Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].COCCOC.[CH3:24][O:25][C:26](=[O:46])/[CH:27]=[C:28](\[CH3:45])/[CH2:29][CH2:30][S:31]([C:34]1[N:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:37]=[N:36][N:35]=1)(=O)=O.C[C@H]([C@@H](O[Si](CC)(CC)CC)CC)C=O>C1COCC1>[CH3:24][O:25][C:26](=[O:46])/[CH:27]=[C:28](\[CH3:45])/[CH2:29][CH2:30][S:31][C:34]1[N:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:37]=[N:36][N:35]=1
Reactant: COC(=O)/C=C(\C)CCS(=O)(=O)c1nnnn1-c1ccccc1
Agent: CC[C@H](O[Si](CC)(CC)CC)[C@@H](C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: C1CCOC1
Product: COC(=O)/C=C(\C)CCSc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
0.5M Potassium bis(trimethylsilyl)amide toluene solution (8.48 ml, 4.24 mmol) was added dropwise to a DME (40 ml) solution of methyl-(2E)-3-methyl-5-[(1-phenyl-1-H-tetrazol-5-yl)sulfonyl]pent-2-enoate (1.19 g, 3.53 mmol) at −60° C. and the reaction solution was stirred at the same temperature for 30 minutes. Subsequently a THF (5 ml) solution of (2R,3S)-2-methyl-3-[(triethylsilyl)oxy]pentanal (1.63 g, 7.06 mmol) was added dropwise at −78° C. and the reaction solution was stirred for two hours. After the reaction solution was warmed to room temperature, distilled water was added. The reaction solution was diluted with ethyl acetate and washed with brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:diethyl ether=50:1) to obtain the title compound (1.17 g) as a colorless oil. The title compound was determined to be a mixture of E:Z 17:1 by 1H-NMR.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][CH2:30][C@H:31]([OH:44])[C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=3)[CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[O:11])=[O:4].Cl>CO.[OH-].[Na+]>[OH:44][C@H:31]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=1)[CH2:30][NH:29][CH2:28][CH:25]1[CH2:24][CH2:23][N:22]([S:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10]([N:6]3[CH2:7][CH2:8][CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[O:11])=[CH:14][CH:15]=2)(=[O:20])=[O:21])[CH2:27][CH2:26]1
Reactant: COC(=O)C1CCCN1C(=O)Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(S(=O)(=O)c3ccc(NC(=O)N4CCC[C@H]4C(=O)O)cc3)CC2)ccc1O
Yield: 36.5 %

Procedure:
A solution of 1-(2S)-1-({4-[(4-{[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-amino]-phenyl}ethyl)amino]methyl}piperidin-1-yl)sulfonyl]-anilinocarbonyl)-pyrrolidine-2-carboxylic acid methyl ester (0.098 g, 0.15 mmol) in methanol (2 mL) and 1N sodium hydroxide (0.55 mL) was stirred at ambient temperature overnight. When the reaction was complete, 1N HCl (0.55 mL) was added. The methanol and water was evaporated. Additional methanol was added, the reaction was filtered through a 0.5 micron filter, and evaporated in vacuo to give the acid (0.035 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.[H-].[Na+].CS(C)=O.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>O1CCCC1>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([O:1][C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2ncccn2)cc(-c2ccc(C)cc2)c1

Procedure:
To a stirred solution of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (300 mg, 1.24 mmol) in tetrahydrofuran (20 mL) at 0° C. was added sodium hydride (60% in mineral oil, 55 mg, 1.37 mmol) over a period of 10 minutes. The reaction mixture was concentrated to afford a green solid. A microwave vial was charged with the resulting green solid, dimethyl sulfoxide (8 mL), and 2-chloropyrimidine (118 mg, 0.98 mmol). The mixture was subjected to microwave irradiation at 100° C. for 4 minutes. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-])=O.C(N(CC)CC)C>CN(C=O)C>[NH2:14][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1

Procedure:
1-Boc-piperazine and 4-nitrobenzenesulfonyl chloride were allowed to undergo the reaction in DMF in the presence of triethylamine, and then the nitro group was reduced in the sama manner as the catalytic hydrogenation shown in Reference Example 3 to obtain tert-butyl 4-[(4-aminophenyl)sulfonyl]piperazine-1-carboxylate. FN: 340.
Reaction SMILES: [OH:1][C:2]1([C:13]([F:16])([F:15])[F:14])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20](Cl)[N:19]=1.[H-].[Na+]>CN(C=O)C>[Cl:17][C:18]1[N:19]=[C:20]([O:1][C:2]2([C:13]([F:16])([F:14])[F:15])[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[CH2:5]2)[CH:21]=[N:22][CH:23]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(O)(C(F)(F)F)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cncc(Cl)n2)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of tert-butyl 3-hydroxy-3-(trifluoromethyl)azetidine-1-carboxylate (0.37 g, 1.5 mmol) and 2,6-dichloropyrazine (0.23 g, 1.5 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (60% mineral oil dispersion; 0.073 g, 1.8 mmol). The reaction mixture was allowed to warm to room temperature. After 15 minutes, the reaction mixture was partitioned between EtOAc (50 mL) and brine (50 mL). The organic layer was washed with additional brine (50 mL). The first aqueous layer was back-extracted with EtOAc (50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 3-[(6-chloropyrazine-2-yl)oxy]-3-(trifluoromethyl)azetidine-1-carboxylate. LRMS calculated for C13H15ClF3N3O3[M+H]+, 354.1; found 298.0 [M-tButyl+H]+. 1H NMR (600 MHz, DMSO-D6) 8.50 (s, 1H); 8.46 (s, 1H); 4.53 (br s, 2H); 4.20 (br d, 2H); 1.37 (s, 9H).
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH3:21])[C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([F:18])[C:12]=1F)(C)C.[OH:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=1)[C:28]([NH:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:18][C:13]1[C:12]2[O:6][CH2:7][CH2:8][N:9]([CH3:21])[C:10](=[O:20])[C:11]=2[CH:16]=[CH:15][C:14]=1[O:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=1)[C:28]([NH:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1)=[O:29]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(F)c1F
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2F)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 140 °C
Yield: 75.1 %

Procedure:
A suspension of N-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2,3,4-trifluoro-N-methylbenzamide (300 mg, 0.86 mmol), 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (278 mg, 0.91 mmol) and potassium carbonate (237 mg, 1.73 mmol) in DMA (20 mL) was heated to 140° C. for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (50 mL) and dried (MgSO4), filtered and evaporated to give an orange oil. This was purified via column chromatography on silica, eluting with 50-100% ethyl acetate in isohexane, to give the desired product as a colourless oil (322 mg). 1H NMR δ (CDCl3): 1.25 (d, 3H), 2.77 (s, 3H), 3.33 (s, 3H), 3.44 (dd, 1H), 3.50 (dd, 1H), 3.71 (s, 3H), 3.74 (t, 2H), 4.25 (t, 2H), 4.49-4.56 (m, 1H), 6.71 (d, 1H), 6.73 (t, 1H), 6.75 (dd, 1H), 7.04 (t, 1H), 7.20-7.20 (m, 1H), 7.22 (d, 1H), 7.47 (dd, 1H), 8.68 (s, 1H); m/z 499 (M+H)+
Reaction SMILES: [Na+].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[CH:11][C:12]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O-:26])=O)=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[C:3]1=[O:27].Cl.[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH2:33].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH:33][C:24](=[O:26])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:12]([CH:11]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][C:3]2=[O:27])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2
Reactant: COC(=O)[C@H](C)N
Reactant: O=C([O-])COc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)COc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 2-[5-(2-oxindol-3-ylidenemethyl)quinol-8-yloxy] acetic acid sodium salt (120 mg, 0.33 mmol), L-alanine methyl ester hydrochloride (100 mg, 0.72 mmol) and triethylamine (0.07 ml) in DMF (10 ml) was added at room temperature N,N'-dicyclohexylcarbodiimide (100 mg, 0.48 mmol) and the stirring was continued overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The oily residue was taken up in dichloromethane, the organic phase washed 3 times with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using as eluant ethyl acetate/methanol (95:5) to give pure title compound in 70% yield (100 mg). C24H21N3O5 calcd: C66.81 H4.91 N9.74; found: C66.55 H4.56 N9.65; MS m/z 431.
Reaction SMILES: [OH:1][C:2]([CH2:10][O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[CH2:13]([Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:11][CH2:10][C:2]([O:1][Si:25]([CH3:28])([CH3:27])[CH3:26])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5])[CH3:14]
Reactant: C#CCC(O)(CCCC)CO[Si](CC)(CC)CC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(CCCC)(CO[Si](CC)(CC)CC)O[Si](C)(C)C
Temperature: 0 °C

Procedure:
To a solution of the 4-hydroxy-4-triethylsilyloxymethyl-1-octyne (prepared in Example 3) and 23.9 g. of imidazole in 50 ml. of dimethylformamide at 0° C., is added with stirring, 21.2 g. of chlorotrimethylsilane. The mixture is stirred for 75 minutes, then poured into ice water and extracted with hexane. The hexane layer is washed with water, then saturated sodium bicarbonate solution, dried over magnesium sulfate and the hexane is removed. The residue is distilled. The fraction boiling at 133°-136° C. (1.2 mm.) is collected giving the desired product as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][CH2:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[CH3:15].CCN(C(C)C)C(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][CH2:7][CH:8]2[CH2:11][N:10]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:9]2)=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(OCC2CNC2)cc(C)c1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCC2CN(S(C)(=O)=O)C2)cc(C)c1Br
Temperature: 0 °C
Yield: 64 %

Procedure:
3-(4-Bromo-3,5-dimethyl-phenoxymethyl)-azetidine (400 mg, 1.48 mmol) and DIPEA (0.48 g, 3.7 mmol) are dissolved in 20 mL of dichloromethane and stirred at 0° C. Methanesulfonylchloride (0.12 mL, 1.48 mmol) is added and the reaction mixture is stirred at 0° C. for 2 h. The reaction mixture is washed with water, the organich phase is separated, dried over sodium sulfate and concentrated under vacuum. The crude product is purified by flash chromatography 0-50% ethyl acetate in cyclohexane) to give the title compound (Yield: 330 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([O:24][CH3:25])=[C:21]([O:26][CH3:27])[CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Product: COc1cc2[nH]c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)c2cc1OC
Yield: 73.2 %

Procedure:
2.36 g (10.8 mmol) of 4-chlorobenzenesulfonylisocyanate and 1.94 g (9.84 mmol) of 2-amino-4,5-dimethoxybenzoic acid were treated in the same way as in Example 1 to obtain 2.86 g of the above-identified compound (yield 73.3%). Properties: colorless crystal, Melting point: >250° C., PMR (δppm, DMSO-d6): 3.79 (3H,s), 3.84 (3H,s), 6.62 (1H,s), 7.22 (1H,s), 7.74 (2H,d), 8.15 (2H,d), 11.36 (1H,br).
Reaction SMILES: [F:1][CH:2]1[C:6](=O)[N:5]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4][C@@:3]1([CH3:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].B>O1CCCC1>[F:1][CH:2]1[CH2:6][N:5]([C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:4][C@@:3]1([CH3:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)C(F)C1=O
Agent: B
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC(F)[C@](C)(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.9 %

Procedure:
To a solution of tert-butyl(3S)-4-fluoro-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]-pyrrolidine-3-carboxylate (isomer B) (1.64 g, 5.10 mmol) in tetrahydrofuran (30 mL), 1.01M solution of borane in tetrahydrofuran (16.7 mL, 16.9 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 15 hours. After concentrating the reaction mixture under reduced pressure, water (5 mL), ethanol (45 mL), and triethylamine (2 mL) were added in an ice bath, and the mixture was heated under reflux for 1.5 hours. After concentrating the reaction mixture under reduced pressure, water (100 mL) was added, and the mixture was extracted with chloroform (200 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (elusion by hexane ethyl acetate, 12:1→2:1) to obtain 1.55 g (99%) of the title compound (isomer B) as a colorless oily substance.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH:6]1([C:12]2[NH:13][S:14](=[O:23])(=[O:22])[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>OS(O)(=O)=O>[CH:6]1([C:12]2[NH:13][S:14](=[O:22])(=[O:23])[C:15]3[CH:21]=[C:20]([N+:1]([O-:4])=[O:2])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=S1(=O)NC(C2CCCCC2)=Nc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Temperature: 25 °C

Procedure:
To a stirred solution of KNO3 (1.2 g; 11.5 mmol) and conc. H2SO4 (8 ml) at 5° C. was added a solution of 3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide in conc. H2SO4 (8 ml). The reaction mixture was allowed to warm up to r.t. and left with stirring over night. The product was precipitated by slow addition of ice and isolated by filtration. The crude product (4.3 g) was used without further purification.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)([OH:3])=O.[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC>>[N:15]1([C:1](=[O:3])[CH2:4][C:5]2[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCCNCC1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)Cc1cccc(CC(=O)N2CCCCCC2)c1
Yield: 49.9 %

Procedure:
Prepared from (3-carboxymethyl-phenyl)-acetic acid (990 mg), azepane (500 g), 1-hydroxybenzotriazole (690 mg), Hunigs base (0.89 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980 mg), using the method of Example 44 (step a), to give 700 mg of the sub-titled compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][NH:17][C:18]3[C:19]([CH3:26])=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=3[CH3:24])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][NH:17][C:18]3[C:19]([CH3:26])=[C:20]([CH:21]=[CH:22][C:23]=3[CH3:24])[O:25][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)CBr
Reactant: COc1cc(CNc2c(C)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: O
Product: COc1cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of 3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]-2,4-dimethyl-phenol (700 mg, 2.0 mmol, 1.0 eq) in 2-butanone (4 mL) was added Cs2CO3 (973 mg, 3 mmol, 1.5 eq). The reaction mixture was stirred for 30 min then isopropyl bromoacetate (432 mg, 2.4 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for a further 1 h then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 100:0 to 30:1) to give the title compound as a colorless oil (570 mg, 63%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([OH:11])[CH2:3]1.[H-].[Na+].F[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C@@H:24]3[CH2:28][CH2:27][CH2:26][N:25]3[CH3:29])=[N:22][N:23]=2)[CH:20]=1>CN(C=O)C.O>[CH3:29][N:25]1[CH2:26][CH2:27][CH2:28][C@H:24]1[C:21]1[N:19]2[CH:20]=[C:15]([O:11][C@@H:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]([NH2:1])[CH2:3]3)[CH:16]=[CH:17][C:18]2=[N:23][N:22]=1
Reactant: N[C@H]1C[C@H](O)c2ccccc21
Reactant: CN1CCC[C@H]1c1nnc2ccc(F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@H]3C[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
(1S,3S)-3-Amino-indan-1-ol (110 mg, 0.74 mmol) was added to a suspension of NaH (60% in mineral oil, 87 mg, 2.17 mmol) in anhydrous DMF (5 mL) at RT and stirred for 20 min. Intermediate 5b (160 mg, 0.72 mmol) was then added in one portion and the mixture heated at 60° C. for 3 h. After cooling the mixture was diluted with water (20 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as give a foam (132 mg, 52%). LCMS (Method 1): Rt 0.34 min, m/z 350 [MH+]. 1H NMR (300 MHz, CDCl3): 1.95-2.16 (6H, m), 2.24 (3H, s), 2.26-2.45 (2H, m), 2.77 (1H, ddd, J 14.1, 7.0, 2.0), 3.23-3.30 (1H, m), 4.02-4.09 (1H, m), 4.71 (1H, t, J 6.8), 5.68 (1H, dd, J 6.2, 1.9), 7.04 (1H, dd, J 9.9, 2.2), 7.29-7.50 (4H, m), 7.64 (1H, dd, J 9.9, 0.9), 8.35 (1H, d, J 2.2).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][N:12]3[C:16]([C:17]4[S:18][C:19]5[N:20]=[CH:21][N:22]=[C:23]([NH2:26])[C:24]=5[N:25]=4)=[C:15]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:14]=[CH:13]3)[CH2:7][CH2:6]2)[O:4]CC1.O.C(O)(C(F)(F)F)=O>CC#N>[NH2:26][C:23]1[C:24]2[N:25]=[C:17]([C:16]3[N:12]([CH2:11][CH:8]4[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]4)[CH:13]=[N:14][C:15]=3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:18][C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCC4(CC3)OCCO4)nc12
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCC(=O)CC3)nc12
Reaction time: 48 h

Procedure:
2-[1-(1,4-Dioxaspiro[4,5]dec-8-ylmethyl)-4-phenyl-1H-imidazol-5-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 178) (634 mg) was dissolved in MeCN (10 mL) and water (10 mL) and TFA (0.5 mL) was added. After 48 hours at ambient temperature, the title compound was obtained by preparative RPHPLC (eluting with a gradient of water and MeCN containing 0.1% TFA) as a colourless solid (570 mg, 99%);
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][NH:29][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: NC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(Nc1ncc(CNC2CCCC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 37.1 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg, 0.30 mmol), cyclopentylamine (45 μL, 0.45 mmol) and sodium triacetoxyborohydride (102 mg, 0.48 mmol) to afford 45 mg (37%) of the desired product after purification.