Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([C:18]3([NH:21][C:22](=[O:27])[C:23]([O:25]C)=O)[CH2:20][CH2:19]3)=[O:17])=[C:10]([F:28])[CH:9]=2)[C:3]=1[C:29]([O:31][CH3:32])=[O:30].[NH3:33]>C(Cl)Cl.CO>[NH2:33][C:23](=[O:25])[C:22]([NH:21][C:18]1([C:16]([NH:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:4]3[C:3]([C:29]([O:31][CH3:32])=[O:30])=[C:2]([F:1])[CH:7]=[CH:6][CH:5]=3)=[CH:9][C:10]=2[F:28])=[O:17])[CH2:20][CH2:19]1)=[O:27]
Reactant: N
Reactant: COC(=O)C(=O)NC1(C(=O)NCc2ccc(-c3cccc(F)c3C(=O)OC)cc2F)CC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(F)cccc1-c1ccc(CNC(=O)C2(NC(=O)C(N)=O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3,3′-difluoro-4′-({[(1-{[methoxy(oxo)acetyl]-amino}cyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate (0.02 g, 0.045 mmol, Example 5) in methylene chloride (2 mL) at room temperature was added ammonia (0.224 mL of a 2M solution in methanol, 0.45 mmol). The reaction mixture was stirred at room temperature for 4 hrs and then concentrated to obtain the crude product. This crude product was purified by reverse phase HPLC (Vydac column #218TP1022, gradient elution 5–95% acetonitrile:water containing 0.1% TFA). The pure fractions were lyophilized to afford the title compound as a solid. Purity was determined by LCMS (ES MS, M++H found:432) and proton NMR (400 MHz, CDCl3: δ 7.86 (1H,s), 7.45(1H,dt, J=5.7 and 8.1 Hz), 7.35 (1H, t, J=7.8 Hz), 7.20–7.00 (4H,m), 6.59 (1H, m), 5.61(1H, s), 4.54 (2H, d,J=6.0 Hz), 3.74(3H,s), 1.68(2H,m), 1.12 (2H,m) ppm.
Reaction SMILES: Cl[C:2]1[C:7]2[S:8][C:9]3[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[N:5]=[CH:4][N:3]=1.[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].Cl.BrC1C=C(C=CC=1)N>C(O)(C)C>[Br:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:7]3[S:8][C:9]4[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=4[C:6]=3[N:5]=[CH:4][N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=[N+]([O-])c1cccc2c1sc1c(Cl)ncnc12
Agent: Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc2c1sc1c(Nc3cccc(Br)c3)ncnc12
Temperature: 85 °C
Reaction time: 7.5 h
Yield: 58.3 %

Procedure:
A mixture of 4-chloro-6-nitrobenzothienopyrimidine (166 mg, 0.62 mmol), m-bromoaniline (0.08 mL, 0.73 mmol) and m-bromoaniline hydrochloride (144 mg, 0.69 mmol) in isopropanol (4.5 mL) was heated at 85° C. stirring under N2 for 7.5 hours. The dark brown solid was collected by Buchner filtration and washed with isopropanol and air dried to give 4-([3-bromophenyl]amino)-6-nitrobenzothieno[3,2-d]pyrimidine (145 mg, 67%), mp 247.0-248.1° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:33][C:34]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:32])[CH2:9][NH:10][C:11](=[O:31])[CH2:12][NH:13]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>C(#N)C>[CH3:1][O:2][CH:3]([O:33][C:34]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:32])[CH2:9][NH:10][C:11](=[O:31])[CH2:12][NH2:13]
Reactant: COc1ccc(C(OC(CCCNC(=O)CNC(=O)CNC(=O)OCC2c3ccccc3-c3ccccc32)OC)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCNCC1
Product: COc1ccc(C(OC(CCCNC(=O)CNC(=O)CN)OC)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To compound 13 (3.00 g, 4.12 mmol) were added acetonitrile (5 mL) and piperidine (2.4 mL) at room temperature, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: dichloromethane-methanol (9:1)+0.05% pyridine) to give glycylglycine-4,4′-dimethoxytrityloxybutylamide (14) (1.13 g, 54%). The instrumental analysis values of glycylglycine-4,4′-dimethoxytrityloxybutylamide (14) are shown below.
Reaction SMILES: CC(C)C([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12]C(=O)C(C)C)[O:9][C@@H:8]([N:18]2[C:22]3[N:23]=[C:24]([NH:29]C=O)[N:25]=[C:26]([O:27]C)[C:21]=3[C:20]([I:32])=[CH:19]2)[CH2:7]1)=O>CC#N>[NH2:29][C:24]1[NH:25][C:26](=[O:27])[C:21]2[C:20]([I:32])=[CH:19][N:18]([C@@H:8]3[O:9][C@H:10]([CH2:11][OH:12])[C@@H:6]([OH:5])[CH2:7]3)[C:22]=2[N:23]=1
Reactant: COc1nc(NC=O)nc2c1c(I)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Solvent: CC#N
Product: Nc1nc2c(c(I)cn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
The title compound (58) is prepared in analogy with Example 51 by proceeding from compound (46) (200 mg, 0.35 mmol). Colorless crystals (126 mg, 92%) are obtained from MeCN. Melting point: 218-220° C. UV (MeOH): λmax 266 (12,000), 285 (sh, 8400). 1H-NMR ([D6 ] DMSO): δ=2.08 (m, Hα --C(2')), 2.30 (m, Hβ --C(2')), 3.48 (m, H--C(5')), 3.74 (m, H--C(4')), 4.26 (m, H--C(3')), 4.89 (t, 5'-OH), 5.18 (d, 3'-OH), 6.25 (dd, H--C(1')), 6.34 (br., NH2), 7.09 (s, H--C(6)), 10.51 (br., NH). Anal. calculated for C11H13IN4O4 (392.2): C, 33.69, H, 3.34, N, 14.29; found: C, 33.78, H, 3.42, N, 14.29.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@H:10](C3C=C([N+]([O-])=O)C=CC=3C([O-])=O)[CH2:11][C@H:7]2[CH2:6][N:5]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-:35].[K+].[K+].C(OCC)(=O)C.CO>CO>[OH:35][C@@H:10]1[CH2:9][N:8]2[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][N:25]=3)[CH2:6][C@@H:7]2[CH2:11]1
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1[C@@H]1C[C@H]2CN(c3ccc(C(F)(F)F)cn3)CCC(=O)N2C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@H](O)CN12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 142.2 %

Procedure:
To (8S,9aS)-5-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]octahydro-1H-pyrrolo[1,2-a][1,4]diazepin-8-yl-4-nitrobenzoate (135 mg, 0.291 mmol, Part C) in methanol (2.5 mL) was added potassium carbonate (24 mg, 0.174 mmol). The mixture was stirred at room temperature for 1.5 hours and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then ethyl acetate/methanol=10:1) to give 78 mg (85% yield) of the titled compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (m, 1H), 2.28 (m, 1 H), 2.45 (m, 1H), 2.63 (m, 1 H), 3.35 (m, 3 H), 3.44 (m, 1 H), 3.92 (m, 1H), 4.17 (m, 1H), 4.42 (m, 2H), 5.09 (br s, 1H), 7.00 (d, J=8 Hz, 1 H), 7.80 (d, J=8 Hz, 1 H), 8.43 (s, 1 H); MS (ESI) m/z 316.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[C:20](=O)[CH2:19]1)=[O:17].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[CH:20]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:19]1)=[O:17]
Reactant: O=C(NCC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Reactant: C1CCNC1
Product: O=C(NCC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1N1CCCC1)c1ccc(Cl)s1

Procedure:
In analogy to example 24B 5-chloro-thiophene-2-carboxylic acid {(1RS,4SR)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-oxo-cyclopentylmethyl}-amide was reacted with pyrrolidine to give 5-chloro-thiophene-2-carboxylic acid {(1RS,4SR)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-pyrrolidin-1-yl-cyclopentylmethyl}-amide. Off-white crystalline solid. 543.3 ([M+H]+).
Reaction SMILES: [C:1]12([C:7]3[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=3)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][CH:1]1[C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cccc(C23CCCC2O3)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(C2CCCC2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4 g (17.2 mmol) of ethyl 3-(6-oxabicyclo[3.1.0]hex-1-yl)benzoate (6) and 50 ml of methylene chloride are introduced into a round-bottomed flask. The mixture is cooled to 0° C. and then 2.2 ml (17.2 mmol) of BF3.Et2O are added dropwise. The reaction mixture is stirred at 0° C. for 1 hour and then 25 ml of a saturated aqueous sodium bicarbonate solution are added. The mixture is separated by settling and the aqueous phase extracted with methylene chloride. The combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20). The title product is obtained in the form of a pale yellow oil (3.4 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=O)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[SH:41]>O1CCCC1>[S:41]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:16]1[C:14]1[CH:13]=[CH:12][C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([CH2:19][O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:9][C:10]=2[CH:15]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)c1ccc2c(c1)nc(COCc1ccccc1)n2-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: c1ccc(COCc2nc3cc(-c4nc5ccccc5s4)ccc3n2-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A 4-neck flask (500 mL) equipped with a reflux condenser was charged with 1-pheny-2-(phenylmethoxy)methylbenzimidazole-5-carboxylic acid (see Working Example 1-1) (4.00 g, 11.16 mmol) and anhydrous tetrahydrofuran (63 mL), and after the addition of oxalyl chloride (1.65 g, 13.0 mmol), this was warmed to 50° C. and stirred for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. Anhydrous THF (30 mL) was again added to the greenish-milky white semisolid residue, and after gradual addition of 2-aminobenzenethiol (1.40 g, 11.22 mmol), this was warmed to 50° C. and stirred for 16 hours. After cooling to room temperature, the precipitated crystals were filtered off and washed with saturated aqueous sodium hydrogen carbonate solution (approx. 20 mL), and the precipitated solid was filtered off to yield a mixture of starting material and the title compound (2.43 g, an approx. 1:1 mixture of starting material/title compound, based on 1H-NMR). The filtrate was allowed to stand for a further 16 hours at room temperature and the precipitated crystals were filtered off, washed with saturated aqueous potassium carbonate solution, washed with distilled water, and then dried under reduced pressure with heating to yield the title compound (0.82 g, 16% yield) as a white powder.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:30])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1ccccc1
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Product: O=C1Nc2cc(C(=O)OCc3ccccc3)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and benzyl alcohol Rf value: 0.6 (aluminium oxide, methylene chloride/methanol=30:1) C35H33N3O3
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[Cl:12][CH2:13][C:14](Cl)=[O:15].C(N(CC)CC)C>C(Cl)Cl>[Cl:12][CH2:13][C:14]([N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH2:7][CH2:8][CH2:9]1)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc2c1NCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc2c1N(C(=O)CCl)CCC2
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 8-methyl-1,2,3,4-tetrahydroquinolin (1) (8.0 g, 54.3 mmol) in dry CH2Cl2 (250 mL) at 0° C. was added chloroacetyl chloride (4.8 mL, 60.3 mmol) followed by addition of triethylamine (8.4 mL, 60.3 mmol). The reaction mixture was stirred overnight under N2 and then diluted with CH2Cl2 (300 mL), washed with 1M HCl (2×225 mL), H2O (2×250 mL) and brine. Dried over Na2SO4, filtered and concentrated under reduce pressure to 12.67 g of crude material which was purified by column chromatography (EtOAc/Hexanes). Obtained 11.76 g (52.6 mmol) of target 2 (off-white solid) in 97% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12](O)=[O:13])=[CH:7]2.B.C1COCC1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][OH:13])=[CH:7]2
Reactant: O=C(O)c1ccc2c(Cl)cccc2c1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(Cl)cccc2c1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
To a cooled (0° C.), stirred suspension of 5-chloro-2-naphthoic acid (1.10 g, 5.32 mmol) in THF (10 mL) was added BH3.THF (1M in THF, 7.50 mL, 7.50 mmol) over 10 minutes. The resulting mixture was then heated under reflux for 1 hour 30 minutes, recooled to 0° C., and saturated aqueous K2CO3 (4 mL) was added. H2O (20 mL) was added and the mixture was extracted with ether. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give a pale yellow solid (0.94 g, 97%), m.p. 72°-75° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)(=[O:20])=[O:19]
Reactant: OCc1ccc(Br)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(Br)cn1
Reaction time: 2.5 h

Procedure:
A solution of (5-bromo-pyridin-2-yl)-methanol (20.0 g, 106 mmol) in 150 mL of dichloromethane was cooled to 0° C. under nitrogen. Triethylamine (19.3 mL, 138 mmol) was added, followed by methanesulfonyl chloride (9.95 ml, 128 mmol). After 2.5 hours, the mixture was quenched with 50 mL of water and diluted with 100 mL of dichloromethane. The organic layer was washed with an additional 50 mL of water and then the aqueous layer was extracted with 100 mL of methylene chloride. The organic extracts were dried over sodium sulfate, filtered and concentrated to provide (5-bromopyridin-2-yl)methyl methanesulfonate as a red solid that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 268.1 for M+H+(81Br).
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[C:10]([C:13]1[CH:14]=[C:15]([CH:19]2[CH2:28][C:27]([CH3:30])([CH3:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:31](O)=[O:32])[CH:25]=3)[NH:20]2)[CH:16]=[CH:17][CH:18]=1)(=[O:12])[NH2:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH:1]1([S:4]([NH:7][C:31]([C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:10]([NH2:11])=[O:12])[CH2:28][C:27]3([CH3:30])[CH3:29])=[O:32])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.1 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (200 mg, 1.65 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (66 mg, 1.65 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A34. A solution of 2-(3-carbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.33 mmol) and 1,1′-carbonyldiimidazole (110 mg, 0.66 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B34. Solution B34 was added to Solution A34 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-(6-cyclopropanesulfonylaminocarbonyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-benzamide (10 mg, 24%) as a white solid: MS (ESI) M+1=428.3.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=4)(=[O:20])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>[OH-].[Na+]>[O:4]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=3)(=[O:19])=[O:20])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC4(CC3)OCCO4)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
N-{4-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 215) (2.2 g, 5.1 mmol) was treated with concentrated hydrochloric acid (50 mL) at 0° C. and then allowed to warm to room temperature. After 30 min., 20 mL of 5 N NaOH was added dropwise and the precipitate was collected by filtration, and dried over P2O5 to give the title compound as a white solid (1.2 g); 1H NMR (300 MHz, DMSO-d6) δ 2.06 (s, 3H), 2.43 (t, J=5.8 Hz, 4H), 3.53 (t, J=5.8 Hz, 4H), 6.85-7.05 (m, 4H), 7.62 (d, J=9.0 Hz, 2H), 7.71 (d, J=9.0 Hz, 2H), 9.81 (s, 1H), 10.35 (s, 1H); MS (ES) m/z: 388.3 (MH+); HRMS Calcd. for C19H21N3O4S(M+):387.1253. Found: 387.1272.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[N:6]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=3)[N:6]=[C:2]2[CH3:1])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1nc(C#Cc2ccnc(C#N)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(C#N)c2)cn1-c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=303.1 (M+H+), was prepared in accordance with the general method of example 7 from 4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine-2-carbonitrile and 4-fluorobenzene boronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9](=[O:10])[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccncc1
Product: O=C(Nc1ccncc1)Oc1ccccc1
Yield: 534 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 6 using 4-aminopyridine and phenyl chloroformate. Yield 6 g, 534% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15](C(O)=O)[CH2:14]1)=[O:11])[CH:7]=[CH:6][S:5]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([NH:12][C:10]([C:9]2[N:8]3[C:4]([S:5][CH:6]=[CH:7]3)=[N:3][C:2]=2[CH3:1])=[O:11])[CH2:14]1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCN(C(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a cold (˜0° C.) solution of (R)-3-[(6-methyl-imidazo[2,1-b]thiazole-5-carbonyl)-amino]-piperidine-1-carboxylic acid tent-butyl ester (1.47 g) in dry DCM (30 mL) was added slowly TFA (4.63 mL). The reaction mixture was stirred at RT for 20 h, 5 eq more of TFA (4.63 mL) was added and the stirring was continued for 2 h. The reaction was concentrated in vacuo to yield the title compound as a bis-trifluoroacetate salt which was used for the next step without further purification.
Reaction SMILES: [CH2:1]([Si:3]([CH2:21][CH3:22])([CH2:19][CH3:20])[O:4][CH2:5][C:6]([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][C:8]#[CH:9])[CH3:2].[CH2:23]([SnH:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:21]([Si:3]([CH2:1][CH3:2])([CH2:19][CH3:20])[O:4][CH2:5][C:6]([O:14][Si:15]([CH3:18])([CH3:16])[CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7]/[CH:8]=[CH:9]/[Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])[CH3:22]
Reactant: C#CCC(CCCC)(CO[Si](CC)(CC)CC)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(CO[Si](CC)(CC)CC)O[Si](C)(C)C
Reaction time: 0.08 h

Procedure:
A mixture of 20.0 g. of 4-triethylsilyloxymethyl-4-trimethylsilyloxy-1-octyne, 18.18 g. of tri-n-butylstannane and 70 mg. of azobisisobutyronitrile is stirred under argon and placed in a bath at 100° C. After 5 minutes an exotherm ensues. The mixture is heated at 130°-140° C. for one hour and then the excess tri-n-butylstannane is removed at 130° C. and reduced pressure. The residue is distilled at 130°-140° C., 0.03 mm. in a Kugelrohr apparatus, giving the desired product as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6](Cl)[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:20][NH2:21]>O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([NH:20][NH2:21])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: COc1c(Cl)nc(SC)nc1Cl
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1c(Cl)nc(SC)nc1NN
Reaction time: 0.5 h

Procedure:
A mixture of 48.1 g (0.21 mol) of 4,6-di-chloro-2-methylthio-5-methoxypyrimidine, 29.5 g (0.21 mol) of potassium carbonate, 80 ml of hydrazine monohydrate, and 80 ml of water was prepared and heated at reflux with stirring for about 30 min at which time the reaction appeared by high pressure liquid chromatography to be complete. The mixture was allowed to cool and was extracted with methylene chloride. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was mixed with hexane and the solids removed by filtration and dried to obtain 34.7 g of the title compound as a tan solid melting at 118°-119° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:19]
Reactant: COC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COC(=O)c1ccccc1CBr
Yield: 92.2 %

Procedure:
A solution of methyl-2-methylbenzoate (250 mg, 1.66 mmol), NBS (296 mg, 1.66 mmol) and dibenzoylperoxide (403 mg, 1.66 mmol) was stirred under reflux for one day. After purification by flash chromatography, 350 mg (1.53 mmol, 92%) of methyl-2-(bromomethyl)benzoate were obtained as a colorless oil.