Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:55]([O:57][CH3:58])=[O:56])[CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH3:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](Cl)=[O:65])=[CH:62][CH:61]=1>>[CH3:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C:51]5([C:55]([O:57][CH3:58])=[O:56])[CH2:52][CH2:53][CH2:54]5)[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:65])=[CH:62][CH:61]=1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(C)cc5)cc4)cc3C2=O)CCC1
Yield: 96 %

Procedure:
The compound of example 581 was prepared analogous to compound of example 97 by reaction of compound of example 574 with 4-methyl benzoyl chloride.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[N:14]([CH2:28][C:29]1[CH:46]=[CH:45][C:32]2[N:33]([CH2:43][CH3:44])[C:34](=[O:42])[C:35]([CH3:41])([CH3:40])[C:36](=[O:39])[N:37]([CH3:38])[C:31]=2[CH:30]=1)[CH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]2[CH3:26])=[CH:18][CH:17]=1)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:43]([N:33]1[C:34](=[O:42])[C:35]([CH3:40])([CH3:41])[C:36](=[O:39])[N:37]([CH3:38])[C:31]2[CH:30]=[C:29]([CH2:28][NH:14][CH2:15][C:16]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]4[CH3:26])=[CH:18][CH:17]=3)[CH:46]=[CH:45][C:32]1=2)[CH3:44]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(Cc3ccc4c(c3)N(C)C(=O)CC4)C(=O)OC(C)(C)C)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccc4c(c3)N(C)C(=O)CC4)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Trifluoroacetic acid (43.2 mg) was added to a dichloromethane solution (5 ml) of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)carbamic acid tert-butyl ester (208 mg), and the mixture was stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction using dichloromethane, and condensed under reduced pressure to give the title compound (148 mg) as a white amorphous.
Reaction SMILES: C1C2C(COC([N:18]=[C:19]=[S:20])=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])[CH3:22].C(OCC)C>C(Cl)(Cl)Cl>[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:19](=[S:20])[NH2:18])[CH2:28][CH2:27]1)=[O:25])[CH3:22]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
9-Fluorenylmethoxycarbonyl isothiocyanate (5.90 g, 21.0 mmol) was dissolved in chloroform (20 ml) and a chloroform (10 ml) solution of piperidine-4-carboxylic acid ethyl ester (3.30 g, 21.0 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo, and the residue obtained by adding diethyl ether was collected by filtration. This was dissolved in N,N-dimethylformamide (20 ml) and piperidine (20 ml) was added and the mixture was stirred at room temperature for 1 hour. After the reaction solution was washed with ethyl acetate and the organic layer was washed with a saturated bline and dried over sodium sulfate, the residue obtained by vacuum concentration was purified by silica gel chromatography (n-hexane:ethyl acetate), and the title compound (4.34 g, 100%) was obtained.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][S:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1.O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:33]([C:32]1[CH:35]=[CH:36][C:29]([S:28][CH3:27])=[CH:30][CH:31]=1)[OH:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CSc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.59 M, 6.92 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.89 g, 11.0 mmol) in THF (38 mL) at −78° C. and the mixture solution was stirred at the same temperature for 30 minutes. To this solution, a solution of 4-methylsulfanylbenzaldehyde (1.67 g, 11.0 mmol) in THF (12 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for one hour, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.14 g, 58%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:9]1([CH2:15][SH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:15]([S:16][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cncc(Br)c1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cncc(SCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
To a solution of 3-bromo-5-methylpyridine (888 mg) in toluene (10 mL) were added phenylmethanethiol (705 mg), N,N-diisopropylethylamine (1.47 g), tris(dibenzylideneacetone)dipalladium(0)(189 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (239 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 1.5 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→17:3) to give the title compound as a yellow oil (yield 1.06 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:5][NH:6]2.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][C:28]([F:32])=[CH:29]2)[C:25]([CH3:34])([CH3:33])[CH2:24][CH2:23][N:22]3[CH:21]=1)=O>>[CH3:33][C:25]1([CH3:34])[C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:4]4[C:3]5[C:7](=[CH:8][CH:9]=[CH:10][C:2]=5[F:1])[NH:6][CH:5]=4)=[CH:21][N:22]3[CH2:23][CH2:24]1)[CH:29]=[C:28]([F:32])[CH:27]=2
Reactant: NC(=O)Cc1c[nH]c2cccc(F)c12
Reactant: COC(=O)C(=O)c1cn2c3c(cc(F)cc13)C(C)(C)CC2
Product: CC1(C)CCn2cc(C3=C(c4c[nH]c5cccc(F)c45)C(=O)NC3=O)c3cc(F)cc1c32

Procedure:
Beginning with (4-fluoroindol-3-yl)acetamide and (6,6-dimethyl-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[H-].[Na+].C1(C)C=CC(S(O[CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=O)=O)=CC=1>CN(C)C=O>[C:34]([O:33][C:31]([NH:30][CH2:29][CH2:28][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)c1cc2c(C)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)cccc2n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
A mixture of ethyl 4-methyl-1H-indole-2-carboxylate (42.9 g, 211 mmol), 60% sodium hydride (9.29 g, 232 mmol) and N,N-dimethylformamide (300 ml) was stirred at room temperature for 1 hour. A solution of 2-tert-butoxycarbonylaminoethyl 4-toluenesulfonate (86.6 g, 275 mmol) in N,N-dimethylformamide (200 ml) was added dropwise and the resulting mixture was stirred at room temperature for 9 hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/97) to obtain 24.4 g of ethyl 1-(2-tert-butoxycarbonylaminoethyl)-4-methyl-1H-indole-2-carboxylate.
Reaction SMILES: FC(F)(C)C(F)(F)C(F)(F)O.[C:12]([CH:16]([C:18]([CH2:21][OH:22])([F:20])[F:19])[F:17])([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].[C:29]([O:33][C:34](=[C:36]([F:38])[F:37])[F:35])([F:32])([F:31])[F:30]>C(#N)C>[C:12]([CH:16]([C:18]([CH2:21][O:22][C:36]([CH:34]([O:33][C:29]([F:32])([F:31])[F:30])[F:35])([F:38])[F:37])([F:20])[F:19])[F:17])([F:15])([F:14])[F:13]
Reactant: OCC(F)(F)C(F)C(F)(F)F
Reactant: FC(F)=C(F)OC(F)(F)F
Agent: CC(F)(F)C(F)(F)C(O)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(C(F)(F)F)C(F)(F)COC(F)(F)C(F)OC(F)(F)F
Temperature: 45 °C
Reaction time: 18 h

Procedure:
Hexafluorobutanol, CF3CFHCF2CH2OH (65.3 g, 0.34 mol), prepared essentially as described in Example 2) was combined with potassium carbonate (9.9 g, 0.072 mol) and 133 g of acetonitrile in a 600 mL Parr reactor. The temperature of the reactor was raised to 45° C. and CF3OCF═CF2 (65.6 g, 0.39 mol) added as a gas over about two hours. The resulting reaction mixture was stirred for about 18 hours at 45° C. The reactor was cooled and the contents of the reactor filtered to remove the potassium carbonate. The resulting product-containing filtrate was distilled using a concentric tube column, with the product cut boiling at 115-119° C. The product structure was confirmed by GCMS.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[C:27](B(O)O)[CH:26]=2)=[CH:21][CH:20]=1>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[C:27]([Pb+3:17])[CH:26]=2)=[CH:21][CH:20]=1
Reactant: [Pb+4]
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1B(O)O
Agent: CC(=O)[O-]
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Temperature: 40 °C
Yield: 100 %

Procedure:
To a mixture of lead tetraacetate (2.15 g, 4.85 mmol) and mercuric diacetate (0.15 g, 0.47 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (6 ml). This mixture is warmed to 40° C., and 4′-chloro-4-ethylbiphenyl-3-ylboronic acid (1.17 g, 4.50 mmol) is added in one portion and the suspension is heated at this temperature for 5 hours. The mixture is then cooled to room temperature, concentrated to a small volume and triturated with hexanes and filtered to yield crude 4′-chloro-4-ethylbiphenyl-3-yllead triacetate (2.70 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[CH:4][CH:3]=1.[N+](=[CH2:17])=[N-].N(N(C)C(N)=O)=O.C(O)(=O)C>C(OCC)(=O)C.C(OCC)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:17])=[O:9])=[C:6]([C:11]([F:14])([F:12])[F:13])[N:5]=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1c(Cl)ccnc1C(F)(F)F
Agent: CN(N=O)C(N)=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1c(Cl)ccnc1C(F)(F)F
Reaction time: 0.25 h
Yield: 104.9 %

Procedure:
To a stirred solution of 4-chloro-2-(trifluoromethyl)nicotinic acid (8.75 g, 38.8 mmol) in ethyl acetate (100 mL) in an ice bath is added a solution of diazomethane [generated from 12 g (116 mmol) of N-nitroso-N-methylurea] in diethyl ether (200 mL). The solution is stirred for 15 minutes, followed by the addition of acetic acid (until effervescence stops). The solution is concentrated in vacuo to afford 9.75 g (99%) of the title compound as a brown oil: 1H NMR (400 MHz, CD3OD), 8.686 (d, 1H), 7.828 (d, 1H), 3.937 (s, 3H). LC/MS (M+1)=240.1
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:12][C:13]1[C:18]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:20]=2[F:27])=[C:17](Cl)[N:16]2[N:29]=[CH:30][N:31]=[C:15]2[N:14]=1>ClCCl>[Cl:12][C:13]1[C:18]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:20]=2[F:27])=[C:17]([NH:4][CH:1]([CH3:3])[CH3:2])[N:16]2[N:29]=[CH:30][N:31]=[C:15]2[N:14]=1
Reactant: CC(C)N
Reactant: Fc1cc(F)c(F)c(-c2c(Cl)nc3ncnn3c2Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1c(-c2cc(F)cc(F)c2F)c(Cl)nc2ncnn12
Yield: 81.9 %

Procedure:
A mixture of isopropylamine (1.5 mmol), triethylamine (1.5 mmol) and dichloromethane (10 ml) was added to a mixture of 5,7-dichloro-6-(2,3,5-trifluorophenyl)-[1,2,4]-triazolo[1,5-a]pyrimidine (1.5 mmol, obtained from Ex. 3) and dichloromethane (20 ml) under stirring. The reaction mixture was stirred for 16 h. at 20 to 25° C. and washed with 5% hydrochloric acid. The organic layer was separated, dried and filtered. The filtrate was evaporated and the residue was purified by column chromatography to yield 0.42 g of the title compound of mp. 151° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH:23]1([CH:26]([NH2:30])[CH:27]2[CH2:29][CH2:28]2)[CH2:25][CH2:24]1>>[CH:23]1([CH:26]([CH:27]2[CH2:29][CH2:28]2)[NH:30][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH2:25][CH2:24]1
Reactant: NC(C1CC1)C1CC1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC(C4CC4)C4CC4)cc3)c2)o1

Procedure:
N-Dicyclopropylmethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and dicyclopropylmethylamine using method I.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([Br:9])[C:7]=1[Cl:8].[BH4-].[Na+].BrC1C=C(C=C(Br)C=1Cl)C(OC)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:9])[C:7]=1[Cl:8])[CH:10]=[O:11]
Reactant: OCc1cc(Br)c(Cl)c(Br)c1
Agent: COC(=O)c1cc(Br)c(Cl)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=Cc1cc(Br)c(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3,5-Dibromo-4-chlorophenyl)methanol: NaBH4 (1.53 g, 40.65 mmol) was added portionwise to a stirred solution of methyl 3,5-dibromo-4-chlorobenzoate (4.45 g, 13.6 mmol) in MeOH (50 mL) at 0° C. The reaction mixture was then stirred at ambient temperature for 8 h. The volatiles were evaporated and the residue was diluted with CH2Cl2 and washed with brine followed by water. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (3.3 g, 80%): 1H NMR (300 MHz, DMSO-d6) δ 7.71 (s, 2H), 5.49 (bs, 1H), 4.48 (d, J=4.5 Hz, 2H); ESIMS m/z 297.9 ([M]+); IR (thin film) 3460, 747, 534 cm−1.
Reaction SMILES: [F:1][C:2]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH3:30])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C@@H:18]1[CH2:19][CH2:20][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:29][CH3:30])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:2]=3[F:1])[N:11]=2)(=[O:14])=[O:15])[CH2:17]1
Reactant: COc1cc(NS(=O)(=O)N2CC[C@@H](NC(=O)OC(C)(C)C)C2)nc(SCc2cccc(F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CC[C@@H](N)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl {(3R)-1-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]pyrrolidin-3-yl}carbamate (0.75 g) in DCM (10 ml) was added TFA (10 ml) slowly. The reaction then stirred at room temperature for 18 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the subtitle compound as a white solid. Yield: 0.17 g
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:23]([C:31]2[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=2)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:7]=[C:8]([C:10]2[S:14][C:13]([N:15]3[CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:22])[CH2:16]3)=[N:12][CH:11]=2)[CH:9]=1)([O-])=O.[Cl-].[NH4+].CN(C=O)C.C(OCC)(=O)C.CCCCCC>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([N:23]([C:31]2[N:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:33][N:32]=2)[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[CH:7]=[C:8]([C:10]2[S:14][C:13]([N:15]3[CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:22])[CH2:16]3)=[N:12][CH:11]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2cnc(N3CCCNC(=O)C3)s2)cc([N+](=O)[O-])c1)c1nccc(C(F)(F)F)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1)c1nccc(C(F)(F)F)n1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a suspension of tert-butyl {3-nitro-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate (314 mg, 0.542 mmol) in ethanol (9 mL) at room temperature under nitrogen, was added iron (605 mg, 10.84 mmol) and a saturated aqueous solution of ammonium chloride (0.25 mL). The mixture was stirred at 40° C. for 30 minutes. N,N′-dimethylformamide (5 mL) was added and the mixture was stirred at 40° C. for 3 hours. An additional portion of iron (300 mg, 5.4 mmol) and saturated aqueous solution of ammonium chloride (1.1 mL) were then added and the resulting mixture was stirred at 40° C. for 2 hours. The reaction was then cooled to room temperature, and concentrated under reduced pressure to remove volatiles. The resulting suspension was filtered through celite, rinsing successively with N,N′-dimethylformamide, ethyl acetate, dichloromethane, and 2-methyltetrahydrofuran. The filtrate was concentrated to remove the volatiles, then diluted with ethyl acetate, washed with water (5×), brine (1×), dried over sodium sulfate, and concentrated to provide a beige solid. This solid was swished in 1:1 ethyl acetate/hexane, the solids collected by filtration, rinsed successively with 1:1 ethyl acetate/hexane and hexane, and dried to afford 250 mg (0.46 mmol, 85%) of tert-butyl {3-amino-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-methoxyindole (500 mg, 3.39 mmol) in acetic acid (34 mL), sodium cyanoborohydride (641 mg, 10.20 mmol) was added in portions. After stirring for 30 min at rt, the mixture was quenched with water (2.0 mL) and concentrated. The yellow residue was dissolved in DCM, washed with aq. sat. NaHCO3-solution and brine. The org. layers was dried (MgSO4), filtered and the solvent removed under reduced pressure to yield 5-methoxyindoline which was stored in the freezer. LC-MS conditions B: tR=0.24 min, [M+H]+=150.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.N1C=CC=CC=1.[NH2:32][C:33]1[CH:34]=[C:35]([CH:40]([CH:49]2[CH2:51][CH2:50]2)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[CH:37][C:38]=1[Cl:39]>ClCCl>[Cl:39][C:38]1[CH:37]=[CH:36][C:35]([CH:40]([CH:49]2[CH2:51][CH2:50]2)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])=[CH:34][C:33]=1[NH:32][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CC(C)(C)OC(=O)CC(c1ccc(Cl)c(N)c1)C1CC1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]([C@H](C(=O)Nc1cc(C(CC(=O)OC(C)(C)C)C2CC2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
45 mg (0.17 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 1 ml of dichloromethane, 36 mg (0.27 mmol) of 1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was stirred at room temperature for 30 min. 411 (0.51 mmol) of pyridine and 50 mg (0.17 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (enantiomer 1; Example 30A), dissolved in 1 ml of dichloromethane, were then added, and the reaction mixture was stirred for another 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product obtained was directly purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 78 mg of the target compound (85% of theory).
Reaction SMILES: [C:1]1([CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCOCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 3-[2-(1-naphthyl)ethoxy]propanoate (Example 7a), 6.19 g) was taken up in dichloromethane (30 mL) and treated with trifluoroacetic acid (5 mL). The resulting solution was stirred at room temperature for 2 hours, an additional 1 mL of trifluoroacetic acid was added and the solution stirred overnight. The mixture was concentrated, taken up in 2M sodium hydroxide solution (30 mL) and washed with ether (2×20 mL). The aqueous layer was subsequently acidified (using 1M hydrochloric acid) and extracted with ether (2×30 mL). The combined organics were washed with brine (20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the sub-titled compound (5.66 g) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18]CC)=[O:17].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[C:3]([C:16]([OH:18])=[O:17])[N:4]=[N:5]2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(Cn2nnc(C(=O)O)c2NS(C)(=O)=O)cc1
Reaction time: 24 h

Procedure:
Ethyl 5-amino-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (0.85 g) and methane sulphonyl chloride (0.72 mL) were stirred in pyridine (20 mL) for 4 d. Further methane sulphonyl chloride (0.72 mL) was added and stirring continued for 24 h. Further methane sulphonyl chloride (0.5 mL) was added and stirring continued for 24 h. The mixture was concentrated in vacuo. The residue was suspended in dilute hydrochloric acid and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid and water then evaporated. The residue was taken up in ethanol (70 mL) and 2 M sodium hydroxide solution (70 mL) and stirred for 18 h. The mixture was concentrated to about half volume and acidified with dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the extracts were washed with water and brine, then dried and evaporated to leave a white solid (0.90 g).