Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:14][SiH:15]([CH3:17])[CH3:16]>C1(C)C=CC=CC=1.ClCCl.C1([Pt](Cl)(Cl)C2C=CC=C2)C=CC=C1>[CH3:14][Si:15]([CH3:17])([CH3:16])[CH:1]([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[SiH](C)C
Reactant: C=CCCCCc1ccc(Cl)cc1
Agent: Cl[Pt](Cl)(C1C=CC=C1)C1C=CC=C1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCC(c1ccc(Cl)cc1)[Si](C)(C)C
Yield: 79.8 %

Procedure:
About 15.9 g (0.082 Mol) of 4-(5-hexenyl)-1-chlorobenzene were dissolved in 10 ml of toluene, 0.8 ml of a 1 percent solution of dicyclopentadienylplatinum dichloride in dichloromethane (corresponding to 100 ppm of Pt) were added, and the mixture was introduced into a 100 ml bench autoclave. About 10 g (0.147 Mol) of trimethylsilane in the condensed state were added, the autoclave was sealed, and 5 MPa of nitrogen were injected. The mixture was warmed at 70° to 80° C. for 90 minutes (8 MPa, internal stirring). The mixture was then cooled, the solvent was stripped off, and the resultant residue fractionated. About 17.6 g of 4-(1-trimethylsilylhexyl)-1-chlorobenzene, corresponding to 77.1 percent of theory, were obtained at 0.1 hPa and at a boiling range of 107° to 112° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH3:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9]=1/[CH:14]=[C:15]1\[C:16](=[O:27])[N:17]([C:24](Cl)=[O:25])[C:18]2[C:23]\1=[CH:22][CH:21]=[CH:20][CH:19]=2>N1C=CC=CC=1.C1COCC1>[OH:4][CH:3]([CH2:5][OH:6])[CH2:2][O:1][C:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:15](=[CH:14]/[C:9]2[NH:10][C:11]([CH3:13])=[CH:12][C:8]=2[CH3:7])/[C:16]1=[O:27])=[O:25]
Reactant: OCC(O)CO
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)CO)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To the solution of glycerol (460 mg, 2.5 mmol) in 1.0 mL of pyridine and 2.0 mL of THF was added a suspention of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride in 2.0 mL of THF at 0° C. The reaction mixture was gradually warmed to room temperature, stirred for 2.5 h, and concentrated. The residue was triturated with ethyl acetate and filtered. The solid was then washed with ethyl acetate, water, ether, and dried to yield 87 mg of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2,3-dihydroxy-propyl ester. The combined filtrate was concentrated and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 120 mg of crude product which was suspended in water, filtered, and washed with small amount of ethyl acetate to afford another 67 mg of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2,3dihydroxy-propyl ester. The combined yield is 83%. 1H NMR (400 MHz, CDCl3) δ 12.51 (s, 1H, NH-1′), 7.90-7.92 (m, 1H), 7.45-7.48 (m, 1H), 7.37 (s, 1H, H-vinyl), 7.18-7.24 (m, 2H), 6.04 (d, J=1.96 Hz, 1H, H-4′), 4.68 (dd, J=3.13, 11.24 Hz, 1H, OCH2CH(OH)CH2OH), 4.45 (dd, J=4.89, 11.24 Hz, 1H, OCH2CH(OH)CH2OH), 4.09 (m, br, 1H, OCH2CH(OH)CH2OH), 3.86-3.99 (m, 2H, OCH2CH(OH)CH2OH), 3.60 (d, J=6.65 Hz, 1H, OCH2CH(OH)CH2OH), 3.45 (dd, J=5.52, 7.82 Hz, 1H, OCH2CH(OH)CH2OH), 2.41 (s, 3H, CH3), and 2.32 (s, 3H, CH3). MS m/z (relative intensity, %) 357 (100, [M+1]+.).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH2:1]([N:5]([CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of N-butyl-N-[2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (102 mg, 0.33 mmol) in anhydrous MeCN (8 mL) under nitrogen at room temperature was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (95.3 mg, 0.33 mmol) and N,N-diisopropyethylamine (57.8 μL, 0.33 mmol). The resultant solution was heated to reflux and stirred for 3 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (2×10 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by Biotage™ chromatography (40 g Silica column) eluted with 1:99–1:49 EtOAc:cyclohexane afforded the title compound as a colourless oil (110 mg).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+].O>O1CCCC1.CN(C)C=O>[O:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccccc1
Reactant: ICCCCC/C=C(\c1ccccc1)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: C(\CCCCCOc1ccccc1)=C(\c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
(E)-1-Iodo-7-phenyl-7-(3-pyridyl)-6-heptene (0.6 g, 1.6 mmoles) and phenol (0.2 g, 2.1 mmoles) were dissolved in a mixture of tetrahydrofuran (10 ml) and dimethylformamide (2 ml), and sodium hydride (60% dispersion in oil, 0.1 g, 2.5 mmoles) was added to the solution. The mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added water (20 ml), followed by extraction of the product with ether. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (2.1) as the developing solvent to give (E)-1-phenoxy-7-phenyl-7-(3-pyridyl)-6-heptene (0.5 g, 73%) (Compound Id-38) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][C:3]=1[F:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[Cl-].[NH4+]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:10])[CH:4]=2)([OH:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Fc1cc([Mg]Br)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)c(F)c2)CC1
Reaction time: 24 h
Yield: 30.4 %

Procedure:
A solution of 4-chloro-3-fluorophenylmagnesium bromide (15 ml, 7.5 mmol, 0.5M in THF) was added, under nitrogen, to 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.02 g, 5.1 mmol). After 24 hours, saturated ammonium chloride solution was added then the organic solvent was removed in vacuo. The mixture was extracted with ethyl acetate, then this extract was washed with brine, dried (MgSO4), filtered and concentrated to afford a residue which was purified by column chromatography (SiO2), eluting with gradient of ethyl acetate/petrol (0% to 20%) to afford the title compound (511 mg, 30%). 1H NMR (Me-d3-OD) δ 1.48 (9H, s), 1.67 (2H, br.d), 1.92 (2H, td), 3.16-3.29 (2H, m), 3.99 (2H, br.d), 7.27 (1H, dd), 7.38 (1H, dd), 7.42 (1H, t).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].Cl[CH2:14][CH:15]([OH:17])[CH3:16].Cl[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24]>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][N:4]1[C:5](=[O:11])[C:6]2[N:7]([CH2:14][CH:15]([OH:17])[CH3:16])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:12]
Reactant: CC(C)(O)CCCCCl
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: CC(O)CCl
Product: CC(O)Cn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
It was also possible to build up the compound starting from 3-methylxanthine in a two-stage reaction sequence, by first introducing the 2-hydroxypropyl group into the 7-position (melting point: 278°-280° C.; yield: 69.6% of theory) with 1-chloro-2-propanol and then alkylating the product in the 1-position (yield: 67.5% of theory) with 1-chloro-5-hydroxy-5-methylhexane (Example 1a).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Cl[C:14]1[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=1>CN(C)C=O>[N:15]1[C:16]2[NH:1][C:2]3[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=3[O:12][C:17]=2[N:18]=[CH:19][CH:14]=1
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: Clc1nccnc1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)Nc1nccnc1O2
Temperature: 160 °C
Yield: 74.2 %

Procedure:
21.3 g of methyl 3-amino-4-hydroxybenzoate and 23 g of 2,3-dichloropyrazine were added to 40 ml of dry N,N-dimethylformamide and the resulting mixture was stirred under heating to 160° C. for 6 hours. Then the reaction mixture was brought back to room temperature and the crystals thus precipitated were taken up by filtration and washed with ethyl acetate. Thus 23 g of the title compound was obtained as brown crystals.
Reaction SMILES: Cl.[Br:2][C:3]1[N:4]=[C:5]([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=12.Cl.[Br:19][C:20]1[N:21]=[C:22]([C@H:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)[N:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[C:24]=12.C(N(CC)C(C)C)(C)C.[CH3:44][O:45][CH2:46][C:47]([Cl:49])=[O:48]>ClCCl>[ClH:49].[Br:2][C:3]1[N:4]=[C:5]([C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=12.[Br:19][C:20]1[N:21]=[C:22]([C@H:30]2[CH2:34][CH2:33][N:32]([C:47](=[O:48])[CH2:46][O:45][CH3:44])[CH2:31]2)[N:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[C:24]=12
Reactant: COCC(=O)Cl
Reactant: Cc1nccn2c([C@@H]3CCNC3)nc(Br)c12
Agent: Cc1nccn2c([C@H]3CCNC3)nc(Br)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)N1CC[C@H](c2nc(Br)c3c(C)nccn23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-1-Bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine hydrochloride was prepared in a similar way as (R)-1-bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine hydrochloride. To (S)-1-bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine hydrochloride (0.31 mmol, 100 mg) in dichloromethane (5 ml) and N,N-diisopropylethylamine (1.778 mmol, 0.311 ml) at 0° C. was added a solution of methoxyacetyl chloride (0.534 mmol, 0.049 ml) in dichloromethane (0.5 ml). After stirring for one hour at room temperature the reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogencarbonate solution, water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) to give (S)-1-(3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-1-yl)-2-methoxyethanone (80 mg).
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([Br:18])[CH:13]=1.[NH2:20][C:21]1[C:29]2[C:25](=[CH:26][N:27]([CH3:30])[N:28]=2)[C:24]([F:31])=[CH:23][CH:22]=1>>[Br:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:20][C:21]2[C:29]3[C:25](=[CH:26][N:27]([CH3:30])[N:28]=3)[C:24]([F:31])=[CH:23][CH:22]=2)=[O:19])[CH:17]=[CH:16][N:15]=1
Reactant: Cn1cc2c(F)ccc(N)c2n1
Reactant: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Product: Cn1cc2c(F)ccc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)c2n1

Procedure:
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(4-fluoro-2-methyl-2H-indazol-7-yl)-benzamide was prepared from 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester and 7-amino-4-fluoro-2-methyl-2H-indazole in analogy to the procedures detailed in Example 4A; 1H-NMR (300 MHz, d6-DMSO) 9.86 (1H, s), 8.60 (1H, s), 8.32 (1H, d), 8.13 (1H, t), 7.83 (1H, d), 7.58-7.61 (2H, m), 7.42 (1H, d), 7.30 (1H, t), 6.82 (1H, dd), 6.72 (1H, t), 6.59 (1H, d), 4.52 (2H, d), 4.22 (3H, s); m/z (ES+) 454, 456 [M+H, Br isotopes]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]4([CH2:17][CH2:18][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4.C(=O)([O-])[O-:20].[Cs+].[Cs+].Br[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1[O:39][CH3:40]>C(#N)C>[OH2:20].[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]4([CH2:17][CH2:18][C:5]=3[C:4]=2[CH:3]=1)[CH2:12][CH2:13][N:14]([CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1[O:39][CH3:40])[CH2:15][CH2:16]4
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2[nH]c3c(c2c1)CCC31CCNCC1
Reactant: COc1cc(C(C)=O)ccc1OCCCBr
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC2(CCc3c2[nH]c2ccc(F)cc32)CC1
Product: O
Temperature: 80 °C
Yield: 18.1 %

Procedure:
To a solution of 1,4-dihydro-7-fluorospiro[cyclopent[b]indole-3(2H), 4-piperidine] (3.00 g) in acetonitrile (30 ml) was added cesium carbonate (6.97 g) and 1-[4-(3-bromopropoxy)-3-methoxyphenyl]ethanone (3.38 g), under nitrogen, with stirring. The reaction mixture was heated at 80° C. for 3 hrs and allowed to cool to ambient temperature. The mixture was extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flashed chromatographed (silica gel) eluting with 1% acetone/dichloromethane. The appropriate fractions were collected and concentrated to give 1.00 g (30%) of product, mp 165-166° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][CH:4]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[CH:22]2)=[CH:17][CH:16]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1.Cl.[CH3:32][NH:33]CCC(O)=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.[C:61]([O:64][CH2:65]C)(=[O:63])[CH3:62]>ClCCl.C(N(CC)CC)C>[CH3:30][CH:2]([CH3:1])[CH2:3][CH:4]([C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:23]=[CH:22]2)=[CH:19][CH:20]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:33][CH2:32][CH2:62][C:61]([O:64][CH3:65])=[O:63])=[O:11])=[CH:8][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CNCCC(=O)O
Reactant: CC(C)CC(Oc1ccc(C(=O)O)cc1)c1ccc(-n2cnc(C(F)(F)F)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1ccc(OC(CC(C)C)c2ccc(-n3cnc(C(F)(F)F)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
4-(3-Methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzoic acid (65 mg, 0.16 mmol), methyl beta-alanine hydrochloride (31 mg, 0.16 mmol), and triethylamine (0.031 mL) were dissolved in dichloromethane (1 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (34 mg, 0.18 mmol) was added. The solution was stirred at room temperature for 15 minutes, and 1-hydroxy-7-azabenzotriazole (34 mg, 0.25 mmol) was then added. The resulting yellow solution was stirred overnight. After 18 hours, the reaction was diluted with ethyl acetate (20 mL) and washed with water (25 mL) and brine (10 mL). The organics were dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-100% ethyl acetate in heptane) gave (+/−)-methyl 3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzamido)propanoate (70 mg, 90%). 1H NMR (400 MHz, CDCl3, δ): 7.84 (s, 1H), 7.67-7.62 (m, 2H), 7.58 (s, 1H), 7.53-7.46 (m, 2H), 7.39-7.34 (m 2H), 6.89-6.84 (m, 2H), 6.72 (t, J=5.9 Hz, 1H), 5.29 (dd, J=8.9, 4.5 Hz, 1H), 3.72-3.65 (m, 5H), 2.63 (m, 2H), 2.03 (m, 1H), 1.95-1.83 (m, 1H), 1.65-1.58 (m, 1H), 1.03 (d, J=6.6 Hz, 3H), 0.99 (d, J=6.3 Hz, 3H). MS (M+1): 504.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2cccc(NC(=O)OC(C)(C)C)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
A mixture of ethyl 7-[(tert-butoxycarbonyl)amino]-1H-indole-2-carboxylate (2.65 g), 1N aqueous sodium hydroxide solution (22.0 mL), tetrahydrofuran (20 mL) and ethanol (30 mL) was stirred at 50° C. for 3 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (2.27 g, yield 94%) as colorless crystals. melting point>246° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[C:6]([NH2:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4].O=S(Cl)[Cl:19]>>[F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[C:6]([NH2:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:19])=[O:9])=[O:4]
Reactant: Nc1c(C(=O)O)cccc1C(=O)C(F)(F)F
Reactant: O=S(Cl)Cl
Product: Nc1c(C(=O)Cl)cccc1C(=O)C(F)(F)F

Procedure:
4.66 g (0.02 mole) of Compound 2, 50 ml EtAc and 15 ml SOCl2 were refluxed until the reaction mixture became a clear, yellow solution (1 h). After removing the solvent and excess reagent, the residue was crystalized from n-hexane. Yield: 4.5 g (85%), m.p. 95-98° C. For the 4-position isomer, yield 4.2 g (81%), m. p. 112-114° C.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:7]([OH:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[S:4]1(=[O:20])=[O:19])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([N:11]1[N:12]=[N:13][C:9]([C:8]2[N:3]([CH2:1][CH3:2])[S:4](=[O:19])(=[O:20])[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[C:7]=2[OH:14])=[N:10]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCN1C(c2nnn[nH]2)=C(O)c2ccccc2S1(=O)=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(c2nnn(Cc3ccccc3)n2)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of 2-ethyl-4-hydroxy-3-(tetrazol-5-yl)-1,2-benzothiazine 1,1-dioxide (0.5 g), potassium carbonate (0.120 g) and benzylbromide (0.21 ml) in dimethylformamide was stirred at room temperature for 16 hours, then poured into water (30 ml). The resulting solids were filtered off, washed with water and dried in vacuo to give crude product (0.638 g), which was recrystallized from toluene to afford the title compound (0.457 g, 70%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[CH:11]=[C:12]([C:14]([O-:16])=[O:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH:1]([O:4][C:5]1[C:10]2[CH:11]=[C:12]([C:14]([OH:16])=[O:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc2oc(C(=O)[O-])cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1cccc2oc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.2 %

Procedure:
To 0.15 g (0.62 mmole) of 4-isopropoxy-1-benzofuran-2-carboxylate in 2.5 mL of methanol and 2.5 mL of THF was added 3 mL of 1N sodium hydroxide solution. The solution was stirred at room temperature for 45 minutes. The reaction mixture was concentrated in vacuo, the residue was diluted with water and neutralized with 1N HCl to pH ˜3-4, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 0.13 g of 4-isopropoxy-1-benzofuran-2-carboxylic acid. Yield 94%. m.p. 148-150° C. MS: 219.1(M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[CH2:44](Cl)[CH:45]=[CH2:46]>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:46][CH:45]=[CH2:44])[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: C=CCCl
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Product: C=CCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 35.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine and allyl chloride to give the title compound.
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:9][C:10]1[CH:11]=[C:12](CN)[CH:13]=[CH:14][CH:15]=1.[CH2:18]([N:20](CC)CC)C>ClCCl>[Br:9][C:10]1[CH:11]=[C:12]([N:20]([CH3:18])[C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:8])[CH:13]=[CH:14][CH:15]=1
Reactant: CCCCCN=C=O
Reactant: CCN(CC)CC
Reactant: NCc1cccc(Br)c1
Solvent: ClCCl
Product: CCCCCNC(=O)N(C)c1cccc(Br)c1
Yield: 293.6 %

Procedure:
A solution of 50 g (0.45 mol) of pentyl isocyanate in 50 mL of dichloromethane is added to a mixture of 82 g (0.45 mol) of (3-bromophenyl)methylamine in 250 mL of dichloromethane in the presence of 20 mL (0.14 mol) of triethylamine. The reaction medium is heated at reflux for 3 days and then hydrolyzed in 200 mL of 1 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water, with saturated sodium chloride solution and evaporated. 123 g (93%) of 1-(3-bromophenyl)-1-methyl-3-pentylurea are obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:17]1[N:21]([CH:22]2[CH2:24][CH2:23]2)[C:20]2[C:25]([Br:30])=[C:26]([F:29])[CH:27]=[CH:28][C:19]=2[N:18]=1)[CH3:16])(C)(C)C>C(Cl)Cl.CO>[Br:30][C:25]1[C:20]2[N:21]([CH:22]3[CH2:23][CH2:24]3)[C:17]([C@@H:15]([NH2:14])[CH3:16])=[N:18][C:19]=2[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(Br)c2n1C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)c(Br)c2n1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
TFA (1 mL) was added to a solution of [(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (133 mg, 0.33 mmol) in DCM (3 mL). After stirring at RT for 2 h, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a colourless oil (87 mg, 87%). LCMS (Method C): RT 1.99 min [M+H]+ 298.10