Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[OH:27].O[CH:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[O:27][CH:33]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32]1
Reactant: N#Cc1cc(O)c(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C#N)cc([N+](=O)[O-])c2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
DIAD (0.309 mL, 1.495 mmol) was added to a solution of 4-chloro-3-hydroxy-5-nitrobenzonitrile (Example 425B) (223 mg, 1.122 mmol), (+/−)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (200 mg, 1.068 mmol) and triphenylphosphine resin (3 mmol/g loading, 560 mg, 2.136 mmol) in THF (5 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-20% ethyl acetate/dichloromethane). (+/−)-tert-butyl 3-(2-chloro-5-cyano-3-nitrophenoxy)pyrrolidine-1-carboxylate (272 mg) was obtained as a yellow solid.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[S:36])[CH:30]=[CH:31][C:32]=1[CH3:33].Cl>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[S:36])[CH:30]=[CH:31][C:32]=1[CH3:33]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(N=C=S)cc1Cl
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(NC(=S)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and 3-chloro-4-methylphenyl isothiocyanate (0.26 g, 1.4 mmol) in acetonitrile (30 mL) at 0° C. The mixture was stirred at ambient temperature for 3 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 1-(3-chloro-4-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-thiourea as a white solid (0.52 g, 84% yield); mp 240-242° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 7.11 (97.48%); 1H NMR (DMSO-d6) δ 1.95-2.06 (m, 1H, CHH), 2.29 (s, 3H, CH3), 2.35-2.47 (m, 1H, CHH), 2.55-2.67 (m, 1H, CHH), 2.84-3.00 (m, 1H, CHH), 4.32 (d, 1H, CHH), 4.46 (d, 1H, CHH), 4.86 (d, J=5.1 Hz, 2H, CH2 and CHH), 5.11 (dd, 1H, CH), 7.25 (dd, 1H, Ar), 7.28 (d, 1H, Ar), 7.47 (d, 1H, Ar), 7.54 (s, 1H, Ar), 7.61 (s, 1H, Ar), 7.70 (d, 1H, Ar), 8.37 (t, 1H, NH), 9.73 (s, 1H, NH), 11.00 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.96, 22.49, 31.20, 47.13, 51.58, 122.14, 122.88, 123.48, 127.13, 130.39, 130.97, 131.12, 132.67, 138.29, 142.27, 143.32, 167.92, 170.99, 172.86, 181.00; LCMS: MH=457/459; Anal. Calcd for C22H21ClN4O3S: C, 57.83; H, 4.63; N, 12.26. Found: C, 57.57; H, 4.51; N, 12.21.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].Cl.[CH3:18][C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([CH3:29])[N:28]=1)[C:22]([NH:24][NH2:25])=O>>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:10][C:22]([C:21]3[CH:26]=[C:27]([CH3:29])[N:28]=[C:19]([CH3:18])[CH:20]=3)=[N:24][N:25]=2)=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2]
Reactant: CCc1sc(C(=O)O)c2c1CC(C)(C)CC2
Reactant: Cc1cc(C(=O)NN)cc(C)n1
Agent: Cl
Product: CCc1sc(-c2nnc(-c3cc(C)nc(C)c3)o2)c2c1CC(C)(C)CC2

Procedure:
4-[5-(3-Ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-pyridine is synthesized from 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid and 2,6-dimethyl-isonicotinic acid hydrazide hydrochloride in analogy to Example 9; LC-MS: tR=0.93 min, [M+1]=368.44; 1H NMR (CD3OD): δ 7.66 (s, 2H), 3.09 (t, J=6.7 Hz, 2H), 2.80 (q, J=7.6 Hz, 2H), 2.60 (s, 6H), 2.39 (s, 2H), 1.67 (t, J=6.7 Hz, 2H), 1.29 (t, J=7.6 Hz, 3H), 1.03 (s, 6H).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[O:4]=[C:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CC=CC=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([CH:6]([C:5](=[O:4])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(C(=O)Cc1ccccc1)C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a suspension of magnesium chloride (1.46 g) in tetrahydrofuran (10 ml) was added a solution of ethyl 3-oxo-4-phenylbutanoate (2.0 g) in tetrahydrofuran (10 ml) and the mixture was cooled to 0° C., then pyridine (25 ml) was added. The mixture was stirred at 20° C. for 30 minutes, then a solution of 4-fluorobenzoyl chloride (2.44 g) in tetrahydrofuran (10 ml) was added at 0° C. After stirring at 20° C. for 2 hours, the mixture was partitioned between 0.5N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (2.15 g) as an oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17](C=O)[CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH2:16][C:17](=[N:26][OH:27])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC1=CC=C(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)CC1=NO
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
Intermediate (b) N-BOC-(R)-2-(3-formyl-4-hydroxybenzyl)morpholine (0.192 g, 0.06 mmol) was dissolved in dry acetone (5 mL) with potassium carbonate (0.165 g, 1.19 mmol), under an atmosphere of nitrogen and iodomethane (0.074 mL, 1.19 mmol) added in one portion. The resulting mixture was stirred at room temperature for 18 hrs and then concentrated in vacuo. The residue was dissolved in water (10 mL) and extracted with diethyl ether (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The orange oil was purified by column chromatography (silica; 35% ethyl acetate/isohexane) to yield the desired product as a yellow oil (0.157 g, 78%). The material was used directly in the next step. N-BOC-(R)-2-(3-formyl-4-methoxybenzyl)morpholine (0.157 g, 0.468 mmol) was dissolved in ethanol (5 mL) and added to a solution of hydroxylamine hydrochloride (42 mg, 0.61 mmol) and sodium acetate (88 mg, 1.08 mmol) in ethanol (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 18 hrs and then heated at 80° C. for 72 hrs. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (20 mL×2). Combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to yield the desired intermediate (a), N-BOC-(R)-2-(3-hydroxyimino-4-methoxybenzyl)morpholine as a yellow oil (85 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].CN(C)C=O.[C:27](Cl)(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C1(C)C=CC=CC=1>[CH2:20]([O:21][C:27](=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])/[CH:19]=[C:17](/[CH2:16][CH2:15][CH2:14][C@@H:12]([CH2:11][CH2:10][CH2:9][C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13])\[CH3:18]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: CCCCCCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C

Procedure:
To a solution of 3 g phytol (3,7,11,15-Tetramethyl-2-hexadecen-1-ol), 1,5 g dimethyl formamide in 50 ml toluene is being added dropwise during one half hour a solution consisting of 2 g caprylic acid chloride (excess) in 25 ml toluene at 20° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:5][CH2:4]1.Br[CH2:30][CH3:31].[OH-].[Na+].CN(C)C=O>O>[OH2:2].[CH2:30]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[C:6]1[S:7][CH:3]([O:2][CH3:1])[CH2:4][N:5]=1)[CH3:31].[CH2:30]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[C:6]1[S:7][CH:3]([O:2][CH3:1])[CH2:4][N:5]=1)[CH3:31]
Reactant: CCBr
Reactant: COc1ccc(N2CCN(c3ccc(NC4=NCC(OC)S4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C1=NCC(OC)S1)c1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
A mixture of 15 parts of 4,5-dihydro-5-methoxy-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-thiazolamine, 5.8 parts of bromoethane, 3 parts of sodium hydroxide pellets and 207 parts of N,N-dimethylformamide was stirred for 16 hours at room temperature. The reaction mixture was diluted with water. The precipitated product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane, ethyl acetate, hexane and methanol (49::30:20:1 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 7.3 parts (44.4%) of N-ethyl-4,5-dihydro-5-methoxy-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-thiazolamine hemihydrate; mp. 131.5° C. (int. 6).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.[H-].[Na+].I[CH3:19]>C1COCC1>[CH3:19][O:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a solution of tert-butyl (1R,3S)-3-hydroxycyclohexylcarbamate (1.78 g, 8.27 mmol) in anhydrous THF (8 mL) was added sodium hydride (0.230 g, 9.09 mmol) in portions under nitrogen at 0° C. The mixture was warmed to room temperature and stirred for 30 min. A solution of iodomethane (0.824 mL, 13.23 mmol) in anhydrous THF (4 mL) was added drop wise to the mixture at 0° C. and the resulting mixture was stirred at room temperature for 20 h. The crude mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo, and then purified by silica gel chromatography (0-50% ethyl acetate in hexanes). The product fractions were combined and concentrated to afford tert-butyl (1R,3S)-3-methoxycyclohexylcarbamate (1.0686 g, 4.66 mmol, 56.4% yield) as a white solid; MS (ESI) m/z 230.5 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:9][CH:10]=[C:5]2[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[Li+].[OH-].Cl>C1COCC1.C(OCC)C>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:10]=[C:5]2[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1
Reactant: CCOC(=O)COc1ccc2c(-c3ccccc3)nn(C)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1nc(-c2ccccc2)c2ccc(OCC(=O)O)nc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A mixture of Ethyl 2-(1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)acetate (0.33 g, 1.059 mmol) and aqueous LiOH (0.446 g, 10.599 mmol in 3.0 mL H2O) in THF (3.0 mL) was stirred at rt for 6 h. The reaction mixture was neutralized with diluted HCl and diluted with diethyl ether. The organic layer was extracted with water and brine and dried over anhydrous Na2SO4. Concentration of the organic layer furnished the crude product as a white solid. The crude product was purified by column chromatography (eluent: 75% EtOAc in hexane) to yield the title compound as a white solid (0.291 g, 97%). [1H-NMR (CDCl3, 300 MHz) δ 8.21 (d, 1H), 7.92-7.84 (m, 2H), 7.52-7.35 (m, 3H), 6.77 (d, 1H), 5.05 (s, 2H), 4.02 (s, 3H); HPLC RtA=4.315 min (97%); LCMS RtC=0.389 min; [M+H]+=283.9]
Reaction SMILES: [Li].C[O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH:23]3[CH2:25][CH2:24]3)=[CH:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.O1CCOCC1.Cl>O>[CH:23]1([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:26])=[O:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[CH:15]=2)[CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CC3)c3ccccc32)cc1
Agent: Cl
Agent: [Li]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
Add lithium hydroxidemonohydrate (181 mg, 4.31 mmol) to a solution of 4-(3-cyclopropyl-indole-1-sulfonyl)-benzoic acid methyl ester (505 mg, 1.42 mmol) in 3:1 dioxane:water (6.0 mL). Stir the mixture at RT for 4 h, dilute with water (80 mL) and add 1N HCl until mixture reaches pH 2. Collect the white solid by filtration and dry overnight under vacuum to give the title compound (450 mg, 93%). MS (ES) 341.9 (M+1)+, 340.1 (M−1)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]2[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]#[N:31])[CH:24]=3)[NH:19]2)[CH:15]=[CH:16][CH:17]=1.N1C=CC=CC=1>ClCCl>[C:30]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]([C:14]1[CH:13]=[C:12]([NH:11][S:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)(=[O:9])=[O:8])[CH:17]=[CH:16][CH:15]=1)[CH2:27][C:26]2([CH3:29])[CH3:28])#[N:31]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccnc3)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 44.2 %

Procedure:
Pyridine-3-sulfonyl chloride (144 mg, 0.81 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (77 mg, 0.97 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. Filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=3:1) to afford pyridine-3-sulfonic acid [3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (100 mg, yield: 44.2%). MS (ESI+APCI) M+1=419.1.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]=[CH:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:26])[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1.ClCCl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCC1N=CCN(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCCC1N(CCN(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.7 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-(2-dimethylamino-ethylideneamino)-cyclopentanecarboxylic acid ethyl ester (0.069 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with a 1.0 M solution N,N′-dicyclohexylcarbodiimide in dichloromethane (0.315 mL, 0.315 mmol). The reaction was stirred for 6 h at 25° C., the urea byproduct was filtered off and the crude material was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, 2-{(2-dimethylamino-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (25.4 mg, 0.047 mmol, 15.6%), as a white solid. LC-MS (ESI) calcd for C22H33N5O7S2 543.18, found 544.4 [M+H+].
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:38][CH2:39][CH3:40])[C:26](NC(C4C=CC=CC=4)CO)=[O:27])=[CH:20][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:42].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH:11]1[C:12]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:38][CH2:39][CH3:40])[C:26]([OH:42])=[O:27])=[CH:20][CH:19]=3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: CCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)NC(CO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)O
Temperature: 90 °C
Yield: 57 %

Procedure:
A solution of [2R diastereomer, N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide (0.45 g, 0.84 mmol) obtained in example 21a in mixture of 1M sulphuric acid (17 mL) and dioxane/water (1:1, 39 mL) was heated at 90° C. for 88 h. The pH of the mixture was adjusted to 3.0 by addition of an aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate (2×25 mL) and the organic extract as washed with water (50 mL), brine (25 mL), dried (Na2SO4) and evaporated. The residue was chromatographed over silica gel using a gradient of 50-75% ethyl acetate in pet. ether to afford the title compound (0.2 g, 57%) as a white solid. mp: 77-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][C:12]4([CH2:17][CH2:16]4)[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:6]3[CH2:11][C:12]4([CH2:16][CH2:17]4)[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1Cc2c([nH]c3ccc(Cl)cc23)CC12CC2
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1Cc2c(n(CCc3ccc(C(F)(F)F)nc3)c3ccc(Cl)cc23)CC12CC2

Procedure:
The title compound is prepared from a mixture of 8′-chloro-2′-methyl-1′,2′,4′,5′-tetrahydrospiro[cyclopropane-1,3′-pyrido[4,3-b]indole], 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23]
Reactant: Oc1cccc(Br)c1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(Br)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
Diisopropyl diazene-1,2-dicarboxylate (1.1 eq.) was added dropwise to a 0° C. solution of 3-bromophenol (1.155 g, 6.68 mmol, 1.0 eq.), 2-(dimethylamino)ethanol (1.1 eq.) and triphenylphosphine (1.1 eq.) in THF (20 mL). The mixture was allowed to warm to room temperature over 16 hours, and then the volatiles were removed under reduced pressure. The resulting residue was partitioned between EtOAc (20 mL) and 1N HCl (20 mL), and the aqueous layer was collected and washed with EtOAc. The aqueous layer was neutralized with saturated NaHCO3 (50 mL), extracted with EtOAc, and dried (MgSO4). Purification via silica chromatography (eluting with 4% MeOH/DCM) afforded 2-(3-bromophenoxy)-N,N-dimethylethanamine (1.032 g, 63%) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][NH:17][C:18]2[C:19]([F:32])=[C:20]([CH:28]=[CH:29][C:30]=2[F:31])[O:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:8]=1)#[N:2].C([O-])([O-])=[O:34].[K+].[K+].OO.Cl>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:16][NH:17][C:18]2[C:19]([F:32])=[C:20]([CH:28]=[CH:29][C:30]=2[F:31])[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:8]=1)(=[O:34])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(C#N)cc(-c3cccc(F)c3)c2)c1F
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(CNc2c(F)ccc(OCC(=O)O)c2F)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.5 %

Procedure:
To a mixture of ethyl 2-[3-[[3-cyano-5-(3-fluorophenyl)phenyl]methylamino]-2,4-difluoro-phenoxy]acetate (see example 24) (200 mg, 0.45 mmol, 1 eq) and K2CO3 (310 mg, 2.3 mmol, 5 eq) in DMSO (10 mL) at 40° C. was added H2O2 (30% aqueous solution, 10 mL) dropwise. The mixture was stirred for 20 min then cooled to room temperature. Water was added, and the reaction neutralised by addition of diluted HCl. The solid precipitate that formed was collected by filtration, washed with water and dried to give the title compound as white solid (90 mg, 46%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](N(C(C)C)CC)(C)C.CI>C(#N)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:18])[C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CNc1cccc(SCc2ccccc2)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CI
Product: CN(C#N)c1cccc(SCc2ccccc2)c1
Temperature: 82.5 °C
Yield: 80 %

Procedure:
To a solution of 3-(benzylthio)phenylcyanamide (0.80 g, 3.33 mmol) dissolved in acetonitrile (8 mL) was added diisopropylethylamine (0.65 g, 5.0 mmol), followed by addition of methyl iodide (0.94 g, 6.66 mmol). The reaction mixture was refluxed at 80-85° C. for 3 hours. After removal of solvents the residue was taken by dichloromethane (40 ml) and the organic solution was washed by water (40 ml). After dried over MgSO4 and filtered, dichloromethane solution was then concentrated in vacuo to afford yellow oil as crude product. Purification by column chromatography (SiO2, Hexane/CH2Cl2, 50% to 100%) to afford 3-(benzylthio)phenyl-N-methylcyanamide as a pale yellow oil (0.67, 80% yield): CH2Cl2 Rf=0.45; 1H-NMR (CDCl3) δ (ppm) 7.3-6.8 (m, 9H, Ar—H), 4.06 (s, S—CH2, 2H), 3.57 (s, 3H, N—CH3).