Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][N:13]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([OH:24])=[O:23])=[CH:21][C:16]=3[N:15]=[C:14]2[CH3:25])=[O:11])=[CH:8][C:7]=1[S:28](=[O:31])(=[O:30])[NH2:29].[CH3:32]O>>[Cl:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][N:13]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([O:24][CH3:32])=[O:23])=[CH:21][C:16]=3[N:15]=[C:14]2[CH3:25])=[O:11])=[CH:8][C:7]=1[S:28](=[O:31])(=[O:30])[NH2:29]
Reactant: CO
Reactant: Cc1nc2cc(C(=O)O)ccc2n1NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)nc(C)n2NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Yield: 75 %

Procedure:
After dropping 1.46 ml of thionyl chloride to a solution containing 8.2 g of 1-(4'-chloro-3'-sulfamoylbenzoyl)amino-2-methyl-5-carboxybenzimidazole in 50 ml of methanol while stirring, the reaction mixture was refluxed for 5 hours. The clear solution obtained was evaporated to dryness under reduced pressure and the solid residue was triturated with 1N sodium bicarbonate solution. After decanting the solution from the solid product, the residue was recrystallized from a mixture of dioxane and water (1:1). Thus, 6.35 g (75%) of 1-(4'-chloro-3'-sulfamoylbenzoyl)amino-5-methoxycarbonyl-2-methylbenzimidazole were obtained, m.p.: 251°-252° C. (with decomposition).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].CN(C=O)C.[H-].[Na+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][N:1]3[C:12](=[O:13])[C:11]4[N:9]([CH3:10])[CH:8]=[N:7][C:6]=4[N:4]([CH3:5])[C:2]3=[O:3])=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnc2c1c(=O)n(Cc1ccc(C(=O)c3ccc(Cl)cc3)cc1)c(=O)n2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a mixture of theobromine (0.90 g) and DMF (20 ml) was added sodium hydride (240 ml) as well as 4-(4-chlorobenzoyl)benzyl bromide (1.55 g) and the mixture was stirred at room temperature for 18 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as colorless powder (1.37 g, 67%). 1H-NMR (CDCl3) δ: 3.60(3H,s), 4.00(3H,s), 5.27(2H,s), 7.38-7.79(8H,m)
Reaction SMILES: N1C=CC=CC=1.[O:7]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[O:7]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1cccc(Oc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
Chromium trioxide (3.00 g.) was added to a stirred solution of pyridine (4.75 g.) in dry methylene chloride (75 ml.), and stirring was continued for a further 15 minutes. 3-Phenoxybenzyl alcohol (1 g.) in methylene chloride (5 ml.) was added, the mixture stirred for a further 15 minutes, decanted and the residue washed with diethyl ether (100 ml.). The filtrate was washed with 5% sodium hydroxide solution (3×50 ml), 2.5 NHCl (50 ml.) and 5% sodium carbonate solution (50 ml.) and dried over Na2SO4 to give 3-phenoxy-benzaldehyde. Alternatively the alcohol can be oxidized using Jones' reagent, a similar yield of aldehyde being obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([S:32]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])=[CH:2]2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc(OC)c1OC
Yield: 85.8 %

Procedure:
Substantially the same procedure as in Example 9 was repeated using Compound 1 (337.4 mg) obtained in Example 1 and benzenesulfonyl chloride (176.6 mg) to give Compound 10 (409.9 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O.CCOC(C)=O>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][N:7]1[C:8]2[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: COC(CBr)OC
Reactant: Ic1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(Cn1ncc2cc(I)ccc21)OC
Temperature: 40 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
To a solution of 5-iodio-1H-indazole (8.28 g, 33.9 mmol) in DMSO (104 mL) was added 2-bromoacetaldehyde dimethyl acetal (7.9 mL, 68 mmol) and Cs2CO3 (44.1 g, 136 mmol). The reaction was stirred at 40° C. for 18 h; then the reaction was diluted with H2O (100 mL) and EtOAc (175 mL). The partitioned material was extracted with EtOAc (4×175 mL). The organics were washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (silica gel, hexanes with 0.1% Et3N/EtOAc with 0.1% Et3N, 100:0 to 90:10) gave the title compound (4.49 g, 46%) as a light orange powder: 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J=1.0 Hz, 1H), 7.92 (d, J=0.5 Hz, 1H), 7.60 (dd, J=9.0, 1.5 Hz, 1H), 7.28 (d, J=9.0 Hz, 1H), 4.71 (t, J=5.5 Hz, 1H), 4.44 (d, J=5.5 Hz, 2H), 3.33 (s, 6H).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([C:21](Cl)=[O:22])[CH2:18][CH2:19][CH3:20]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:10][C:21](=[O:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCC(=O)Cl
Reactant: NC(=O)C(c1ccccc1)c1ccccc1
Product: CCCCC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 83° C. and MS: m/e=296.3 (M+H+) was prepared in accordance with the general method of example 39 from 2,2-diphenylacetamide and butanecarboxylic acid chloride.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O.[SH-].CO>O>[NH2:1][C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [SH-]
Solvent: CO
Solvent: O
Product: Nc1cccc(C(=O)O)c1[N+](=O)[O-]

Procedure:
In one non-limiting reaction scheme, dinitrobenzoic acid may be reacted with about one to about five equivalents of an alkali hydrosulfide in a methanol:water mixture at reflux temperature for about 20 to about 40 minutes to produce an aminonitrobenzoic acid. As is described in the Example below, 2,6-dinitrobenzoic acid may be allowed to react with about three equivalents of sodium hydrosulfide in a methanol:water mixture at reflux temperature for about 30 minutes to produce 2-amino-6-nitrobenzoic acid. In some non-limiting embodiments, three equivalents of sodium hydrosulfide may be reacted with one equivalent of the sodium salt of 2,6-dinitrobenzoic acid in refluxing methanol/water followed by acidification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)O)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:2].B(F)(F)F.CCOCC.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH2:15][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:22]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(CC)(Oc1ccccc1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(CC)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[(4-Benzyloxyphenyl)-hydroxymethyl]-2-phenoxy-butyric acid ethyl ester (9.5 mmol) in anhydrous CH2Cl2 (30 mL) was cooled to 0° C. and treated with BF3-Et2O (1.16 mL, 9.5 mmol) and triethylsilane (1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and gradually warmed to ambient temperature. Saturated aqueous Na2CO3 (15 mL) was added and the mixture was stirred vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 2-(4-benzyloxybenzyl)-2-phenoxybutyric acid ethyl ester as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].FC(F)(F)C(O)=O.[F:23][C:24]([F:37])([F:36])[C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][N:26]=1>>[CH:13]([O:12][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:7]=1[C:8]([N:33]1[CH2:32][CH2:31][N:30]([C:28]2[S:29][C:25]([C:24]([F:36])([F:23])[F:37])=[N:26][N:27]=2)[CH2:35][CH2:34]1)=[O:10])([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(C#N)cc1C(=O)O
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(C#N)cc1C(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1
Yield: 80 %

Procedure:
Prepared in analogy to example 1 (b) from 5-cyano-2-isopropoxy-benzoic acid (Example A28) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white solid (yield 80%). MS (m/e): 426.0 (M+H+, 100%).
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[CH:29]=[N:28][N:27]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:26]=1)(=O)C.[ClH:38].C(=O)([O-])O.[Na+]>C(O)C>[ClH:38].[CH:14]1([C:12](=[O:13])[CH:11]([N:8]2[CH2:9][CH2:10][CH:5]([SH:4])/[C:6](=[CH:24]/[C:25]3[CH:29]=[N:28][N:27]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:26]=3)/[CH2:7]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][CH2:16]1
Reactant: CCOC(=O)CCCn1ncc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCn1ncc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Reaction time: 2 h

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({2-[3-(ethoxycarbonyl)propyl]-2H-1,2,3-triazol-4-yl}methylidene)piperidine (570 mg) in ethanol (50 ml) was introduced HCl gas at 0° C. for 30 minutes. The mixture was stirred under tightly sealed condition for 2 hours, and the solvent and excess hydrogen chloride were removed in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N HCl, 35/65, v/v) to afford a fraction containing the product. This fraction was treated with a saturated aqueous sodium hydrogen carbonate solution, and the liberated base was extracted with ethyl acetate to afford the free base of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7])=[C:4](C)[CH:3]=1.[Li+].CC([N-]C(C)C)C.[F:24][C:25]([F:33])([F:32])[C:26](N(OC)C)=[O:27]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])=[O:7])=[C:13]([C:26](=[O:27])[C:25]([F:24])([F:32])[F:33])[CH:14]=1
Reactant: CON(C)C(=O)C(F)(F)F
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(Br)cc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromo-N,N-diethyl-2-methylbenzamide (500 mg, 1.851 mmol) in Tetrahydrofuran (4.63 ml) was cooled to −78 C and treated with LDA (2.313 ml, 4.63 mmol) for 15 minutes before 2,2,2-trifluoro-N-methoxy-N-methylacetamide (320 mg, 2.036 mmol) in Tetrahydrofuran (4.63 ml) was added to the reaction mixture and allowed to warm to room temperature. The reaction was stirred overnight and then partitioned between 1N HCl (100 mL) and EtOAc (100 mL). The aqueous layer was further extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (150 mL), dried over magnesium sulfate, filtered and concentrated. Purification using MPLC (0-20% EtOAc/Hex) affords 4-bromo-N,N-diethyl-2-(trifluoroacetyl)benzamide. LC-MS (IE, m/z): 366 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)[CH:13]([OH:17])[C:14](O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:24]1C(=O)CC[C:25]1=O.C(Cl)CCl.CN>C(Cl)Cl.C1COCC1>[CH:19]1([CH2:18][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]([OH:17])[C:14]([NH:24][CH3:25])=[O:15])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(NC(CC1CCC1)C(O)C(=O)O)OCc1ccccc1
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)C(O)C(CC1CCC1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-4-cyclobutyl-2-hydroxybutanoic acid (250 mg, 0.81 mmol) in DCM (20 mL) was added HOSu (140 mg, 1.22 mmol), EDC (234 mg, 1.22 mmol). After stirring for 1 hour, methylamine in THF (2 N, 0.81 mL) was added to the above mixture. The reaction mixture was stirred for 18 hours and then concentrated in vacuo. The residue was purified by Gilson Prep to afford the title compound (135 mg). 1H-NMR (CDCl3): δ 7.54-7.28 (m, 5H), 6.67 (NH, 1H), 5.03 (dd, 2H), 3.68 (m, 1H), 2.73 (m, 3H), 2.26 (m, 1H), 1.97-1.31 (m, 9H). (M+1) 321.
Reaction SMILES: N1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)C=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:39]1[CH:43]=[CH:42][N:41]=[CH:40]1.IC1C=C2C(C=CN2C)=CC=1>C1(C)C(C)=CC=CC=1>[N:39]1([C:5]2[CH:14]=[C:13]3[C:8]([CH:9]=[CH:10][N:12]3[CH3:11])=[CH:7][CH:6]=2)[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: c1c[nH]cn1
Agent: Cn1ccc2ccc(I)cc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Product: Cn1ccc2ccc(-n3ccnc3)cc21
Temperature: 160 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
An oven-dried re-sealable Schlenk tube was flushed with argon and charged with copper(I) trifluoromethanesulfonate benzene complex (1.39 g, 2.76 mmol), 1.10-phenanthroline (5.69 g, 31.6 mmol), dibenzylideneacetone (740 mg, 3.16 mmol) and cesium carbonate (10 g, 30.7 mmol). Imidazole (3.23 g 44.8 mmol), 6-iodo-1-methyl-1H-indole (8.13 g, 31.6 mmol) and xylene (16 mL) were added and the tube was purged with argon. The tube was sealed and heated with stirring at 160° C. for 18 h. The mixture was cooled to room temperature and partitioned between CH2Cl2 (35 mL) and saturated aqueous NH4Cl (5 mL). The organic layer was separated and washed with brine. Then the organic extract was dried over MgSO4, filtered and concentrated. The crude concentrate was filtered though a pad of silica gel and evaporated. Purification by HPLC afforded 6-imidazol-1-yl-1-methyl-1H-indole as a brown oil (3.1 g, 50%). [Ref: Kiyoori, A.; Marcoux, J-F.; Buchwald, S. L. Tetrahedron Lett., 1999, 40, 2657.]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([CH:16]1[C:21]2[CH:22]=[CH:23][S:24][C:20]=2[CH2:19][CH2:18][NH:17]1)[CH3:15]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:17]3[CH2:18][CH2:19][C:20]4[S:24][CH:23]=[CH:22][C:21]=4[CH:16]3[CH2:14][CH3:15])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CCC1NCCc2sccc21
Product: CCC1c2ccsc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 60 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-ethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=3[CH:18]=[C:19]([CH3:29])[CH:20]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc(-c2cc(C)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3ccc(C)cc3)c2O1

Procedure:
The title compound was prepared (0.049 g, 44%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(4-methylphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.37 mmol) and methylamine (0.114 g, 3.7 mmol). mp 184-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:43]=[CH:42][C:8]2[N:9]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[C:17]([C:22]3[C:27]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)=[CH:26][CH:25]=[C:24]([OH:35])[CH:23]=3)[CH:16]=[CH:15]4)=[N:11][C:7]=2[CH:6]=1)=[O:4].N1C=CC=CC=1.[O:50](S(C(F)(F)F)(=O)=O)[S:51]([C:54]([F:57])([F:56])[F:55])(=O)=[O:52]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[CH:43]=[CH:42][C:8]2[N:9]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[C:17]([C:22]3[C:27]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)=[CH:26][CH:25]=[C:24]([O:35][S:51]([C:54]([F:57])([F:56])[F:55])(=[O:52])=[O:50])[CH:23]=3)[CH:16]=[CH:15]4)=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(O)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OS(=O)(=O)C(F)(F)F)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1 g (1.7 mmol) of Compound 475a in 20 mL of DCM, 550 μL (6.8 mmol) of pyridine, and 21 mg (0.17 mmol) of DMAP were added and the entire mixture was cooled to 0° C. Dropwise, 860 μL of Tf2O was added. The reaction was then stirred at room temperature for 1 h. Finally the reaction mixture was evaporated, and the product dissolved in ethyl acetate, washed with cold water (2×), brine (2×), dried with Na2SO4 and evaporated again to give the title intermediate as a white solid foam in quantitative yield.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N+:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]([CH3:21])=[CH:19][N:20]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([N:10]1[CH2:11][CH:12]=[C:13]([C:16]2[O:17][C:18]([CH3:21])=[CH:19][N:20]=2)[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cnc(-c2cc[n+](Cc3ccccc3)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cnc(C2=CCN(Cc3ccccc3)CC2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
21.6 g sodium borohydride was added to 130 g 1-benzyl-4-(5-methyl-oxazol-2-yl)-pyridinium in 1.5 L ethanol at 0° C. under nitrogen atmosphere. After 30 min at 0° C., the solution was stirred at RT for 2 h. The mixture was concentrated and treated with water and ethyl acetate. The organic layers were separated and aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The resulting crude product was purified by flash chromatography (silica gel) to give 81.2 g of the desired product. Rf: 0.3 (petrolether/ethyl acetate:1/1), (M+H)+: 255
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>C1COCC1>[I:41][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To N-Boc-4-piperidine-ethanol (5.00 g, 21.8 mmol) in THF (100 mL) was added triphenylphosphine (6.29 g, 24.0 mmol), imidazole (1.64 g, 24.1 mmol) and iodine (6.09 g, 24.0 mmol). The reaction was stirred at rt for 2 h. The mixture was filtered through Celite® purified by flash chromatography to provide the title compound of step A (6.31 g, 18.6 mmol, 85%). 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (dq, J=12.2, 4.3 Hz, 2H), 1.42 (s, 9H), 1.49-1.58 (m, 1H), 1.62 (d, J=13.2 Hz, 2H), 1.75 (q, J=7.1 Hz, 2H), 2.67 (td, J=12.9, 2.5 Hz, 2H), 3.18 (t, J=7.1 Hz, 2H), 4.06 (d, J=13.0 Hz, 2H).
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[F:27][C:28]1[CH:29]=C([CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38])C#N>C1COCC1>[F:27][C:28]1[CH:29]=[C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)[CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38]
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: CC(C)Oc1ccc(C#N)cc1F
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(-c3ccc(OC(C)C)c(F)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (500 mg, 2.259 mmol) in THF (5 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (1595 μl, 2.71 mmol) and the solution was stirred for 0.5 h before addition of 3-fluoro-4-isopropoxybenzonitrile (405 mg, 2.259 mmol) in THF (5 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected washing with water to give 3-(3-fluoro-4-isopropoxyphenyl)-6-methoxyisoquinolin-1-ol (520 mg, 70% yield) as a solid after drying. MS: MS m/z 328.1 (M++1).
Reaction SMILES: [NH:1]=[C:2]([C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=12)[S:3][CH2:4][C:5](=O)[C:6]([OH:8])=O.ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>C1COCC1>[CH:36]1([NH:39][C:6]([C:5]2[N:1]=[C:2]([C:10]3[N:11]=[CH:12][N:13]4[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=34)[S:3][CH:4]=2)=[O:8])[CH2:38][CH2:37]1
Reactant: Cn1nnc2c(C(=N)SCC(=O)C(=O)O)ncn2c1=O
Reactant: NC1CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nnc2c(-c3nc(C(=O)NC4CC4)cs3)ncn2c1=O
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 3-(imino(3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazin-8-yl)methylthio)-2-oxopropanoic acid (0.500 g; 1.8 mmol) in dry THF (30 mL) under nitrogen was added isobutyl chloroformate (0.47 mL; 3.6 mmol), followed by triethylamine (0.51 mL; 3.6 mmol). The mixture was stirred for 1 hours, and then cyclopropylamine (0.206 g; 3.6 mmol) was added, and stirring continued for a further 3 hours. The precipitate was filtered, washed with water (5×20 mL) and diethyl ether (2×15 mL) to yield the title compound as a pale yellow solid (0.278 g; 49%). δH (DMSO-d6) 8.94 (1H, s), 8.41 (1H, s), 8.22 (1H, d, J=4.3), 3.89 (3H, s), 2.88 (1H, m), 0.66-0.76 (4H, m).