Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:14]([O:16]C)=O)[C:10]([O:12]C)=O.[NH2:18][C:19]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][NH:21][N:20]=1.C(N(CCCC)CCCC)CCC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([OH:12])=[N:18][C:19]2[N:20]([N:21]=[CH:22][C:23]=2[C:24]([O:26][CH3:27])=[O:25])[C:14]=1[OH:16]
Reactant: COC(=O)C(C(=O)OC)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1c[nH]nc1N
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)c1cnn2c(O)c(-c3ccc(Cl)cc3Cl)c(O)nc12
Temperature: 185 °C
Reaction time: 3 h

Procedure:
5.5 g of dimethyl 2-(2,4-dichlorophenyl)malonate and 2.8 g of methyl 3-aminopyrazole-4-carboxylate were mixed with 4 g of tri-n-butylamine and stirred at 185° C. for 3 h; the liberated methanol was distilled off during this operation. The mixture was then cooled and excess tri-n-butylamine was removed under reduced pressure. The resulting product was reacted crude, without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][P:26](=[O:29])([OH:28])[OH:27])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1.C([O-])([O-])=O.[Ca+2:34]>O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][P:26](=[O:27])([O-:28])[O-:29])(=[O:23])=[O:24])=[CH:20][CH:21]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1.[Ca+2:34]
Reactant: COc1ccc(-c2c(Cl)ncn2-c2ccc(S(=O)(=O)NP(=O)(O)O)cc2)cc1F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: COc1ccc(-c2c(Cl)ncn2-c2ccc(S(=O)(=O)NP(=O)([O-])[O-])cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A suspension of N-[4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]phenylsulfonyl]phosphoramidic acid (0.3 g, 0.65 mmol) (obtained in example 6) and CaCO3 (66 mg, 0.66 mmol) in H2O (38 mL) was stirred at room temperature for 1 h. A white solid was formed, which was collected by filtration, washed with H2O and dried, to afford the title compound of the example in 71% yield.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH:14]([N:21]=[C:22]=[S:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:22]([NH:21][C@@H:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[S:23])(=[O:10])=[O:11]
Reactant: CC(N=C=S)c1ccccc1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: C[C@@H](NC(=S)NS(=O)(=O)c1sc(Cl)cc1N)c1ccccc1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and D-α-methylbenzyl isothiocyanate by a procedure analogous to the procedure described in example 3-a (yield 96% impure product); 1H-NMR (DMSO-d6): δ1.46 (d, 3H, CH3), 5.36 (quint, 1H, CH), 6.45 (br s, 2H, NH2), 6.64 (s, 1H, H-4), 7.2-7.4 (m, 5H, ArH), 8.53 (br d, 1H, NH), 11.3 (br s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]1[CH2:16][O:15]1)[C:7]#[N:8])([O-:3])=[O:2].[CH:17]12[CH2:25][CH:21]([CH2:22][NH:23][CH2:24]1)[CH2:20][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18]2.O>CC(O)C>[C:7]([C:6]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH:14]([OH:15])[CH2:16][N:23]2[CH2:24][CH:17]3[CH2:25][CH:21]([CH2:20][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18]3)[CH2:22]2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)#[N:8]
Reactant: N#Cc1ccc(OCC2CO2)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3[N+](=O)[O-])C2)C1
Yield: 54 %

Procedure:
3-Nitro-4-(2-oxiranylmethoxy)benzonitrile (2.9 g; 13.2 mmol; from step (a) above) was added to a stirred solution of tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (3 g; 13.2 mmol; see Example F above) in IPA:H2O (12.5 mL; 9:1), and the reaction mixture was refluxed for 3 h. Concentration of the reaction mixture and purification by column chromatography (DCM:MeOH; 15:1) gave the title compound in a 54% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:23]=[CH:22][C:14]3[O:15][C:16]4[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=4[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>[Ni].C(O)C>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:23]=[CH:22][C:14]3[O:15][C:16]4[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=4[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc2oc3c(c2c1)CCCC3)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(C(=O)Nc2ccc3oc4c(c3c2)CCCC4)cc1
Yield: 26.1 %

Procedure:
A mixture of 4-nitro-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (0.67 g, 2.0 mmol) and Raney nickel (-1 g wet weight) in ethanol (200 mL) was hydrogenated at 40 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was recrystallized from acetonitrile to give 4-amino-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (0.16 g). Mp 207-208° C; Anal. Calcd. for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14; Found: C, 74.29; H, 5.74; N, 9.08.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[F-].[Cs+]>O1CCOCC1.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>[CH2:15]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)[CH:14]=[CH2:13]
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: C=CCc1ccc(C(=O)OC)c(F)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
Methyl 4-bromo-2-fluorobenzoate (424 mg, 1.82 mmol), allyl tributyl tin (0.846 mL, 2.73 mmol), tetrakis(triphenylphosphine)palladium (0) (105 mg, 0.091 mmol) and cesium fluoride (415 mg, 2.73 mmol) were heated to reflux in 1,4-dioxane (10 mL) for 7 hours under argon atmosphere. The mixture was cooled to room temperature, and then filtered through diatomaceous earth by ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2%→10%) to give methyl 4-allyl-2-fluorobenzoate (333 mg, 94%) as a pale yellow viscous material.
Reaction SMILES: [C:1]1([C@@H:7]2[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH2:9][N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:10]1[CH2:9][N:8]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC(OS(=O)(=O)C(F)(F)F)=C[C@H]1c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Temperature: 90 °C

Procedure:
A deoxygenated mixture of crude tert-butyl (2S)-2-phenyl-4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydro-1H-pyrrole-1-carboxylate (5-4, 7.65 mmol), 2,5-difluorophenyl boronic acid (1.81 g, 11.5 mmol), aqueous Na2CO3 solution (2 M, 11.5 mL, 23.0 mmol), and Pd(PPh3)4 (0.442 g, 0.383 mmol) in dioxane (100 mL) was heated at 90° C. for 45 min. The reaction mixture was cooled, then partitioned between brine (200 mL) and a 1:1 mixture of ethyl acetate and hexane (200 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (SiO2, 0-50% EtOAc/hexanes gradient) to provide tert-butyl (2S)-4-(2,5-fluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5) as a white solid. LRMS m/z (M+H—CH3) 358.0 found, 358.2 required.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[N:18]=1)[CH2:14][CH2:15][CH3:16].C[Si]([N:31]=[C:32]=[S:33])(C)C>C1C=CC=CC=1>[CH2:13]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][CH2:22][CH2:21][CH:20]([C:32](=[S:33])[NH2:31])[C:19]=2[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1ccc2c(n1)CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: c1ccccc1
Product: CCCCc1ccc2c(n1)C(C(N)=S)CCC2
Yield: 16.1 %

Procedure:
By the method described in Example 11 using di-isopropylamine (4.45 ml 0.03 mol) in benzene (50 ml), n-butyl lithium solution (9% w/v, 13.5 g, 0.03 mol), 2-butyl-5,6,7,8-tetrahydroquinoline (6 g, 0.03 mol) and trimethylsilyl isothiocyanate (4.45 ml 0.033 mol) was obtained 2-butyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (1.2g, 15%) m.p. 54-6° C. (Found: C, 68.0; H, 8.4; N, 11.2. C14H20N2S requires C, 67.8; H, 8.1; N, 11.3%).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1>>[O:16]=[C:12]([CH3:11])[CH2:13][C:14]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(C)O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)CC(=O)OC(C)(C)C

Procedure:
To tert-butyl alcohol [79 g (1.07 mol.)] heated at 80° to 85° C. was added, while stirring, anhydrous sodium acetate [0.4 g (4.8 mmol.)]. To the mixture was then added dropwise diketene [96 g (1.14 mol.)] in the course of 2.5 hours. During the initial 15 minutes, the addition was carried out at 60° to 70° C., then while heating up to 110° to 115° C. After the dropwise addition of diketene, the resulting blackish brown reaction mixture was stirred for further 30 minutes, immediately followed by distillation under reduced pressure to afford tert-butyl 3-oxobutyrate, b.p. 85° C./20mmHg. The yield was 135 g (80%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.CN(C)C=O.[CH2:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:31][C@@H:30]([F:32])[C@H:29]([F:33])[CH2:28]2)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH2:14]([C:21]1[C:26]([I:1])=[CH:25][CH:24]=[C:23]([N:27]2[CH2:28][C@@H:29]([F:33])[C@H:30]([F:32])[CH2:31]2)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: F[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1F
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: F[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1F
Reaction time: 8 h
Yield: 100.2 %

Procedure:
94 mg of N-iodosuccinic acid imide was added little by little to 5.0 ml of an N,N-dimethylformamide solution containing 104 mg of 2-benzyl-6-[(3R,4R)-3,4-difluoropyrrolidine-1-yl]pyridine under ice-cooling, followed by stirring overnight as it was. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic phase was washed with an aqueous sodium thiosulfate solution, water and brine, and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (10:1), to give 152 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1.[NH2:32][CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35].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>CN(C=O)C>[CH3:37][N:36]([CH3:38])[C:34]([CH2:33][NH:32][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:29])([F:31])[F:30])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:15])=[O:35]
Reactant: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(=O)CN
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: CN(C)C=O
Product: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N(C)C)ccc21
Yield: 29.5 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (35.0 mg) was prepared by following General Procedure F starting from 1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-amino-N,N-dimethyl-acetamide (25.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 537.6; and 1H NMR (DMSO-d6, 400 MHz): δ 8.59 (1H, m), 7.90 (1H, br. s), 7.72 (1H, br. s), 7.56-7.54 (1H, m), 7.38-7.31 (2H, m), 7.18 (1H, m), 4.30-4.27 (2H, t), 4.11-4.10 (2H, d), 3.70-3.67 (2H, t), 3.25 (3H, s), 3.03 (3H, s), 2.87 (3H, s), —NH proton signal was not observed.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1>CO.[Pd]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[O:9])=[CH:15][CH:14]=1
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To a solution of (4-Methyl-piperazin-1-yl)-(4-nitro-phenyl)-methanone (14 g, 0.05623 mol) in MeOH (100 mL) was added Pd/C 10% (1.4 g) in portions and the Parr reaction vessel was purged with nitrogen for 10 min. reaction vessel was fixed in Parr shaker at 60 psi pressure for 3 h. The reaction mixture was filtered through the Celite® pad and the filtrate was concentrated under reduced pressure to afford the title compound [11 g, 89%]; LC-MS (ESI): Calculated mass 219.1; Observed mass: 220.1 [M+H]+ (RT: 0.16 min).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([F:20])[CH:13]=2)=[CH:8][CH:7]=1.[CH3:21][N:22]([CH3:28])[C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1>>[CH3:21][N:22]([CH3:28])[C@@H:23]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([F:20])[CH:13]=3)=[CH:8][CH:7]=2)[CH2:24]1
Reactant: N#Cc1ccc(-c2ccc(OCCCCl)cc2)cc1F
Reactant: CN(C)[C@@H]1CCNC1
Product: CN(C)[C@@H]1CCN(CCCOc2ccc(-c3ccc(C#N)c(F)c3)cc2)C1
Yield: 63 %

Procedure:
The product from Example 166C and (3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described in Example 164D to provide the title compound (63% yield). 1HNMR (300 MHz, CDCl3) δ1.68 (m, 2H), 2.15 (m 4H), 2.23 (s, 6H), 2.30-2.95 (m, 5H), 4.15 (m, 2H), 7.00-7.63 (m, 7H); MS (ESI) m/z 368 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=[C:25]2[N:34]([CH3:38])[N:35]=[C:36]([CH3:37])[C:24]=12.O>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:23]2[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=[C:25]3[N:34]([CH3:38])[N:35]=[C:36]([CH3:37])[C:24]=23)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)NCc2cccnc2)cc1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnc2c(c(C)nn2C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
To a solution of 1.39 g (5 mmol) of (4-methoxybenzenesulfonyl)(3-pyridinylmethyl) amine in 4 ml of anhydrous 1-methyl-2-pyrrolidinone was added 0.2 g (5 mmol) of sodium hydride (60% in oil) and the mixture stirred at room temperature until gas evolution ceased. To this mixture was added 1.15 g (4.54 mmol) of ethyl 4-chloro-1,3-dimethylpyrazolo[3,4-b]pyridine-5-carboxylate and 2 ml of anhydrous 1-methyl-2-pyrrolidinone. The mixture was stirred in a sealed tube under nitrogen in an oil bath at 90° C. for 3 days. The mixture was cooled, poured into water and extracted with ethyl acetate. The extract was washed with H2O, brine and dried (Na2SO4). The solution was filtered through a thin pad of hydrous magnesuim silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated to dryness under vacuum to give 1.3 g of solid. Chromatography on silica gel with ethyl acetate as solvent gave 0.35 g of product as a solid, mp 152-154° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2.[OH:26]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2)=[O:26]
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCSc3cc(Br)ccc3Br)ccc2N1
Product: O=C1CCc2cc(OCCCCS(=O)c3cc(Br)ccc3Br)ccc2N1

Procedure:
Prepared analogous to Example 123 from 6-[4-(2,5-dibromophenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=O.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1
Reactant: COc1ccc(C(=O)c2ccc3ccccc3c2)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cc2ccc3ccccc3c2)c(Br)c1
Temperature: 50 °C
Yield: 82 %

Procedure:
To the methanone of Step 1 (14.0 g) and triethylsilane (15 mL) in 15 mL of CHCl3 was added TFA and was heated to 50° C. overnight. The solution was cooled and quenched with NaOH (2N) to provide the title compound in 82% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](I)=[C:6]([CH3:9])[C:7]=1[CH3:8].[Cu](C#N)[C:12]#[N:13].ClCCl>C(#N)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:12]#[N:13])=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)nnc(I)c1C
Reactant: N#C[Cu]C#N
Solvent: ClCCl
Solvent: CC#N
Product: Cc1c(Cl)nnc(C#N)c1C
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
A mixture of D10 (0.225 g, 0.84 mmol), copper cyanide (0.15 g, 1.67 mmol) in acetonitrile (2 ml) was stirred at 160° C. for 20 min., under microwave irradiation. Dichloromethane was then added and the mixture filtered over celite. The solvent was evaporated in vacuo and the residue purified by column chromatography (silica gel; dichloromethane/heptane 1:1 to 7:3) to yield D11 (0.120 g, 85%) as a solid. C7H6ClN3 requires 167. Found 166 (MH−).
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[CH:26])=[N:23][CH:24]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:2]2[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:4][CH:3]=2)=[N:23][CH:24]=1
Reactant: C#Cc1ccc(Br)cn1
Reactant: CC1CCN(CCOc2ccc(I)cc2)CC1
Product: CC1CCN(CCOc2ccc(C#Cc3ccc(Br)cn3)cc2)CC1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-phenoxy)-ethyl]-4-methyl-piperidine (345 mg, 1.00 mmol) and 5-bromo-2-ethynyl-pyridine (83 mg, 0.39 mmol).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([N:14]4[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)[C:11]([F:13])=[CH:12][C:7]=3[N:6]3[C:27](=[O:33])[N:28]([OH:32])[C:29](=[O:31])[CH:30]=[C:5]23)[CH2:3][CH2:2]1.[ClH:34]>O1CCOCC1>[ClH:34].[CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]([F:13])=[CH:12][C:7]=3[N:6]3[C:27](=[O:33])[N:28]([OH:32])[C:29](=[O:31])[CH:30]=[C:5]23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)n2c(=O)n(O)c(=O)cc2n3C2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1cc2n(C3CC3)c3cc(N4CCNCC4)c(F)cc3n2c(=O)n1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
tert-Butyl 4-[5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-2-hydroxy-1,3-dioxopyrimido[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate (350 mg, 0.76 mmol) is treated with a 2.5N hydrochloric acid solution in dioxane (4 ml), whereby a white precipitate forms immediately. The suspension is stirred at room temperature (25°) for 18 hours. The separated crystals are filtered off and dissolved in water (10 ml). The solution is treated with active charcoal, then filtered and cooled to 0°. The separated crystals are filtered off, washed with ethanol and ether and dried in a high vacuum. There are obtained 176 mg (58%) of 5-cyclopropyl-8-fluoro-2-hydroxy-7-(1-piperazinyl)-pyrimido[1,6-a]benzimidazole-1,3(2H,5H)-dione hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[S:14]([NH:17]C(C)(C)C)(=[O:16])=[O:15].O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[S:14]([NH2:17])(=[O:16])=[O:15]
Reactant: CC(C)(C)NS(=O)(=O)c1c(Cl)cccc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)c1c(Cl)cccc1-c1ccccc1
Yield: 83.6 %

Procedure:
A solution of 2-chloro-N-(1,1-dimethylethyl)-6-phenylbenzenesulfonamide (23 g, 0.071 mol) in a mixture of 120 ml trifluoroacetic acid (TFA) plus 4 ml water was heated to reflux for 2 hours. The TFA was evaporated in vacuo and the residue partitioned between methylene chloride and water. The organic layer was dried (MgSO4), evaporated, and the residue crystallized from ether/methylene chloride to afford 15.9 g of crystalline solid in two crops, m.p. 185°-87°. NMR (90 MHZ, CDCl3) 6.45 (s, br, NH2). 7.3-7.7 (m, 8H) ppm.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([C:11]1[O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2C=1C(O)=O)[CH2:8][CH2:9][CH3:10].CN(C=O)C>C(Cl)Cl.C1C=CC=CC=1>[CH2:7]([C:11]1[O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:1]=1[C:2]([Cl:4])=[O:3])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1oc2ccccc2c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
Oxalyl Chloride (10.0 mL, 114.6 mmol) was added under nitrogen at room temperature to a solution of 2-butyl-benzofuran-3-carboxylic acid (5.00 g, 22.9 mmol), prepared in the previous step, in 200 mL of methylene chloride. After the addition a catalytic amount of DMF (100 μL) was added and the reaction stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure to give a brown oil. The oil was dissolved in benzene and the solvent removed under reduced pressure to give 2-butyl-benzofuran-3-carbonyl chloride (5.46 g, 100%) as a brown oil. The material was immediately used in subsequent reactions with out additional purification.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:20])=[C:13]([C:15](OCC)=[O:16])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:20])=[C:13]([CH2:15][OH:16])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1nc2c(NCc3c(C)cccc3C)cccn2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C)c1CNc1cccn2c(C)c(CO)nc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.2 %

Procedure:
Ethyl 8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridine-2-carboxylate (5.2 g, 0.015 mol) was solved in tetrahydrofuran (100 ml) and LiAlH4 (1.15 g 0.03 mol) was added. After stirring the mixture at room temperature for 45 min, 1.15 ml of water was added dropwise, followed by 1.15 ml of 15% sodium hydroxide and then 3.45 ml of water. The solids were removed by filtration and washed thoroughly with methylene chloride. The filtrate and washings were combined and dried and the solvents were removed under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride:methanol (10:2) as eluent gave 3.2 g (73%) of the title compound.