ethyl acetate. Combined organic portions were washed with brine, dried, and evaporated to give 4.00 g of white solid. 1H nmr δ(CD3)2COTMS 8.15-7.20 (m), 6.7-6.3 (m, NH), 4.95 (q, area 21), 4.55 (s, area 18), consistent with a ca. 60/40 mixture of 2-(bromomethyl)-/4-(bromomethyl)benzenesulfonamides. The sample was fractionally recrystallized from chloroform, but without significant change in isomeric content.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([Br:12])[CH:6]=1.[C:13](=[O:15])=[O:14].Cl>CCOCC.O>[Br:12][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([F:11])[CH:8]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C=O
Reactant: Fc1cc(Br)cc(Br)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1cc(F)cc(Br)c1
Reaction time: 1 h
Yield: 55.4 %

Procedure:
Magnesium turnings (1.97 g) and iodine (catalytic amount) were added to ether (150 ml), and 1,3-dibromo-5-fluorobenzene (19.6 g) in ether (20 ml) was added dropwise under nitrogen atmosphere at such a rate that gentle reflux occurred. The mixture was refluxed for 3 hours, and left to cool. Crushed dry ice was added thereto, and the mixture was stirred for 1 hour. The reaction mixture was poured into water, and acidified with hydrochloric acid. The mixture was extracted with ether (200 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1), to thereby yield 9.37 g of the target compound (yield: 55.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:18])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:22]1[CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:18][C:15]2[C:16]3[N:17]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[CH:9]=[CH:10][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:25][CH2:24][CH2:23]1.[CH:25]1([CH2:22][NH:18][C:15]2[C:16]3[N:17]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[CH:9]=[CH:10][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:23][CH2:24]1
Reactant: Nc1ncnc2ccc(-c3cccc(F)c3)nc12
Reactant: BrC1CCC1
Agent: [H-]
Agent: [Na+]
Product: Fc1cccc(-c2ccc3ncnc(NC4CCC4)c3n2)c1
Product: Fc1cccc(-c2ccc3ncnc(NCC4CC4)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the amine 1 (100 mg, 0.42 mmol) was treated with sodium hydride 60% dispersion in mineral oil (25 mg, 0.62 mmol) and bromocyclobutane (56 mg, 0.42 mmol) to provide N-cyclobutyl-6-(3-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine 27 and N-(cyclopropylmethyl)-6-(3-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine 28. LC/MS (ESI+): m/z 295 (M+H). 1H NMR (400 MHz, DMSO) δ 8.80 (t, J=6.1 Hz, 1H), 8.48 (d, J=7.2 Hz, 2H), 8.39 (d, J=10.9 Hz, 1H), 8.22 (d, J=7.9 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.60 (dd, J=14.3, 7.9 Hz, 1H), 7.34 (td, J=8.5, 2.4 Hz, 1H), 3.50 (t, J=6.5 Hz, 2H), 1.27 (dd, J=13.4, 6.1 Hz, 1H), 0.52-0.42 (m, 2H), 0.42-0.31 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:19]4[C:18]5[CH2:20][NH:21][CH2:22][CH2:23][C:17]=5[NH:16][C:15]=4[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:19]4[C:18]5[CH2:20][N:21]([C:24](=[O:26])[CH3:25])[CH2:22][CH2:23][C:17]=5[NH:16][C:15]=4[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1cc(Nc2ccc3c(c2)CCC3)c2c3c([nH]c2n1)CCNC3
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc5c(c4)CCC5)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
Indan-5-yl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (75 mg, 0.25 mmol), acetic anhydride (25 μL, 0.25 mmol), and triethylamine (102 μL, 0.74 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 64 (21 mg, 25% yield) as an oily residue. LC-MS (M+H=347, obsd.=347).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11].Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[NH:31][C:30]4[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=4[CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[N:14]=1>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[NH:31][C:30]4[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=4[CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5ccc(F)cc5F)nc34)cc21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 36.5 %

Procedure:
To NaH (60 wt % in mineral oil; 0.071 g, 1.763 mmol) in 1 mL DMF was added 2,4-difluorophenol (0.229 g, 1.76 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added and the reaction became dark red. The reaction was sealed and heated to 90° C. for 4 h, then cooled to RT and stirred overnight. The reaction was cooled and partitioned between saturated aq. NH4Cl and EtOAc. The organic layer was washed with saturated aq. NaHCO3 (1×), water (1×), saturated aq. NaCl (1×), and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-50% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 2-(2-(2,4-difluorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.036 g, 0.092 mmol, 37% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.99 (1H, br. s), 8.52 (1H, d, J=9.0 Hz), 8.09 (1H, dd, J=7.6, 1.4 Hz), 7.79-7.85 (1H, m), 7.55-7.69 (2H, m), 7.51 (1H, t, J=7.7 Hz), 7.47 (1H, d, J=9.0 Hz), 7.30 (1H, dddd, J=9.2, 7.9, 3.1, 1.5 Hz), 6.91-6.94 (1H, m), 6.90 (1H, d, J=2.3 Hz), 3.34-3.40 (2H, m), 2.52-2.57 (2H, m). m/z (ESI, +ve) 392.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][C:11](O)=[O:12])[C:3]=1[Cl:14].[NH3:15]>>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][C:11]([NH2:15])=[O:12])[C:3]=1[Cl:14]
Reactant: Nc1c(Cl)cnc(OCC(=O)O)c1Cl
Reactant: N
Product: NC(=O)COc1ncc(Cl)c(N)c1Cl
Temperature: 70 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a 75 milliliter stainless steel bomb is added 15 grams (0.06 mole) of 4-amino-3,5-dichloro-2-(pyridyloxy)acetic acid:ethyl ester, prepared as in Example I. The bomb was cooled to about minus 70° C. in a dry ice bath and thereafter 7 grams (0.04 mole) of ammonia was distilled into the bomb. The bomb was sealed and allowed to stand at room temperature for 48 hours. The bomb was opened and the unreacted ammonia allowed to escape. The solid residue which remained was removed from the bomb and recrystallized from 250 milliliters of ethanol. The 4-amino-3,5-dichloro-2-(pyridyloxy)acetamide product was dried azeotropically with benzene and was recovered in a yield of 72 percent of theoretical and melted at 192°-193° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[Cl:10]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][N:2]=1
Reactant: c1cnc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1n[nH]c2ncccc12
Temperature: 45 °C

Procedure:
1H-pyrazolo[3,4-b]pyridine (89 mg) and N-chlorosuccinimide (220 mg) were combined in CH2Cl2 (4 mL) and heated at 45° C. for 16 hr, then cooled to room temperature. The resultant mixture was purified by flash chromatography (silica gel, 50% hexane/ethyl acetate) to afford 3-chloro-1H-pyrazolo[3,4-b]pyridine.