Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:19]([O:20]C(=O)C)=[CH:18][C:5]2[CH:6]=[C:7]([C:9](=[O:17])[CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[O:8][C:4]=2[C:3]=1[CH3:24].[BH4-].[Na+].O>CO>[OH:17][CH:9]([C:7]1[O:8][C:4]2[C:3]([CH3:24])=[C:2]([CH3:1])[C:19]([OH:20])=[CH:18][C:5]=2[CH:6]=1)[CH2:10][N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CC(=O)Oc1cc2cc(C(=O)CN3CCOCC3)oc2c(C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(O)cc2cc(C(O)CN3CCOCC3)oc2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
A solution of acetic acid 6,7-dimethyl-2-(2-morpholin-4-yl-acetyl)-benzofuran-5-yl ester (35 mg), prepared as in Example 17, in MeOH (10 mL) was stirred while NaBH4 (40 mg) was added, and the mixture was stirred at room temperature for an additional 4 h. The mixture was poured into water, and extracted with ethylacetate. The organic layer was dried over MgSO4 and evaporated. The residue was purified by silica gel column eluting with 5% MeOH in DCM to give 21 mg of 2-(1-hydroxy-2-morpholin-4-yl-ethyl)-6,7-dimethyl-benzofuran-5-ol as an oil. Conversion into HCl salt gave a yellow solid. 1H NMR (CD3OD, 300 MHz) δ: 6.77 (s, 1H), 6.67 (s, 1H), 5.29 (dd, J=10.4, 3.3 Hz, 1H), 4.04(m, 2H), 3.85(q, 2H), 3.70–3.50 (m, 4H), 3.30(m, 2H), 2.40(s, 3H), 2.20(s, 3H) ppm. 13C NMR (CD3OD, 75 MHz) (as HCl salt) δ: 154.72, 151.88, 149.40, 125.02, 121.67, 120.21, 104.51, 102.50, 63.77, 63.69, 61.70, 60.19, 53.82, 51.28, 11.24, 11.10 ppm. M/S 292 (M+H+).
Reaction SMILES: [O:1]=[C:2]([CH3:35])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[O:19]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].Cl[CH2:37][C:38](=[O:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[O:1]=[C:2]([CH3:35])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[O:19]2)[CH:10]=[C:11]([O:17][CH2:37][C:38](=[O:40])[CH3:39])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCOc1c(OCC(C)=O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of trans-2-[3-(2- oxopropylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]5- (3,4,5-trimethoxyphenyl)tetrahydrofuran (51 mg, 0.1 mmol), chloroacetone(16 uL, 0.2 mmol) and potassium carbonate (28 mg, 0.2 mmol) in DMF (1 mL) was stirred at room temperature for 40 h. The reaction mixture was diluted with ethyl ether and washed with water and brine. The organic extracts were dried (MgSO4), filtered, and evaporated to a residue (58 mg), which was purified by preparative TLC (hexane ethyl acetate; 3:2. v/v). The title compound was isolated as a colorless foam: Rf 0.38; MS, m/z 564M+.; NMR (CDCl3) δ 1.08(t, CH2CH2CH3), 2.33 & 2.38 (2 s, OCH2COCH3 & SO2CH2COCH3), 4.48 (s, SO2CH2), 4.68 (s, OCH2CO), 5.20 (m, H-2 & H-5), 6.62 (s, 2 H, C5ArH), 7.20 & 7.52 (2 d, 2 H, C2ArH)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH3:12][C:13]1([CH3:16])[CH2:15][S:14]1.O>C1C=CC=CC=1>[CH3:12][C:13]([SH:14])([CH3:16])[CH2:15][N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: CC1(C)CS1
Reactant: CCOC(=O)C1CCNCC1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1CCN(CC(C)(C)S)CC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
Ethyl piperidine-4-carboxylate (3.6 g, 22.9 mmol) was dissolved in benzene (5 mL), and 2,2-dimethylthiirane (5.04 g, 57.3 mmol) was added. The reaction mixture was stirred at 80° C. for 20 hours, poured into water and extracted several times with EtOAc. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The volatiles were evaporated and the residue was dried under vacuum to afford 5.45 g (97%) of the title compound. 1H NMR (300 MHz, CD3OD) δ 4.12 (q, J=7.1 Hz, 2H), 2.92-2.96 (d, J=11.9 Hz, 2H), 2.19-2.40 (m, 6H), 1.61-1.86 (m, 4H), 1.29 (s, 6H), 1.25 (t, J=7.1 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[F:20][C:21]([F:40])([F:39])[C:22]([NH:24][CH2:25][C:26]1[C:27]([F:38])=[CH:28][C:29]([Cl:37])=[C:30]([CH:36]=1)[C:31]([N:33]=[C:34]=[O:35])=O)=[O:23].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:37][C:29]1[C:30]([C:31]2[NH:33][C:34](=[O:35])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:4][CH:5]=3)[N:10]=2)=[CH:36][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:21]([F:40])([F:39])[F:20])=[C:27]([F:38])[CH:28]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Yield: 6.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 0.300 g), 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate (Intermediate-69, 0.300 g), DCM (20 mL), trifluoro acetic acid (5.0 mL) to afford 0.030 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 4.49 (m, 2H), 7.74-7.77 (m, 1H), 7.78-7.80 (m, 1H), 7.87 (d, J=5.1 Hz, 2H), 8.19 (d, J=4.2 Hz, 2H), 10.06 (m, 1H), 12.76 (s, 1H); MS (m/z): 467.15 (M+H)+.
Reaction SMILES: [H-].[K+].[Cl:3][C:4]1[C:5]([Cl:25])=[CH:6][C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.Br[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:3][C:4]1[C:5]([Cl:25])=[CH:6][C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13][C:9]=3[N:10]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:11]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Cl)c(Cl)cc3c2CC1
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCCc3ccccc3)c3cc(Cl)c(Cl)cc23)CC1
Reaction time: 0.25 h
Yield: 79.2 %

Procedure:
Potassium hydride (45 mg, 1.1 mmol) was added to a solution of tert-butyl 8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.20 g, 0.56 mmol) in DMF (1.0 mL). After 15 min, 1-bromo-3-phenylpropane (0.13 mL, 0.86 mmol) was added. After 5 h, the reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (3:1) to give 0.21 g (78%) of a yellow solid: mp 119-124° C.; IR (diffuse reflectance) 2980, 2973, 2941, 2932, 1686, 1478, 1462, 1417, 1365, 1247, 1178, 1160, 1112, 855, 699 cm−1; MS (EI) m/z 472 (M+), 416, 227, 226, 224, 211, 188, 153, 115, 90, 56; Anal. Calcd for C26H30Cl2N2O2: C, 65.96; H, 6.39; N, 5.92; found: C, 66.01; H, 6.47; N, 5.82.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14](=[O:29])[CH:15]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH2:16][C:17]([O:19]CC)=[O:18])[CH2:8]2>O.CO>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14](=[O:29])[CH:15]([C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[CH2:16][C:17]([OH:19])=[O:18])[CH2:8]2
Reactant: CCOC(=O)CC(C(=O)N1Cc2ccc(Cl)cc2C1)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC(C(=O)N1Cc2ccc(Cl)cc2C1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
With stirring at rt the solution of lithium hydroxide monohydrate (0.29 g) in water (1.5 ml) was added to the solution of ethyl 4-(5-chloro-2-isoindolinyl)-3-(4-chlorophenyl)-4-oxobutanoate (0.64 g) in methanol (10 ml). The cloudy solution was stirred at rt for 2 h. Then the methanol was removed by distillation and the residue was diluted with water (3 ml). With ice-cooling conc. HCl (1 ml) was added dropwise to the stirred solution. The precipitate formed is kept at 0° C. for 0.5 h and collected by suction filtration. After washings with 1M HCl and water the solid is dried in vacuo to provide 4-(5-chloro-2-isoindolinyl)-3-(4-chlorophenyl)-4-oxobutanoic acid (0.56 g) as colourless solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:18]=[CH:17][O:16][CH:15]=1.[NH:19]1[C:27](=[O:28])[C:25](=O)[C:23](=[O:24])[NH:22][C:20]1=[O:21]>O1CCCC1>[Cl:13][C:14]1[CH:18]=[CH:17][O:16][C:15]=1[CH:25]1[C:23](=[O:24])[NH:22][C:20](=[O:21])[NH:19][C:27]1=[O:28]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Clc1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1NC(=O)C(c2occc2Cl)C(=O)N1
Temperature: 25 °C

Procedure:
n-Butyl lithium and an equivalent of diisopropylamine are reacted with an equivalent of 3-chlorofuran for 1.5 hours in tetrahydrofuran at -80° C. according to the procedure of Ly and Schlosser [Helv. Chim. Acta 60 (6), p. 2087 (1977)]. At the same temperature, an equivalent of alloxan in tetrahydrofuran is added dropwise and the mixture allowed to warm to room temperature for 2 hours. 5-(3-Chloro-2-furyl)-2,4,6-(1H,3H,5H)pyrimidinetrione is isolated by the procedure of Example 5.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH2:15]([O:17][CH:18]([N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1)[CH3:19])[CH3:16].O>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:23]2[CH:22]=[N:21][N:20]([CH:18]([O:17][CH2:15][CH3:16])[CH3:19])[CH:24]=2)[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)cn1
Temperature: 100 °C
Yield: 46.7 %

Procedure:
A biphasic solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.40 g, 1.4 mmol) and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.46 g, 1.7 mmol) in toluene (4 mL) and 10% sodium carbonate in water (3.0 mL, 2.9 mmol) was degassed under N2. Tetrakis(triphenylphosphine)palladium(0) (83 mg, 0.072 mmol) was added and the mixture was bubbled with N2 for 5 min and heated at 100° C. overnight. The resulting solution was cooled to room temperature and the organic layer was purified on silica gel (eluting with 0-40% of ethyl acetate in hexanes) to give the desired product (0.22 g, 45%). LCMS calculated for C17H22ClN2O3 (M+H)+: m/z=337.1. found: 337.1
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:29]1[N:28]=[C:27]([C:20]2[C:21]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:18][CH:19]=2)[CH:32]=[CH:31][N:30]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Nc1ccccc1Cl
Product: Clc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 19.6 %

Procedure:
Using the procedure of example 1, 2-chloro-aniline (103 mg) was reacted with compound 1f (100 mg) to provide compound 12 (17 mg, 20%). 1H NMR (400 MHz, CD3OD) δ 8.75 (d, J=7.6 Hz, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.20 (s, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.25 (d, J=5.2 Hz, 1H), 7.22 (dd, J=7.6 Hz, 4.8 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H). MS (ESI) m/z 322: (M+H)+.
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH:6]2[CH2:11][S:10][C@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:7]2=[O:24])[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.[CH3:31][Si:32](C)([CH3:36])[CH2:33]CO>CCOCC.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:4]1(=[O:25])[N:5]([CH:6]2[CH2:11][S:10][C@H:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:8]([CH2:18][C:19]([O:21][CH2:22][CH2:23][Si:32]([CH3:36])([CH3:33])[CH3:31])=[O:20])[C:7]2=[O:24])[C:1](=[O:30])[C:2]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:3]12
Reactant: CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CS[C@@H]1c1ccccc1
Reactant: C[Si](C)(C)CCO
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOCC
Product: C[Si](C)(C)CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CS[C@@H]1c1ccccc1

Procedure:
(R)-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (isomer A) (1.0 g., 2.36 mmole) is heated in 2-trimethylsilylethanol (5.58 g., 47.2 mmole) in the presence of titanium (IV) ethoxide (135 mg., 0.59 mmole). Upon completion of the reaction, the reaction mixture is diluted with ether, washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and concentrated in vacuo. The residue is purified chromatographically on silica gel eluting with hexane/ethyl acetate (3:1) to give (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C:21]3([NH:25][C@@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH:22]3I)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C>CO.[Pd]>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COC(=O)[C@H]1CC(I)C2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reaction time: 8 h

Procedure:
To a solution of methyl(2R,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-4-iodo-1,8-diazaspiro[4.5]decane-2-carboxylate (860 mg, 1.179 mmol) in methanol (20 ml), triethylamine (0.822 ml, 5.89 mmol) was added followed by palladium on carbon 10% (172 mg, 0.162 mmol). Resulting mixture was hydrogenated at atmospheric pressure of H2 at room temperature overnight.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([C:29](O)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:29]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[O:30])[CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: COCCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described for Example 1, Step A except using 1-tert-butoxycarbonyl-2(S)-(3-methoxypropyl)piperazine (0.215 g, 0.832 mmol), naphthalene-1-carboxylic acid (0.143 g, 0.83 mmol), HOBT (0.128 g, 0.83 mmol), EDC.HCl (0.160 g, 0.83 mmol) in DMF (5 mL). The title compound was obtained as an oil (0.310 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)(=[O:20])=[O:19])[C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([N:17]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)(=[O:19])=[O:20])[C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCCc1nc2c(NS(=O)(=O)c3cccc(F)c3)cccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(N(Cc3ccccc3)S(=O)(=O)c3cccc(F)c3)cccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
The product from step d.) (45 mg, 0.103 mmol) was dissolved in DMF (1 mL), treated with K2CO3 (20 mg, 0.145 mmol), benzyl bromide (25 μL, 0.206 mmol), and stirred at 80° C. for 3.5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed several times with water and concentrated under reduced pressure to give the sub-title compound that was used in crude form without purification.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[N:21]=3)[C:16](O)=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][NH2:43])[CH2:37][CH2:36]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[N:21]=3)[C:16]([NH:43][CH2:42][CH2:41][N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)=[O:17])=[CH:9][CH:8]=2)=[CH:23][CH:24]=1
Reactant: Cc1cc(C(=O)O)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: NCCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCN2CCOCC2)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
In a 50 mL vial with a screw-top septum 2-(4-(4-fluorophenoxy)phenyl)-6-methylisonicotinic acid (300 mg, 0.9 mmol) was dissolved in DCM (5 mL). To the solution were added 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide (144 mg, 0.9 mmol) and 1-hydroxybenzotriazole (63 mg, 0.46 mmol). The reaction mixture was stirred for 20 minutes at room temperature. Then, 2-morpholinoethanamine (121 mg, 0.9 mmol) was added. The reaction mixture was stirred for 20 hours at room temperature and was then chromatographed directly by combiflash without workup using a 40-gram silica column and a gradient of MeOH (40% max) in chloroform to provide 2-(4-(4-fluorophenoxy)phenyl)-6-methyl-N-(2-morpholinoethyl) isonicotinamide as a clear oil (142 mg). 1H NMR (CD3OD): 8.05-7.99 (m, 2 H), 7.98 7.94 (m, 1 H), 7.56-7.51 (m, 1 H), 7.19-7.03 (s, 6 H), 3.75-3.67 (m, 4 H), 3.62-3.54 (m, 2 H), 2.68-2.60 (m, 5 H), 2.59-2.52 (m, 4 H). LCMS: m/z=436 [M+H+]+.
Reaction SMILES: [O-][CH2:2]C.[Na+].[NH:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:26])[C:15]4[C:20]([S:21](=[O:25])(=[O:24])[C:22]=3[CH:23]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][N:7]=[N:6]1.CI>C(O)C>[CH3:2][N:7]1[N:6]=[N:5][C:9]([C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:26])[C:15]4[C:20]([S:21](=[O:24])(=[O:25])[C:22]=3[CH:23]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8]1
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: Cn1nnc(-c2ccc3c(c2)S(=O)(=O)c2ccccc2C3=O)n1

Procedure:
To a solution of sodium ethoxide in ethanol (20 ml) (prepared from 0.46 g sodium) was added 3-(5-tetrazolyl) thioxanthone-10,10-dioxide (6.24g). Methyl iodide (2.84 g) was added and the mixture boiled under reflux for 2 hrs. During the reflux period a yellow product was deposited. On cooling it was filtered off, washed with water and recrystallised twice from acetic acid to give 3-(2-methyl-5-tetrazolyl)thioxanthone-10,10-dioxide as yellow needles, m.p. 204°-205° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=N)[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.C([NH2:30])CCC>>[NH2:30][CH2:1][CH2:2][CH2:6][CH2:5][NH:4][CH:8]=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Reactant: CCCCN
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=CNCCCCN)cc1

Procedure:
The compound of Example 11 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of n-butylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 269.36; found mol. wt. (M+H) 270.3; 539.1 (Dimer)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:25][CH:24]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 4-trifluoromethoxyphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 25.9, 29.6, 42.6, 60.2, 121.7, 127.1, 127.4, 129.0, 137.9, 139.8, 142.3 and 148.5.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](Br)[CH:20]=2)[C:15]([CH3:24])([CH3:23])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C>[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[C:15]([CH3:24])([CH3:23])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(C(=O)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
n-Butyl lithium (5.0 mL of a 2.5 M solution in hexanes, 12 mmol) was added dropwise to a solution of 6-bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (3.27 g, 10.0 mmol) in diethyl ether (20 mL) at −78° C. The resulting orange slurry was stirred 30 minutes at this temperature, then a solution of N-methoxy-N-methyl-benzamide (2.3 mL, 15.0 mmol) in diethyl ether (10 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred 1 h further, then quenched with saturated aqueous ammonium chloride and the two layers were separated. The aqueous fraction was further extracted with EtOAc (2×20 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (0-30% EtOAc/petrol) to give the title compound (2.4 g, 67%) as a yellow solid. MS: [M+H]+=353.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>C(OCC)C>[CH2:12]([N:14]([CH2:15][CH3:16])[S:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:10])=[O:9])[CH3:13]
Reactant: CCNCC
Reactant: O=S(=O)(Cl)CCCCCCCl
Solvent: CCOCC
Product: CCN(CC)S(=O)(=O)CCCCCCCl
Yield: 92.8 %

Procedure:
6-Chlorohexanesulfonyl chloride (6.57g, 30 mmol) was added dropwise to a solution of diethyl ether (60 ml) and diethylamine (4.83g, 66 mmol) with stirring under ice-cooling. Thereafter, the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was washed twice with water (10 ml) and then with brine (10 ml), and thereafter dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation In vacuo. The crude product was purified by column chromatography on silica gel with ethyl acetate-n-hexane (1:4), to give N,N-diethyl-6-chlorohexanesulfonamide (7.12 g) as a pale yellow oil.