Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[O:3]=[S:4]1(=[O:36])[C:10]2[CH:11]=[C:12]([O:16][CH:17](C(OCC)=O)C)[C:13]([Br:15])=[CH:14][C:9]=2[N:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][C:6]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:30][CH3:31])[CH2:5]1.[CH3:37][C:38]([OH:40])=[O:39]>CCO>[O:36]=[S:4]1(=[O:3])[C:10]2[CH:11]=[C:12]([O:16][CH2:17][CH2:37][C:38]([OH:40])=[O:39])[C:13]([Br:15])=[CH:14][C:9]=2[N:8]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:7][C:6]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:30][CH3:31])[CH2:5]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC(C)C(=O)OCC)cc2S(=O)(=O)C1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCCC(=O)O)cc2S(=O)(=O)C1
Yield: 65 %

Procedure:
Sodium hydroxide (0.045 g, 1.13 mmol) was added to a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(1-ethoxycarbonylethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 39; 0.050 g, 0.090 mmol) in EtOH (4 ml, 95%) and heated under reflux. After 1.5 hours AcOH (0.2 ml) was added and most of the solvent was removed under reduced pressure. The crude product was extracted (DCM/H2), dried (MgSO4) and evaporated to give the title compound 0.031 g (65%) as white solid. NMR (500 MHz, CD3OD) 0.70-0.85 (m, 6H), 0.95-1.25 (m, 4H), 1.35-1.70 (m, 4H), 2.65 (d, 3H), 3.10-3.35 (m, 2H), 3.45-3.95 (m, 2H), 4.70 (q, 1H), 6.90-7.35 (m, 6H), 7.45 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: COc1ccc2c(c1/C=C\CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1/C=C\CCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A solution of tert-butyl (Z)-4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-enyl]piperazine1-carboxylate (0.0562 g, 0.139 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0203 g, 0.139 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((Z)-4-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-enyl)piperazine-1-carboxylate (0.0672 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:35]([NH:37]O)=[NH:36])=[CH:31][N:30]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:27][N:37]=[C:35]([C:32]5[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=5)[N:36]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1cnc(N)nc1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5cnc(N)nc5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) (195 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) as a yellow solid (143 mg, 56%). MS (EI) 506.1 [(M)+]; mp 272° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[CH:16]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CN(C)C=O>[CH:16]([C:8]1[O:7][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=1)=[CH2:1]
Reactant: O=Cc1cc2ccccc2o1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=Cc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
92 ml of a 1N solution of potassium tert-butoxide in tetrahyclrofuran are added dropwise to a vigorously stirred mixture at 0° C. of 68.4 mmol of benzofuran-2-carboxaldehyde and 92 mmol of methyltriphenylphosphonium bromide in 200 ml of tetrahydrofuran and 150 ml of dimethylformamide. The medium is stirred for 2 h at room temperature, poured into 2 liters of ice-water and extracted with ether. After concentration of the solvents, the residue is taken up in 1 liter of petroleum ether and the precipitate is filtered off and washed with petroleum ether. The expected product is obtained by evaporation of the filtrate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](Cl)=[O:6].[C:13]1([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(=S)=S>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([C:23]1[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[O:20][C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1C
Solvent: S=C=S
Product: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1C
Temperature: 25 °C

Procedure:
To a cooled, stirred solution of 10.8 g. (0.058 mol.) of 3-methyl-4-methoxybenzoic acid chloride and 9.6 g. (0.054 mol.) of 2-phenylbenzofuran in 40 ml. of carbon disulfide is added dropwise over a 20 minute interval 28.2 g. (0.108 mol.) of stannic chloride. After addition, the reaction mixture is warmed to ambient temperature and stirred for two hours. The mixture is then poured onto 100 ml. of ice-water and stirred for one hour. The solvent is removed, and the product extracted into chloroform and the extracts are washed with water, dried (Na2SO4) and concentrated under reduced pressure to give 3-(3-methyl-4-methoxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([CH2:10]Cl)[C:3]=1[CH2:12][CH3:13].[C-:14]#[N:15].[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:12][CH3:13])=[C:4]([CH2:10][C:14]#[N:15])[C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: CCc1ccc(Br)c(CC)c1CCl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1ccc(Br)c(CC)c1CC#N
Temperature: 50 °C

Procedure:
To a solution of 6.28 g (24 mmol) 1-bromo-3-chloromethyl-2,4-diethyl-benzene in 120 ml tetrahydrofurane/N,N-dimethylformamide 1:1 cooled to 0° C. were added 1.76 g (36 mmol) sodium cyanide. The mixture was warmed to 50° C. and stirred at this temperature over night. Then the reaction mixture was diluted with ethyl acetate and extracted several times with water. The organic phase was dried over Na2SO4, filtered and evaporated: 7.2 g (3-bromo-2,6-diethyl-phenyl)-acetonitrile that did not require further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])[CH3:3].[Si](C=[N+]=[N-])(C)(C)[CH3:19]>C(Cl)Cl.CO>[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:15]([O:17][CH3:19])=[O:16]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCN)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H](CCCCN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of N-α-Boc-D-lysine 12 (1.00 g, 4.06 mmol) in CH2Cl2 (20 mL) and MeOH (5.0 mL) was charged with TMS-diazomethane [(CH3)3SiCHN2 0.6 M solution in hexane, 13.5 mL, 8.12 mmol] at 0° C. and stirred at the same temperature for 1 h and at room temperature for another 1 h. The solvent was removed under reduced pressure to afford crude product 14 (1.04 g, crude) as a yellow oil, which was directly used for the next step without further purification: 1H NMR (400 MHz, CD3OD) δ 4.12-4.05 (m, 1H), 3.70 (s, 3H), 2.62 (t, J=7.0 Hz, 2H), 1.82-1.70 (m, 1H), 1.69-1.58 (m, 1H), 1.54-1.32 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH2:6][CH2:5]2.C([O:18][N:19]=O)CC(C)C.Cl.O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[C:6](=[N:19][OH:18])[CH2:5]2
Reactant: CC(C)CCON=O
Reactant: O=C1CCc2cc(F)c(F)cc21
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1C(=NO)Cc2cc(F)c(F)cc21
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5,6-difluoroindan-1-one (Preparation 76) (3.1 g, 18.4 mmol) in MeOH at 40° C. was added isoamylnitrite (3.22 mL, 23.9 mmol) followed by conc. HCl (1.8 mL). The reaction was stirred at 40° C. for 45 min, cooled to rt and poured into water (50 mL). The precipitate was collected by filtration and air-dried to give the title compound: δH(DMSO-d6) 3.77 (2H, s), 7.72-7.85 (2H, m), 12.79 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:21])([F:20])[CH:17]([OH:19])[CH3:18]>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:19][CH:17]([CH3:18])[C:16]([F:21])([F:20])[F:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CC(O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F

Procedure:
Prepared in analogy to Example B1(b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example B1(a)) and rac-1,1,1-trifluoro-propan-2-ol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 311.3 ([M−H]−, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.CN([CH:15]=[O:16])C.O=P(Cl)(Cl)Cl>>[Cl:1][C:2]1[C:3]([CH:15]=[O:16])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)cc(OC)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Cl)c(C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a mixture of 5-chloro-1,3-dimethoxybenzene (25 g, 0.14 mol) in DMF (175 mL, 2.27 mol) at 0° C. was added POCl3 (42.5 mL, 0.46 mol) dropwise. The mixture was stirred at room temperature for 30 min and heated to reflux at 100° C. for an additional 2 h. The reaction mixture was poured onto ice and the yellow precipitate was collected by filtration, rinsed with cold water and dried under high vacuum to give a light yellow solid (22.7 g. Yield 78.3%). 1H NMR (400 MHz, CDCl3) δ0.43 (s, 1H), 6.59 (s, 1H), 6.42 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H); MS (ESI) m/z=201 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[N:16]([CH:17]([CH3:19])[CH3:18])[C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[N:13]=1)[CH2:9][C:10]#[CH:11]>>[CH:17]([N:16]1[C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[N:13]=[C:12]1[CH2:8][CH2:9][C:10]#[C:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:19])[CH3:18].[NH:13]1[C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[N:16]=[CH:12]1
Reactant: Ic1ccccn1
Reactant: C#CCCc1nc2ccccc2n1C(C)C
Product: CC(C)n1c(CCC#Cc2ccccn2)nc2ccccc21
Product: c1ccc2[nH]cnc2c1
Yield: 41 %

Procedure:
The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (81 mg, 0.39 mmol) and 2-(but-3-ynyl)-1-isopropyl-1H-benzo[d]imidazole (84 mg, 0.39 mmol). The crude residue was purified over silicagel chromatography (prepacked 5 g silicagel column, DCM/MeOH: from 100/0 to 96/4 as eluent) to afford 47 mg of 1-isopropyl-2-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole as a light brown oil (Yield: 41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([C:15]#[C:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BrH:29].C(O)(=O)C>C(Cl)Cl>[Br:29][C:16]1[CH:15]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:18]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:17]=1
Reactant: Br
Reactant: COc1cc(C(=O)C#CCNS(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(-c2cc(Br)cn2S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(p-toluenesulfonylamino)-1-propinyl 3,4,5-trimethoxyphenyl ketone (4.03 g, 10.0 mmol) in CH2Cl2 (40 ml), a 33% HBr/acetic acid solution (2.63 ml, 15.0 mmol) is added dropwise at 4° C. within 10 min. The reaction mixture is stirred for 1 h at 40° C. and extracted with CH2Cl2 and aqueous 1 N HCl solution. The organic layer is dried over MgSO4, the solvents evaporated, and the residue chromatographed on SiO2 with gradients of hexane/ethyl acetate (4:1 to 3:1) to yield the title compound as a greyish solid. 1H-NMR (300 MHz, CDCl3): 7.49 (d, J=2.0 Hz, 1H); 7.3-7.2; 7.2-7.1 (2m, 4H); 6.38 (s, 2H); 6.17 (d, J=2.0 Hz, 1H); 3.92 (s, 3H); 3.77 (s, 6H); 2.38 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])[CH2:4][C@H:3]1[N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([N:37]1[CH:41]=[C:40]([C:42]([OH:44])=O)[CH:39]=[N:38]1)=[N:17][C:18]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[NH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[CH2:46][NH:45][C:42]([C:40]1[CH:39]=[N:38][N:37]([C:16]2[N:15]=[C:14]3[C:19]([N:20]=[CH:21][N:13]3[C@@H:3]3[CH2:4][C@H:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])[C@@H:6]([OH:7])[C@H:2]3[OH:1])=[C:18]([NH:22][CH2:23][CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:17]=2)[CH:41]=1)=[O:44]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)O)cn4)nc32)[C@H](O)[C@@H]1O
Reactant: NCc1ccccn1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)NCc5ccccn5)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture comprising 1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid (0.06 g, 0.01 mmol) in dry DCM (10 ml) is treated with 2-aminomethylpyridine (0.021 g, 0.2 mmol) followed by HOBt (0.027 g, 0.2 mmol), 1-[Bis(dimethylamino)methylene]-1H-benzotriazoliumhexafluorophosphate-3-oxide HBTU (0.076 g, 0.2 mmol), N-methyl morpholine (0.02 g, 0.2 mmol) and DMAP (1 ml). The resulting mixture is stirred at room temperature for 24 h and then concentrated in vacuo. The resulting residue purified by preparative TLC eluting with 10% MeOH in chloroform to afford the title compound. (MH+ 687.1)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH3:20]C1C=CC=C2C=1C=CN2>>[CH3:20][C:5]1[CH:4]=[CH:3][CH:2]=[C:10]2[C:6]=1[CH:7]=[C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[NH:9]2
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: Cc1cccc2[nH]ccc12
Product: Cc1cccc2[nH]c(B3OC(C)(C)C(C)(C)O3)cc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 4-methyl-1H-indole.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH2:29][CH2:30][CH3:31]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: CCCCOc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.70 g), 4-butoxyphenyl borate (0.45 g) and potassium carbonate (0.58 g) in toluene/ethanol/water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.12 g), and the mixture was refluxed for 20 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:1) to give colorless crystals of methyl 7-(4-butoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (672.6 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[O:17])[CH:10]=[C:11]([C:12]([OH:14])=O)[C:5]=2[N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Cl:62][C:63]1[CH:64]=[C:65]([CH:67]=[CH:68][C:69]=1[CH3:70])[NH2:66]>CN(C=O)C.C(OCC)(=O)C>[Cl:62][C:63]1[CH:64]=[C:65]([NH:66][C:12]([C:11]2[C:5]3[N:4]=[C:3]([N:2]([CH3:28])[CH3:1])[NH:7][C:6]=3[CH:8]=[C:9]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:25])([F:26])[F:27])=[O:17])[CH:10]=2)=[O:14])[CH:67]=[CH:68][C:69]=1[CH3:70]
Reactant: CN(C)c1nc2c(C(=O)O)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Reactant: Cc1ccc(N)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(NC(=O)c3ccccc3C(F)(F)F)cc3[nH]c(N(C)C)nc23)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylic acid (50 mg) and HATU (82 mg) in DMF (1 mL), were added N,N-diisopropylethylamine (88 μL) and 3-chloro-4-methylaniline (26 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (65 mg) as white powder. This was suspended in MeOH (1.5 mL), 2N hydrogen chloride/MeOH (1 Eq) was added, and it was stirred and concentrated. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (40 mg) as white powder.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)C.ClC(N(C)C)=C(C)C.[NH2:30][C:31]1[N:35](C(OC(C)(C)C)=O)[N:34]=[C:33]([CH2:43][CH2:44][C:45]2[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([O:53][CH3:54])[CH:46]=2)[CH:32]=1.Cl.O1CCOCC1>C1COCC1.N1C=CC=CC=1>[CH3:52][O:51][C:49]1[CH:50]=[C:45]([CH2:44][CH2:43][C:33]2[NH:34][N:35]=[C:31]([NH:30][C:19]([C:17]3[S:18][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][CH:16]=3)=[O:21])[CH:32]=2)[CH:46]=[C:47]([O:53][CH3:54])[CH:48]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)s2)CC1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCNCC4)s3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 13.5 %

Procedure:
5-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]thiophene-2-carboxylic acid (150 mg, mmol) was dissolved in dry THF (10 ml) under nitrogen, 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (177 μl, mmol) was added and the mixture was stirred at room temperature for 3.5 h. Tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (167 mg, mmol) and pyridine (47 μl, mmol) were added and the reaction was heated to 65° C. for 18 h. The reaction mixture was then cooled to room temperature and 4M HCl in dioxane (2.0 ml, 2.0 mmol) added. The mixture was stirred overnight at room temperature, evaporated and the residue was purified by acidic prep. HPLC, eluting with a gradient of 24-32% MeCN in 0.1% TFA in water. The clean fractions were taken and evaporated to give the title compound as a pale green solid (28.7 mg, 11%); 1H NMR (399.902 MHz, DMSO) δ 2.79 (s, 4H), 3.21 (s, 4H), 3.34 (s, 4H), 3.64 (s, 6H), 6.29 (m, 5H), 7.77 (m, 1H), 8.71 (s, 1H), 10.37 (s, 1H) MS: m/z=442 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][CH2:21][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23].C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:20][CH2:21][C:22](=[O:23])[NH:24][CH:25]([CH3:27])[CH3:26])=[O:9]
Reactant: CC(C)NC(=O)CN
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 365.4 %

Procedure:
To a solution of 5-fluoro-2-nitrobenzoic acid (2.3 g, 12.4 mmol) in dichloromethane (20 mL) was added oxalyl chloride (3.2 g, 2.2 mL, 24.8 mmol) dropwise. After 1 h the solution was concentrated to dryness. 2-Amino-N-isopropylacetamide (INTERMEDIATE I.1) (0.30 g, 2.6 mmol) was dissolved in dichloromethane (20 mL) and diisopropylethylamine (DIEA) (6.8 mL, 38.9 mmol) added. The acid chloride in dichloromethane (10 mL) was added dropwise and the reaction mixture stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, the residue dissolved in dichloromethane and washed with 1 N NaOH (aq.), 1 N HCl (aq.) and brine. The organic layers were dried (MgSO4) and concentrated in vacuo to yield 5-fluoro-N-(isopropylcarbamoylmethyl)-2-nitrobenzamide (2.7 g, 9.5 mmol, 81%) as a yellow solid.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[CH:6]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[CH3:10])[NH:5][NH:4][C:3]1=[S:14].[OH-].[Na+].[CH3:17]COCC.CI>O>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH:11]2[CH2:12][CH2:13]2)[CH3:10])=[N:5][N:4]=[C:3]1[S:14][CH3:17]
Reactant: CCOCC
Reactant: CC(C1CC1)C1NNC(=S)N(N)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nnc(C(C)C2CC2)c(=O)n1N
Temperature: 10 °C
Reaction time: 4 h

Procedure:
(according to process A): ##STR19## 789 g (3.72 mols) of 4-amino-6-(1-cyclopropylethyl)-5-oxo-3-thioxo-tetrahydro-1,2,4-(2H,4H)-triazine are dissolved in a solution of 151 g (3.77 mols) of sodium hydroxide in 4 l of water. 3 ml of alkylarylpolyglycol ether are added, the mixture is cooled to 10° C., 542 g (3.82 mols) of methyl iodide are added and the mixture is stirred for 4 hours at room temperature. The mixture is filtered off with suction and the residue is washed with water and also with petroleum ether and dried at 60° C. in vacuo, after which 748 g (89% of theory) of the above compound of melting point 111°-113° C. are obtained. The purity as determined by gas chromatography is 99%.