Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[C:21]2[C:16](=[N:17][C:18]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[N:20]=2)[N:15]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]1[C:21]2[C:16](=[N:17][C:18]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[N:20]=2)[N:15]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:14][CH2:13]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CCC3O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CCC3=O)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of oxalyl chloride (0.085 ml, 0.973 mmol) in DCM (20 ml) at −78° C. under nitrogen was added a dropwise solution of DMSO (0.168 ml, 2.373 mmol) in DCM (10 ml). After stirring at −78° C. for two hours, a solution of tert-butyl 8-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 1) (200 mg, 0.463 mmol) in DCM (5 ml) was added dropwise and the mixture was left to stir for 15 minutes at −78° C. under an atmosphere of nitrogen. Triethylamine (0.331 ml, 2.373 mmol) was added and after 5 minutes the reaction mixture allowed to warm to 18° C. under an atmosphere of nitrogen overnight. The reaction mixture was diluted with DCM (30 ml) and was sequentially washed with 2M NaOH (30 ml), water (30 ml) and brine (30 ml). The organic layer was separated and dried using a hydrophobic frit and the solvent evaporated to afford the titled compound as a yellow solid;
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[O-:24][C:25]#[N:26].[K+]>O>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][C:25]([NH2:26])=[O:24])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: N#C[O-]
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 60 °C
Yield: 79.8 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.5 gms, 1.41 mmole) and potassium cyanate (0.137 g, 1.69 mmol) added to 30 mL stirring water, and the mixture was heated to 60° C. for five minutes. The reaction mixture was then cooled to room temperature, and the resulting white precipitate was collected by filtration, washed with cold water, and dried under vacuum to give 0.408 g of (R)-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea, M+H=363.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[O:28][CH2:29][C:30]1[C:34]([CH2:35][OH:36])=[C:33]([CH:37]([CH3:39])[CH3:38])[O:32][N:31]=1.O[C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:56]=[C:55]3[C:50]([CH:51]=[C:52]([C:57]([O:59][CH3:60])=[O:58])[N:53]=[CH:54]3)=[CH:49][CH:48]=2)=[CH:43][CH:42]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[O:28][CH2:29][C:30]1[C:34]([CH2:35][O:36][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:56]=[C:55]4[C:50]([CH:51]=[C:52]([C:57]([O:59][CH3:60])=[O:58])[N:53]=[CH:54]4)=[CH:49][CH:48]=3)=[CH:45][CH:46]=2)=[C:33]([CH:37]([CH3:39])[CH3:38])[O:32][N:31]=1
Reactant: COC(=O)c1cc2ccc(-c3ccc(O)cc3)cc2cn1
Reactant: Cc1cccc(C)c1OCc1noc(C(C)C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(-c3ccc(OCc4c(COc5c(C)cccc5C)noc4C(C)C)cc3)cc2cn1
Temperature: 90 °C
Yield: 36.5 %

Procedure:
To a solution of triphenylphosphine (160 mg, 0.611 mmol), [3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methanol (153 mg, 0.556 mmol) and methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate (155 mg, 0.556 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.110 mL, 0.611 mmol) dropwise. The solution was heated in a microwave reactor at 90° C. for 10 minutes and then purified by chromatography (silica gel, 0-25% acetone in hexanes gradient elution) to afford methyl 7-[4-({[3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate (109 mg, 37%). 1H-NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 8.29-8.20 (m, 2H), 7.86 (d, J=9 Hz, 2H), 7.19 (d, J=9 Hz, 2H), 7.00-6.90 (m, 3H), 5.09 (s, 2H), 4.90 (s, 2H), 3.91 (s, 3H), 3.41 (septet, J=7 Hz, 1H), 2.14 (s, 6H), 1.28 (d, J=7 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[C@H:24]([C:25]([O:27]C)=[O:26])[CH2:23][C:18]2([S:22][CH2:21][CH2:20][S:19]2)[CH2:17]1)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:18]2([S:19][CH2:20][CH2:21][S:22]2)[CH2:17]1)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)[C@H](C)NC(=O)OCc1ccccc1)SCCS2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Temperature: 25 °C

Procedure:
Dissolve 1.05 g of 7-[N-benzyloxycarbonyl(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, methyl ester in 100 ml of methanol. Add 10 ml of 2.5 N sodium hydroxide and stir the mixture at room temperature for sixteen hours. Concentrate the mixture under nitrogen, dissolve the oil in 0.1 N sodium hydroxide and dilute with ice water. Adjust to pH2 with concentrated hydrochloric acid, then extract with ethyl acetate. Dry the organic phase over magnesium sulfate and concentrate it. Place the residue on a column of silica gel (100 g, 60-200 mesh) and elute with chloroform:glacial acetic acid 19:1 to obtain 7-[N-benzyloxycarbonyl-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, [α]D26 =-15.8° (ethanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15](=O)[NH2:16])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C([O:25][C:26]([C:28]2[N:29]=[N:30][C:31]([CH2:47][CH2:48][CH2:49][CH3:50])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[CH:36][CH:35]=3)[CH:33]=2)=O)=C(F)C(F)=C(F)C=1F>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:26]([C:28]2[N:29]=[N:30][C:31]([CH2:47][CH2:48][CH2:49][CH3:50])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]4)=[CH:36][CH:35]=3)[CH:33]=2)=[O:25])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(N)=O)CC1
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nnc(C(=O)NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-carbamoyl-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (1.01 mmol, 0.25 g) in THF (4.0 mL), was added BH3:THF (2 mL, 1M solution in THF) and stirred for 12 h. All volatiles were removed under reduced pressure. The residue was taken in DCM (2 mL) and 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (Example 93, 0.29 mmol, 0.15 g) was added followed by TEA (0.5 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with NaOH (0.5 M) solution (2×5 mL) water (2×5 mL), brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl acetate:hexanes (3:7) to provide 4-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([O:21]C)=[O:20])=[N:4][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:12][CH:13]=2)=[CH:6][N:7]=1.[OH-].[Na+].Cl>CO.O>[NH2:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[N:4][C:5]([C:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CCS(=O)(=O)N1CC=C(c2cnc(N)c(C(=O)OC)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(C(=O)O)n2)CC1
Temperature: 60 °C
Yield: 65 %

Procedure:
A solution of methyl 3-amino-6-(1-ethylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylate (5.5 g, 16.85 mmol) in MeOH (30 mL) was treated with a solution of NaOH (8.425 mL of 2 M, 16.85 mmol) in H2O (30 mL). The resulting mixture was heated to 60° C. for 2 hours. After this time the solution was allowed to cool, neutralised with HCl and the resultant precipitate filtered (3.6 g, 65% Yield). 1H NMR (400.0 MHz, DMSO) d 1.20 (3H, t), 2.65 (2H, br s), 3.11 (2H, q), 3.44 (2H, m), 3.94 (2H, m), 6.60 (1H, m), 7.51 (2H, br s), 7.95 (1H, s), 8.52 (1H, s) ppm; MS (ES+) 312.97
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH2:10])[CH:3]=1.C(N(CC)CC)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[C:4]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH2:10])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(c1ccc(C)cc1)c1cc(Br)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(c1ccc(C)cc1)c1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 23.7 h

Procedure:
To a solution of 82 mg (0.3 mmol) of 4-bromo-2-[(1-p-tolyl)vinyl]phenol (Compound R) in 3 mL of dichloromethane (under a blanket of argon) was added 0.05 mL (36 mg, 0.34 mmol) of triethylamine followed by 0.3 mL (0.3 mmol) of tert-butyldimethylsilylchloride (1M in dichloromethane). The resultant yellow solution was stirred at ambient temperature overnight (23.7 hours), concentrated in vacuo and purified by flash chromatography (silica, 100% hexane) to give the title compound as a clear, colorless oil.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][CH:10]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:28])[C:9]1=[O:41])=[O:6])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:11][CH:10]([NH:26][C:27](=[O:28])[NH:29][C:30]2[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=2)[C:36]([OH:38])=[O:37])[C:9]1=[O:41])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C3CCCCC3)c3ccc(C)cc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C1CCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
1-(1-tert-Butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea (370 mg) was suspended in methanol (5 ml), aqueous lithium hydroxide monohydrate (142 mg) solution (5 ml) was added to the suspension, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was filtrated. The filtrate was acidified with 1N hydrochloric acid, and methanol was evaporated. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was recrystallized from isopropyl alcohol, to thereby obtain 300 mg of the title compound (Yield: 83%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:29][C:28]([CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)=[N:27][N:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:29][C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][N:26]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N2C[C@@H](CC[C@H]2c2nnc(C3CCNCC3)o2)N1OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 171.8 %

Procedure:
CF3COOH (5 mL) was slowly added to a solution of tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (719 mg, 1.5 mmol) in DCM (20 mL) at 0° C. The mixture was stirred at 0° C. for 3 hrs then, the solvent was concentrated in vacuum to afford (2S,5R)-6-(benzyloxy)-2-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (988 mg) as a brown oil, which was used directly in the next step. ESI-MS (EI+, m/z): 384.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:6]12[CH2:13][CH2:12][C:9]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)(Cl)=O.[C:27]([C:29]1[C:34]([C:35]#[N:36])=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:32]=[CH:31][C:30]=1O)#[N:28].Cl>N1C=CC=CC=1>[CH2:1]([C:6]12[CH2:7][CH2:8][C:9]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][C:30]4[CH:31]=[CH:32][C:33]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:34]([C:35]#[N:36])[C:29]=4[C:27]#[N:28])=[O:19])=[CH:16][CH:15]=3)([CH2:10][CH2:11]1)[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC12CCC(c3ccc(C(=O)O)cc3)(CC1)CC2
Reactant: CCCCCc1ccc(O)c(C#N)c1C#N
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCc1ccc(OC(=O)c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)c(C#N)c1C#N
Temperature: 80 °C

Procedure:
36.5 mmoles of 4-(4-pentyl-1-bicyclo(2,2,2)-octyl)-benzoic acid were refluxed with 50 ml of thionyl chloride for 1 hour. The excess thionyl chloride was distilled off. The resulting acid chloride was added dropwise to a solution of 36.5 mmoles of 2,3-dicyano-4-pentylphenol in 100 ml of pyridine. The reaction mixture was stirred at 80° C. until the reaction had ended and was then poured onto dilute hydrochloric acid. The product was extracted with methylene chloride. For purification, the product was recrystallized. It displays an enantiotropic nematic phase (K 130.9 N (137.9) I) and has a negative DCA.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([O:16]C)=[O:15])[S:7][N:6]=1)[CH3:4]>O.CO>[CH2:3]([C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([OH:16])=[O:15])[S:7][N:6]=1)[CH3:4]
Reactant: CCc1nsc(C(=O)OC)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nsc(C(=O)O)c1C(=O)OC
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of 14.9 g of NaOH in 120 ml of water and 150 ml of methanol is added dropwise to 85.5 g of dimethyl 3-ethylisothiazole-4,5-dicarboxylate in 300 ml of methanol, while cooling with ice. After 2 hours, the mixture is evaporated down, 1.5 l of water are added to the residue and the mixture is stirred, and extracted with ether. The aqueous phase is acidified with concentrated hydrochloric acid and extracted by shaking with dichloromethane. The organic phases are evaporated down to give 76.4 g of 3-ethyl-4-methoxycarbonylisothiazole-5-carboxylic acid of melting point 43°-45° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH3:22])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:31][C:32](ON1C(=O)CCC1=O)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[CH2:24]([O:31][C:32]([N:10]1[CH2:11][C@H:12]([CH3:22])[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:23])[CH2:9]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a solution of tert-butyl-((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (3.2 g, 9.4 mmol) (40% purity) in DCM (25 mL), N-(benzyloxycarbonyloxy)succinimide (2.6 g, 10 mmol) was added, followed by triethylamine (1.4 mL, 10 mmol). The mixture was stirred for 16 h at room temperature. The reaction mixture was then diluted with EtOAc, washed with water and brine and dried over Na2SO4. The solvent was evaporated under reduced pressure and the resulting crude product was purified by silica gel chromatography eluting with 25% EtOAc in hexanes to give the sub-title compound as a white solid (1.71 g, 38%). LCMS calc. for C25H42N2O5SiNa (M+Na)+ m/z=501.3. found 501.0.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][N:7]([OH:9])[CH:8]=1.Cl[CH2:11][S:12][C:13]#[N:14].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[N:6][N:7]([O:9][CH2:11][S:12][C:13]#[N:14])[CH:8]=1
Reactant: N#CSCCl
Reactant: On1cc(Cl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CSCOn1cc(Cl)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.6 %

Procedure:
50 ml of a 5% strength aqueous sodium hydroxide solution were added to 5 g (42 mMol) of 4-chloro-1-hydroxypyrazole, 13.5 g (126 mMol) of chloromethyl thiocyanate and 50 ml of methylene chloride. After the addition of 1 g (4 mMol) of tetra-n-butylammonium hydroxide, the mixture was stirred at room temperature for 24 hours. Thereafter, the organic phase was separated off, dried and evaporated down. Distillation of the residue under reduced pressure (airbath at 140° C./3 mbar) gave 5.7 g (71% of theory) of 4-chloro-1-[(thiocyanato)-methoxy]-pyrazole (compound No. 1), which was recrystallized from ether/petroleum ether (mp. 60° C.).
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:19](=[O:39])[C:20]5[CH:25]=[CH:24][C:23]([C:26]6[C:27]([CH3:38])=[N:28][C:29]([N:32]7[CH2:36][CH2:35][CH2:34][C:33]7=[O:37])=[CH:30][CH:31]=6)=[CH:22][CH:21]=5)[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.ClC(OC(Cl)C)=O>ClCCCl>[CH3:38][C:27]1[C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:19]([N:15]3[C:16]4[CH:17]=[C:18]5[C:5]6([CH2:8][O:9][C:10]5=[CH:11][C:12]=4[CH2:13][CH2:14]3)[CH2:6][CH2:7][NH:2][CH2:3][CH2:4]6)=[O:39])=[CH:25][CH:24]=2)=[CH:31][CH:30]=[C:29]([N:32]2[CH2:36][CH2:35][CH2:34][C:33]2=[O:37])[N:28]=1
Reactant: Cc1nc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cc1nc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCNCC2)CO4)cc1

Procedure:
1'-Methyl-5-[4-(2-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]benzoyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E5, 0.30 g, 0.59 mmol) was stirred under argon in 1,2-dichloroethane (20 ml) with dilsopropylethylamine (0.15 ml, 0.89 mmol) and 1-chloroethyl chloroformate (0.16 ml, 1.5 mmol) for 16 h. The mixture was concentrated in vacuo, and the residue was heated at reflux in methanol (100 ml) for 1.5 h. The solution was evaporated to dryness, and this residue was dissolved in dichloromethane, washed with 10% Na2CO3, dried (Na2SO4) and evaporated to dryness. The material was purified by conversion to the N-t-butoxycarbonyl derivative (di-t-butyldicarbonate, CH2Cl2, 1h), chromatography, and deprotection with trifluoroacetic acid to afford the title compound. The hydrochloride salt was formed by dissolution in dichloromethane, treatment with 1 M HCl in Et2O, and trituration in acetone. This gave 0. 123 g, 39% of a white powder.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:5]=[C:4]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)[CH:3]=1.[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34]>>[F:1][C:2]1[C:10]2[O:9][CH:8]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][N:18]=4)[CH2:15][CH2:16]3)[CH2:7][C:6]=2[CH:5]=[C:4]([C:26]2[CH2:27][CH2:28][N:29]([S:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:30][CH:31]=2)[CH:3]=1
Reactant: CCCc1cnc(N2CCC(C3Cc4cc(C5=CCNCC5)cc(F)c4O3)CC2)nc1
Reactant: CCCS(=O)(=O)Cl
Product: CCCc1cnc(N2CCC(C3Cc4cc(C5=CCN(S(=O)(=O)CCC)CC5)cc(F)c4O3)CC2)nc1

Procedure:
Example 5 was prepared from Compound 3H and propane-1-sulfonyl chloride in a similar manner to the procedure described in Example 1. 1H NMR (500 MHz, CDCl3) δ ppm 8.15 (s, 2 H), 6.95 (s, 1 H), 6.92 (d, J=12.1 Hz, 1 H), 5.94 (ddd, J=3.4, 1.9, 1.8 Hz, 1 H), 4.76-4.87 (m, 2 H), 4.63-4.73 (m, 1 H), 3.97 (q, J=2.8 Hz, 2 H), 3.53 (t, J=5.6 Hz, 2 H), 3.24 (dd, J=15.7, 9.1 Hz, 1 H), 3.04 (dd, J=15.7, 8.3 Hz, 1 H), 2.91-2.98 (m, 2 H), 2.78-2.89 (m, J=12.9, 12.9, 6.1, 2.8 Hz, 2 H), 2.52-2.59 (m, 2 H), 2.39 (t, J=7.4 Hz, 2 H), 2.05 (d, J=13.2 Hz, 1 H), 1.97 (dddd, J=11.4, 7.9, 7.7, 3.6 Hz, 1 H), 1.82-1.91 (m, 2 H), 1.75 (d, J=12.9 Hz, 1 H), 1.57 (sxt, J=7.4 Hz, 2 H), 1.39 (qd, J=12.4, 4.3 Hz, 2 H), 1.07 (t, J=7.4 Hz, 3 H), 0.93 (t, J=7.4 Hz, 3 H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C=O)C.[CH:14]1([C:17]2[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[C:20]([OH:27])=[CH:19][C:18]=2[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[CH2:16][CH2:15]1>O>[Cl:1][C:19]1[C:20]([OH:27])=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=[C:17]([CH:14]2[CH2:16][CH2:15]2)[C:18]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)cc1O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)c(Cl)c1O
Reaction time: 3 h
Yield: 91 %

Procedure:
N-Chlorosuccinimide (1.65 g) was added at room temperature to a DMF (40 mL) solution of methyl 2-cyclopropyl-2′,4′-difluoro-5-hydroxybiphenyl-4-carboxylate (3.13 g), and the mixture was stirred at the same temperature as above for 3 hours in a nitrogen atmosphere. Then, N-chlorosuccinimide (0.549 g) was further added thereto, and the mixture was stirred at the same temperature as above for 16 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was stirred at 0° C. for 1 hour. The deposited crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (3.17 g).