Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]([O:12][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:11])[C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: OCc1ccccc1
Reactant: Cc1cc(O)c([N+](=O)[O-])c(=O)n1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cc(O)c([N+](=O)[O-])c(=O)n1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
0.5 g (2.19 mmol) of 4-hydroxy-6-methyl-3-nitro-2-oxo-1,2-dihydropyridine-1-acetic acid is suspended in 5 ml of dichloromethane, 250 μgl (2.41 mmol) of benzyl alcohol and 0.5 g (2.45 mmol) of 1,3-dicyclohexylcarbodiimide in solution in 5 ml of dichloromethane are added. The mixture is kept stirred for 3 hours at room temperature, it is diluted with 20 ml of dichloromethane, filtered and evaporated. The residue is recrystallized from ethanol. 0.57 g of product is obtained.
Reaction SMILES: [O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3]([Cl:14])=[O:4]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(=O)c1cccs1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a solution of oxo-thiophen-2-yl-acetic acid (8 g, 51.2 mmol), suspended in DCM (80 ml) and cooled to 5° C., is added oxalylchloride (5.3 ml, 61.5 mmol), followed by DMF (0.1 ml). Stirring is continued for 1 hour at 5° C. and 18 hours at room temperature. The reaction mixture is evaporated to dryness, toluene is then added and the mixture is evaporated once more to give the title compound as a dark oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[CH:4][CH:3]=1.[N+:32]([O-:35])([OH:34])=[O:33]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[N+:32]([O-:34])=[O:33])[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[CH:20][C:21]([N+:32]([O-:35])=[O:33])=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Solvent: CC(=O)OC(C)=O
Product: O=c1c2cnn(-c3ccc([N+](=O)[O-])cc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Product: O=c1c2cnn(-c3ccccc3[N+](=O)[O-])c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (50 mg, 0.104 mmol) is dissolved in 5 mL of acetic anhydride. Concentrated nitric acid (300 μL) is added dropwise over 2 minutes. After the reaction mixture is stirred for 15 minutes, the voiatiles are stripped off and the resulting crude material is purified by column chromatography to give 5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(2-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one and 5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]([CH3:31])[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH:7]2SC>[Ni].CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]([CH3:31])[CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21]2)=[O:15])=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: CSC1C(=O)Nc2c(Cl)ccc(C(=O)N3CCC(N(C)CCc4ccccc4)CC3)c21
Agent: [Ni]
Solvent: CO
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2ccc(Cl)c3c2CC(=O)N3)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
1.50 g of 7-chloro-3-methylthio-4-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinylcarbonyl}-oxindole was added to a suspension of 15 g of Raney nickel in 30 ml of methanol. The mixture was stirred at room temperature for 1 hour. The Raney nickel was separated by decantation and washed with methanol. The decanted solution and the washings were combined and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (eluant: methylene chloride/methanol=30/1). The product was converted into a hydrochloride in ethanol to obtain 0.63 g of 7-chloro-4-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinylcarbonyl}oxindole hydrochloride as a colorless amorphous.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH2:13]([O:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:27][N:28]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:26])=[CH:29][CH:30]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 90 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-(benzyloxy)benzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 247 mg of the title compound (90%) as a yellow powder in 98.9% purity by HPLC (Rt: 5.03, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: COCC[NH2:5].[Br:6][CH2:7][C:8](Br)=[O:9].[C:11]([O:14][CH2:15]C)(=O)[CH3:12]>ClCCl>[CH3:15][O:14][CH2:11][CH2:12][CH:7]([Br:6])[C:8]([NH2:5])=[O:9]
Reactant: COCCN
Reactant: O=C(Br)CBr
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: COCCC(Br)C(N)=O
Reaction time: 8 h
Yield: 66 %

Procedure:
2-methoxyethylamine (0.750 g, 10 mmol) was dissolved in 50 ml dichloromethane in a 100-ml round-bottom flask, and cooled in an ice-water bath. Bromoacetyl bromide (1 g, 5 mmol) was added dropwise via syringe, and the reaction was continued overnight. The reaction mixture was added to 260 ml ethyl acetate and 2.5 ml dichloromethane, and the solution was washed with two portions each of water and of saturated NaCl(aq). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation to leave 0.64 g of 2-methoxyethylbromoacetamide (66% yield) as a yellow oil.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH:15]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>>[CH:15]1([C:20]([N:6]2[CH:7]([C:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:23][CH:24]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=C(Cl)C1CCCC1
Product: O=C(C1CCCC1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
Cyclopentyl-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, cyclopentanecarboxylic acid chloride, and indole according to GP 2. Yield, 10%. 1H-NMR (DMSO-d6): δ=1.28-1.43 (m, 2H), 1.47-1.75 (m, 4H), 1.90-2.04 (m, 2H), 3.14-3.26 (m, 1H), 6.07 (s, br., 1H), 6.95-7.10 (m, 3H), 7.16 (td, J=7.6 Hz, J=1.6 Hz, 1H), 7.20-7.31 (m, 3H), 7.35-7.42 (m, 1H), 7.44-7.52 (m, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.93 (d, J=7.4 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 10.61 (s, 1H); (+)-ESI-MS: m/z=393 [M+H]+, 276 [M-indole+H]+, 180.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C@H:8]1[CH2:11][C@H:10]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:9]1.O.C[O-].[Na+]>CO>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C@H:8]1[CH2:9][C@H:10]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:11]1
Reactant: COC(=O)c1ccc2nc([C@H]3C[C@H](N4CCCC[C@@H]4C)C3)sc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCCN1[C@H]1C[C@H](c2nc3ccc(C(=O)O)cc3s2)C1
Temperature: 23 °C
Reaction time: 24 h

Procedure:
Methyl 2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxylate (Example 143A, 2.0 g, 5.8 mmol) was dissolved in methanol (600 mL), followed by H2O (300 mg, 16.7 mmol) and sodium methoxide (1.4 g, 26 mmol) at 23° C. The reaction mixture was then allowed to stir at 23° C. for 1 day. Solvent and excess of water were removed. HCl (2N) was added to make the mixture slightly acidic (pH ˜5-6). Excess of water was removed. The solid was triturated with CH2Cl2/MeOH, and filtrated. The solvents of the filtrate were removed under vacuum. The residue was treated with CH2Cl2 and filtrated again. Removal of the solvent gave the desired product as an off-white solid (2.13 g, 100%). 1H NMR (300 MHz, CD3OD): δ=8.54 ppm (d, J=1.3 Hz, 1H), 8.11 (dd, J=8.9, 1.3 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 4.00 (m, 1H), 3.80 (m, 1H), 2.70-3.10 (m, 7H), 2.00 (m, 2H), 1.80 (m, 2H), 1.65 (m, 2H), 1.41 (d, J=6.8 Hz, 3H). MS (ESI, M+H+): 331.0.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:36])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[O:35][CH:34]=[N:33][CH:32]=4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[CH:44]1([NH:47][C:48](OC2C=CC=CC=2)=[O:49])[CH2:46][CH2:45]1.C(OCC)(=O)C>CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:36])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[O:35][CH:34]=[N:33][CH:32]=4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][N:14]([C:48]([NH:47][CH:44]2[CH2:46][CH2:45]2)=[O:49])[CH2:13][CH2:12]1
Reactant: O=C(CC1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCNCCS1(=O)=O)NOC1CCCCO1
Reactant: O=C(NC1CC1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CC1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCN(C(=O)NC2CC2)CCS1(=O)=O)NOC1CCCCO1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (100 mg) in N,N-dimethylformamide (3 ml) was added triethylamine (57 mg) and cyclopropylaminocarbonyloxybenzene (40 mg) and the reaction mixture was heated at 50° C. for 4 hours. The mixture was added ethyl acetate and the solution was washed with successively water, a 5% aqueous citric acid-solution, a satuated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel 60 (2% methanol-chloroform) to give N-(2-tetrahydropyranyloxy)-2-[4-cyclopropylaminocarbonyl-7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (65 mg) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[C:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[C:25]([N:28]1[CH2:33][CH2:32][N:31]([C:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]3[NH:13][C:12]4[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=4[N:10]=3)=[O:6])=[CH:3][C:2]=2[Cl:1])=[O:24])[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CC1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, N-acetylpiperazine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.13 minutes; C22H21Cl2N5O3 (474.35); mass spectrum: (M+H)+=474.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:21])[NH:17][C:18](=[S:20])[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:22]#[N:23])[CH3:2].IC.[CH:26](N(C(C)C)CC)(C)C.CCCCCC>C(O)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:21])[N:17]=[C:18]([S:20][CH3:26])[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:22]#[N:23])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(=S)NC3=O)cc12
Solvent: CCCCCC
Solvent: CCO
Solvent: CI
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
To the suspension of 4-ethoxy-6-[4-oxo-2-thioxo-thiazolidin-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14f) (1.7 g, 5 mmol), iodomethane (0.62 mL, 10 mmol) and DIEA (diisopropylethylamine) (1.7 mL, 10 mmol) in anhydrous ethanol (25 mL) was stirred at room temperature for 24 h. After adding hexane (50 mL), the solid was collected by filtration, washed with hexane and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded to obtain 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile(1.25 g, 75%) as a yellow solid. LC-MS m/e 356 (MH+)
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15](O)=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:25]1([C:31](=[O:39])[CH2:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:9][C:10]2[S:11][C:12]([C:15]([N:36]3[CH2:37][CH2:38][N:33]([CH2:32][C:31]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:39])[CH2:34][CH2:35]3)=[O:16])=[CH:13][N:14]=2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(C(=O)c2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acid (53 mg, 0.15 mmol), 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (42 mg, 0.19 mmol), and HBTU (71 mg, 0.19 mmol) were weighed out and added to a 25 mL reaction flask. DMF (2 mL) and DIEA (65 μL, 0.37 mmol) were added. The reaction was stirred under nitrogen at ambient temperature overnight. The reaction was diluted with EtOAc (10 mL) and quenched with saturated aqueous NH4Cl (10 mL). After separation and extraction with EtOAc (2×5 mL) the combined organic portions were dried over MgSO4. Purification with silica gel chromatography (10% EtOAc and 1% MeOH in CH2Cl2) afforded 17 mg (31%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O.O=[C:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[C:3]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)/C=C/c1ncc(Cl)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1ncc(Cl)cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
To a dichloromethane (377 ml) solution of ethyl (2E)-3-(3-amino-5-chloropyridin-2-yl)acrylate (37.7 g) and trifluoroacetic acid (12.7 ml) was added tert-butyl 4-oxopiperidine-1-carboxylate (49.7 g). After stirring at room temperature for 15 minutes, sodium triacetoxyborohydride (70.5 g) was added, and stirred at 40° C. for 1.5 hours. After the reaction solution was brought back to room temperature, dichloromethane and a saturated aqueous sodium hydrogen carbonate solution were added and the solution was separated, and the aqueous layer was extracted with dichloromethane. The collected organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in methanol (2 ml), and 1.7% palladium-fibroin (10 g) was added, followed by stirring at room temperature for 18 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-{[5-chloro-2-(3-ethoxy-3-oxopropyl)pyridin-3-yl]amino}piperidine-1-carboxylate (55.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N:10]([CH3:12])[CH3:11])[C:5]([Cl:13])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31]CNC[CH2:27]2)=[N:18]1.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N:10]2[CH2:12][CH2:27][N:26]([C:19]3[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[S:17][N:18]=3)[CH2:31][CH2:11]2)[C:5]([Cl:13])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CN(C)C=Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(Cl)c(C=CN2CCN(c3nsc4ccccc34)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,5-Dichloro-4-(2-dimethylaminoethenyl)-nitrobenzene (15 g, 0.057 mol) and 4-(1,2-benzisothiazol-3-yl)-piperazine (18.9 g, 0.086 mol) were combined in acetic acid (150 ml) and stirred overnight at room temperature under a nitrogen atmosphere. The slurry was poured slowly into a mixture of hexanes (300 ml) and isopropanol (300 ml) with stirring. The product was isolated by filtration as a brick red solid and washed with hexanes. The yield was 23.4 g, 93%; mp 194°-5° C. NMR (CDCl3) δ 8.05 (s, 1), 7.95-7.80 (m, 2), 7.56-7.35 (m, 3), 7.01 (d, 1), 5.60 (d, 1), 3.95-3.46 (m, 8). Analysis Calculated for C19H16N4O2Cl2S: C, 52.41; H, 3.70; N, 12.87. Found: C, 52.05; H, 3.36; N, 12.58.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Cl.C(OCC)(=O)C>CN(C)C=O.O>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Cl:1]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1nc2ccccc2n1Cc1ccccn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
61.0 g of 2-chlorobenzimidazole are first added at 25° C. to a suspension of 41.9 g of sodium hydride (55-60% dispersion) in 500 ml of dimethylformamide, and 66.0 g of 2-picolyl chloride-hydrochloride are then added. The mixture is stirred for 1 hour at room temperature and for a further 2 hours at 60° C. After dilution with 1 liter of ethyl acetate, 250 ml of water are carefully added dropwise, the phases are separated, and the ethyl acetate phase is concentrated in vacuo. The remaining product melts at 75°-77° C.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH2:35][OH:36])[CH:24]=[C:23]1[CH2:37][CH2:38][N+:39]([O-:41])=[O:40])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:45]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]([OH:45])=[O:36])[CH:24]=[C:23]1[CH2:37][CH2:38][N+:39]([O-:41])=[O:40])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:11])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1CO
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1C(=O)O

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-4-(2-nitroethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 221, 4.1 g, 6.92 mmol) according to the procedure described for Intermediate 19. The desired product was obtained as an off-white foam (4.0 g, 98%).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:12])=O>ClCCl>[ClH:12].[Cl:12][CH2:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ncccc1F
Solvent: ClCCl
Product: Cl
Product: Fc1cccnc1CCl
Temperature: -10 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a solution of 2-hydroxymethyl-3-fluoropyridine (3.43 g, 27 mmol) in dichloromethane (30 mL) cooled to -10° C. was added neat thionyl chloride (4.4 mL, 60 mmol) dropwise over 5 minutes. The resultant pale green solution was stirred at -10° C. for 3 hours followed by evaporation to dryness to provide 4.66 g (.95%) of the titled product as an off-white crystalline solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>ClCCl>[Br:13][CH2:12][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Cl)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1CBr
Temperature: 80 °C
Reaction time: 16 h
Yield: 25.2 %

Procedure:
A mixture of methyl 5-chloro-2-methylbenzoate (3.13 g, 17.0 mmol), N-bromosuccinimide (3.17 g, 17.8 mmol), benzoyl peroxide (0.41 g, 1.70 mmol), and carbon tetrachloride (80 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the mixture was diluted with dichloromethane (200 mL) and washed with saturated sodium hydrogen carbonate aqueous (150 mL), and brine (150 mL). The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (60:1) to afford 1.13 g (25%) of the title compounds as colorless oil: 1H-NMR (CDCl3) δ 7.96 (1H, d, J=2.2 Hz), 7.46–7.40 (2H, m), 4.92 (2H, s), 3.96 (3H, s).