Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([NH:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C:5]([F:16])([F:15])S(C2C=CC=CC=2)(=O)=O)[CH2:3][CH2:2]1.CC([O-])=O.[Na+].CC(O)=O.[Mg]>CN(C=O)C.O>[CH:1]1([CH:4]([NH:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH:5]([F:16])[F:15])[CH2:3][CH2:2]1
Reactant: CC(C)(C)S(=O)NC(C1CC1)C(F)(F)S(=O)(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Mg]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)NC(C(F)F)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[1-cyclopropyl-2,2-difluoro-2-(phenylsulfonyl)ethyl]-2-methylpropane-2-sulfinamide (0.8 g, 2.2 mmol) in DMF (30 mL) was added a solution of NaOAc (4.5 g, 55 mmol) in AcOH (4.5 g, 75 mmol) and H2O (7.0 mL). Magnesium turning (0.8 g, 33 mmol) was added in portions at room temperature under a water bath. The reaction mixture was stirred at room temperature overnight. Water (90 mL) was added to the solution, and the aqueous layer was extracted with EtOAc. The combined organics were washed with sat. NaHCO3, dried, concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (400 MHz, CDCl3) 5.75 (t, 1H); 3.50 (d, 1H); 2.58-2.70 (m, 1H); 1.18 (s, 9H); 0.90-1.00 (m, 1H); 0.58-0.70 (m, 2H); 0.35-0.50 (m, 2H).
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[C:12]([C:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:18]=1.[Cu](C#N)[C:20]#[N:21].[CH3:24]N(C)C=O>>[C:20]([C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[C:12]([C:15]([O:17][CH3:24])=[O:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:18]=1)#[N:21]
Reactant: O=C([O-])c1ccc2c(c1)-c1nc(I)cn1CCO2
Reactant: CN(C)C=O
Reactant: N#C[Cu]C#N
Product: COC(=O)c1ccc2c(c1)-c1nc(C#N)cn1CCO2
Yield: 81 %

Procedure:
2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate (370.1 mg, 1.0 mmol) and Copper cyanide (268.6 mg, 3.000 mmol) were mixed in 8 ml of N,N-Dimethylformamide. The reaction was microwaved on 200 watts, 150° C., for 40 minutes. The reaction mixture was partitioned between 25 ml of 5% ammonia in water and 25 ml of EtOAc. The aqueous layer was additionally extracted with 3×20 ml EtOAc, combined extracts were washed with water, brine and dried over MgSO4 to afford 225 mg of methyl 2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate. Yield 81%. (MS: 270.0).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C)C=O>[Cl-:1].[CH3:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][CH2:13][C:12]([C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][N+:31]5([CH3:30])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:8][CH:7]=4)=[O:11])=[CH:18][C:17]=3[CH:19]=2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: CN1CCCCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCCCC4)cc2)CCO3)cc1
Product: [Cl-]

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g) and 1-methylpiperidine (0.14 ml) in dimethylformamide (15 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which were recrystallized from ethanol-diethylether to give 1-(N-(7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carbonyl)-4-aminobenzyl)-1-methylpiperidinium chloride (Compound 97) (0.15 g) as colorless crystals.
Reaction SMILES: I[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].[NH3:16]>C(Cl)(Cl)Cl>[NH2:16][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15]
Reactant: N
Reactant: CSc1ccc2c(c1)CCC(I)C(=O)N2
Solvent: ClC(Cl)Cl
Product: CSc1ccc2c(c1)CCC(N)C(=O)N2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 0.5 g of 3-iodo-7-methylthio-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one and 15 g of ammonia in 20 mL of chloroform was shaken in a bomb at 100° C. for 3 hours. The bomb was cooled, vented and the contents transferred to a separatory funnel. The mixture was washed with water, dried over magnesium sulfate, filtered and solvents removed under vacuum to give the product. 1H NMR (200 MHz, CDCl3): 1.90 (m,1H), 2.3-2.7 (m,2H), 2.45 (s,3H), 2.85 (m,1H), 3.39 (dd;8,11 Hz;1H), 6.89 (d,8 Hz,1H), 7.10 (m,2H), 8.3 (br s,1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl.C(OCC)(=O)C>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: ClCc1ccccn1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2ccn(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere: to a solution of 1H-indole-6-carboxylic acid methyl ester (for synthesis see example 2a), 2.47 g, 14.1 mmol) in NMP (140 mL) was added Cs2CO3 (10.1 mg, 31 mmol) at 0° C. After stirring for 15 min 2-picolyl chloride hydrochloride (2.77 g, 16.9 mmol) was added and the mixture was stirred at room temperature for 18 h. Ethyl acetate (200 mL) was added and the mixture was washed with saturated aqueous ammonium chloride (3×150 mL) and brine (200 mL). The organic phase was dried (Na2SO4) and concentrated. The crude product was purified using column chromatography (ethyl acetate/heptane 1:3) to give the title compound as a colourless oil, which slowly crystallised on standing (2.72 g, 10.2 mmol, 72%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:18])[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)(C)(C)C.[Si]([I:24])(C)(C)C.CO>CC#N>[IH:24].[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:18]
Reactant: C[Si](C)(C)I
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1cccnc1
Solvent: CC#N
Solvent: CO
Product: I
Product: NCCC(=O)Nc1cccnc1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of [2-(pyridin-3-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (0.075 g, 0.28 mmol) in MeCN (3 ml) is added dropwise TMSI (0.05 ml, 0.34 mmol). After 30 minutes, MeOH (1 ml) is added and stirring continued for a further 20 minutes. The solvent is removed in vacuo and the crude residue is triturated with MeOH/EtOAc to afford the title compound as a cream crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[N:56][C:55]([Br:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Br:58][C:55]1[N:56]=[CH:57][C:52]([NH:51][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)=[N:53][CH:54]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Reactant: Nc1cnc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (200 mg, 0.56 mmol) and triphenylphosphine (195 mg, 0.73 mmol) in methylene chloride (4.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (128 mg, 0.73 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-bromopyrazine (200 mg, 1.12 mmol, prepared according to Tetrahedron 1988, 44, 2977–2983) and 2,6-lutidine (0.28 mL, 2.24 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution (1×20 mL), a saturated aqueous sodium bicarbonate solution (1×20 mL) and water (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate eluted to 4/6 hexanes/ethyl acetate) afforded N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (120 mg, 42%) as an off-white foam: [α]23589=−24.6° (c=0.50, chloroform); EI-HRMS m/e calcd for C20H21BrClN3O4S (M+Na)+ 536.0017, found 536.0022.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C(OC([NH:13][C@@H:14]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=1)[C:15]([O:17][CH2:18][C@H:19]([O:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])[CH3:20])=[O:16])=O)(C)(C)C.C(OC)(C)(C)C>O1CCOCC1>[S:2]([OH:5])(=[O:4])(=[O:3])[CH3:1].[NH2:13][C@@H:14]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=1)[C:15]([O:17][CH2:18][C@H:19]([O:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])[CH3:20])=[O:16]
Reactant: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: C[C@H](COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1)OC(=O)c1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
Methanesulfonic acid (3.9 mL, 60.1 mmol) was slowly added to a solution of (2R)-2-phenylcarbonyloxypropyl (2S)-2-(tert-butoxycarbonyl)amino-3-(3,4-dihydroxyphenyl)propanoate 2 (11.0 g, 22.1 mmol) in 1,4-dioxane (30 mL) while stirred at room temperature. The reaction mixture was stirred for 2 h. The solution was slowly added to methyl tert-butyl ether (MTBE) (600 mL) with vigorous stirring. The resulting suspension was filtered. The filter cake was washed three times with methyl tert-butyl ether and air dried to afford 5.48 g (54% yield) of the mesylate salt 1 as an off-white solid.
Reaction SMILES: ClC(OCC)=O.C(N(CC)CC)C.[C:14]1([CH:20]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:26][CH:25]=2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.COC([O:47][NH2:48])(C)C>C1COCC1>[CH:39]1[CH:38]=[CH:37][C:36]([CH2:35][CH:20]([C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27](/[CH:30]=[CH:31]/[C:32]([NH:48][OH:47])=[O:33])=[CH:28][CH:29]=2)=[O:22])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:41][CH:40]=1
Reactant: COC(C)(C)ON
Reactant: O=C(O)C=Cc1ccc(NC(=O)C(Cc2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(NC(=O)C(Cc2ccccc2)c2ccccc2)cc1)NO
Reaction time: 0.17 h

Procedure:
Ethyl chloroformate (1.26 mmol, 0.12 mL) and triethylamine (1.37 mmol, 0.19 mL) were added to a cooled (0° C.) solution of 3-[4-(2,3-Diphenylpropionylamino)phenyl]-2-propenoic acid (1.05 mmol, 0.39 g) in dry THF (10 mL), and the mixture was stirred for 10 min. The solid was filtered off, and O-(2-methoxy-2-propyl)hydroxylamine (3.15 mmol, 0.23 mL) was added to the filtrate. The solution was stirred for 15 min at 0° C., then was evaporated under reduced pressure, and the residue was diluted in methanol (10 mL). Amberlyst® 15 ion-exchange resin (105 mg) was added to the solution of the O-protected hydroxamate, and the mixture was stirred at room temperature for 1 h. After, the reaction was filtered and the filtrate was concentrated in vacuo to give the crude MC1895 which was purified by crystallization. 1H NMR (DMSO-d6) δ 3.05 (m, 1H, PhCH2), δ 3.60 (m, 1H, PhCH2), δ 3.75 (m, 1H, PhCHCO), δ 6.36 (d, 1H, PhCH═CHCOOEt), δ 7.15-7.70 (m, 15H, benzene protons and PhCH═CHCOOEt), δ 9.00 (s, 1H, OH), δ 10.23 (s, 1H, CONHPh), δ 10.85 (s, 1H, NHOH). Anal. C, H, N, O.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[C:9]([Cl:15])[CH:8]=1)[CH3:6])[CH3:2].C(O[CH:20]([CH3:31])[C:21](OCC)(OCC)OCC)C.Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:31]=[CH:20][CH:21]=[N:14]2)=[C:9]([Cl:15])[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(C)C(OCC)(OCC)OCC
Reactant: CCOC(=O)C(C)c1ccc(NN)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(-n2cccn2)c(Cl)c1
Yield: 82.8 %

Procedure:
2.11 g (8.7 mmoles) of 2-(3-chloro-4-hydrazinophenyl)propionic acid ethyl ester and 1.91 g of tetra-ethoxypropane are dissolved in 2 ml of absolute ethanol. The solution is saturated with hydrochloric acid gas and left to stand for half an hour. The solvent is evaporated off; the residue is distilled. 2 g (83%) of 2-[3-chloro-4-(pyrazol-1-yl) phenyl] propionic acid ethyl ester (b.p. 120° C./10-2 mm Hg) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[S:13])=[CH:10][N:9]=1.[CH3:17][O:18][C:19](=[O:26])[CH2:20][C:21](=O)[CH:22](Br)[CH3:23].[CH2:27](O)C>>[CH2:17]([O:18][C:19](=[O:26])[CH2:20][C:21]1[N:14]=[C:12]([C:11]2[CH:10]=[N:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:16][CH:15]=2)[S:13][C:22]=1[CH3:23])[CH3:27]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=S)c1ccc(-c2ccccc2F)nc1
Reactant: CCO
Product: CCOC(=O)Cc1nc(-c2ccc(-c3ccccc3F)nc2)sc1C

Procedure:
A mixture of 6-(2-Fluoro-phenyl)-thionicotinamide (1.5 g, 6 mmol) and 4-Bromo-3-oxo-pentanoic acid methyl ester (1.51 g, 7.2 mmol) in ethanol (100 mL) is heated to reflux for 24 h, and concentrated. The residue is purified by column chromatography on silica gel yielding 1.7 g of the product.
Reaction SMILES: CN1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[C:5](=O)N(C)C1=O.COC1N=C(OC)C(B2OC(C)(C)C(C)(C)O2)=CN=1.CCN(CC)CC.[CH3:46][O:47][C:48]1C=C(Br)C=[CH:50][C:49]=1[OH:55].COC1C=C(C=C(B2OC(C)(C)C(C)(C)O2)C=1OC)C=O.B([O-])([O-])[O-]>>[CH3:46][O:47][C:48]1[CH:5]=[C:6]([B:8]2[O:9][C:10]([CH3:15])([CH3:16])[C:11]([CH3:13])([CH3:14])[O:12]2)[CH:7]=[CH:50][C:49]=1[OH:55]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(=O)n(C)c1=O
Reactant: COc1cc(Br)ccc1O
Agent: COc1cc(C=O)cc(B2OC(C)(C)C(C)(C)O2)c1OC
Agent: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Agent: [O-]B([O-])[O-]
Solvent: CCN(CC)CC
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Solution 1 was transferred under N2 to a pressure-equalising dropping funnel and added to Solution 2 over 6 h. Stirred at RT overnight before heating at 40-50° C. for 8 h. After stirring overnight at RT a white ppt had formed. NEt3 (149 ml; 1.07 mol) was added followed by slow addition of 2-methoxy-4-bromophenol (91.6 g; 0.451 mol). Finally, the activated catalyst (Solution 3) was added and the resultant dark brown solution was stirred at 100° C. GC analysis after 20 hours showed the desired borate compound at 11.1 minutes (62%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O:24]1[CH2:29][CH2:28][O:27][C:26]2[C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=[CH:33][C:25]1=2>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:34]([C:30]2[C:26]3[O:27][CH2:28][CH2:29][O:24][C:25]=3[CH:33]=[CH:32][CH:31]=2)=[O:35])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3cccc4c3OCCO4)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid as brown solid (40%). MS 480 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[N+:18]([O-:20])=[O:19])[CH2:4][CH3:5])[CH3:2].C(O)C.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].C(=O)(O)[O-].[Na+]>O>[CH2:1]([CH:3]([NH:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([CH3:17])[C:10]([CH3:16])=[CH:11][C:12]=1[NH2:13])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: CCC(CC)Nc1c(N)cc(C)c(C)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 3 h

Procedure:
N-(1-Ethylpropyl)-2,6-dinitro-3,4-xylidine (100 g.) is dissolved in 2500 ml. of ethanol and a solution of sodium sulfide nonahydrate (240 g.) and sodium bicarbonate (84 g.) in 500 ml. of water is added at 25°-42° C. The mixture is heated to 65° C. and held at 60°-65° C. for 3 hours. The mixture is then poured into water and extracted 3 times with 1 liter portion of ether. The ether extracts are combined and dried over magnesium sulfate. Removal of the drying agent and solvent leaves a dark solid which is recrystallized 3 times from hexane and then 3 times from hexane-ethanol. The product (35.0 g.), an orange solid, has m.p. 80°-82° C. Analysis Calcd. for C13H21N3O2 : C, 62.12; H, 8.41; N, 16.71. Found: C, 62.41; H, 8.33; N, 16.47.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:18])[N:6]([CH2:8][CH2:9][C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5](=[O:18])[N:6]([CH2:8][CH2:9][C:10]#[C:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:7]=2)=[CH:22][CH:21]=1
Reactant: O=c1ccc(Br)cn1CCC#Cc1ccccn1
Reactant: OB(O)c1ccc(F)cc1
Product: O=c1ccc(-c2ccc(F)cc2)cn1CCC#Cc1ccccn1
Yield: 35.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 83, from 5-bromo-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one (50 mg, 0.16 mmol) and 4-fluorophenylboronic acid (35 mg, 0.25 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 18 mg (57 μmol, 34%) of 5-(4-fluoro-phenyl)-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:16]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](=[O:33])[C:23]2[C:18](=[CH:19][C:20]([Cl:34])=[CH:21][CH:22]=2)[N:17]=1)[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:45]1([CH3:54])[CH:50]=[CH:49][C:48]([C:51](Cl)=[O:52])=[CH:47][CH:46]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C@@H:12]([C:16]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](=[O:33])[C:23]2[C:18](=[CH:19][C:20]([Cl:34])=[CH:21][CH:22]=2)[N:17]=1)[CH:13]([CH3:15])[CH3:14])[C:51](=[O:52])[C:48]1[CH:49]=[CH:50][C:45]([CH3:54])=[CH:46][CH:47]=1)([CH3:3])([CH3:4])[CH3:2].[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:16]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](=[O:33])[C:23]2[C:18](=[CH:19][C:20]([Cl:34])=[CH:21][CH:22]=2)[N:17]=1)[CH:13]([CH3:15])[CH3:14])[C:51](=[O:52])[C:48]1[CH:49]=[CH:50][C:45]([CH3:54])=[CH:46][CH:47]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(NCCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)[C@@H](c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Reaction time: 6 h

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, nitrogen inlet and cold bath was charged with 16.0 g of {3-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-propyl}carbamic acid tert-butyl ester (the compound of Formula 302 prepared, e.g., as described in Example 1.7 or 3.2), 80 mL of DCM and 9.1 g (12 mL) (2.2 eq) of DIPEA and stirred until dissolved. To the stirring solution, p-toluoyl chloride 5.5 g (4.7 mL) (1.1 eq) was added and stirring continued for approximately 6 hours until the reaction was determined to be completed by TLC (hexanes/ethyl acetate 1:1). The reaction was quenched with methanol (5 mL) and stirred for an additional 30 minutes, then cooled followed by addition of 1N hydrochloric acid (exothermic) to wash until acidic. The resulting solution was dried over sodium sulfate, the solvents stripped under vacuum at 30–40° C. The crude product thus obtained was purified on a silica gel column (eluted with 15% ethyl acetate in hexanes) and concentrated to give the title compound of Formula 304 {3-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester as an off-white foam solid, 10.8 g (60% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[OH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[C:32]([CH3:39])=[C:33]([CH:37]=O)[NH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:37]\[C:33]1[NH:34][C:35]([CH3:36])=[C:31]([CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([OH:23])[CH2:29][CH2:28]2)[C:32]=1[CH3:39])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCC(O)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCC(O)CC1
Temperature: 25 °C

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (150 mg, 0.42 mmol), 4-(4-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (99 mg, 1 eq.) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for days. The reaction was concentrated and the residue was purified on a silica gel column to give the titled compound as a pale greenish-brown solid.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[NH2:10][CH2:11][C:12]1[O:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>O>[NH2:8][C:7]1[C:2]([NH:10][CH2:11][C:12]2[O:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=2)=[N:3][CH:4]=[N:5][C:6]=1[Cl:9]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: NCc1ccc(CO)o1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1c(Cl)ncnc1NCc1ccc(CO)o1
Reaction time: 10 h
Yield: 76.6 %

Procedure:
A mixture of 16.3 parts of 4,6-dichloro-5-pyrimidinamine, 14 parts of 5-(aminomethyl)-2-furanmethanol, 12 parts of N,N-diethylethanamine and 200 parts of water was stirred for 10 hours at reflux temperature. The reaction mixture was evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH(NH3) 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 19.5 parts (76.6%) of 5-[[(5-amino-6-chloro-4-pyrimidinyl)amino]methyl]-2-furanmethanol; mp. 136.7° C. (interm. 17).
Reaction SMILES: [NH:1]1[C:6](=[O:7])[C:5](=[O:8])[NH:4][C:3]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:2]1=2.O.[BH4-].[Na+].Cl>C(O)C>[OH:16][CH:15]1[C:2]2[NH:1][C:6](=[O:7])[C:5](=[O:8])[NH:4][C:3]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]1=2
Reactant: O=C1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c2c([nH]c1=O)C(O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a stirred suspension of 9H-indeno[1,2-b]pyrazine-2,3,9(1H,4H)-trione.-1H2O (5.0 g, 21.5 mmol) in 200 ml of ethanol and 30 ml of water was added sodium borohydride (1.76 g, 46.5 mmol) in four portions over 2 hours, then 200 ml of water was added and the mixture was stirred for 18 hours at room temperature. The reaction mixture was acidified with hydrochloric acid (70 ml, 1N) to pH 1.5 and the precipitate was filtered off, washed with water and dried to give 4.59 g (91%) of the title compound. M.p.>300° C. 1H-NMR (DMSO-d6, δ): 5.1 (d, 1H), 5.72 (d, 1H), 7.15 (t, 1H), 7.28 (t, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 12.0 (s, 1H), 12.25 (s, 1H).