Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH:16]3[CH2:21][CH2:20][C:19](=[CH:22][O:23]C)[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH:22]=[O:23])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC=C1CCC(C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Solvent: Cc1ccccc1
Solvent: O=CO
Product: O=C[C@H]1CC[C@H](C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A solution of 0.95 g of 4'-fluoro-4-[[4-(methoxymethylidene)cyclohexyl]ethynyl]biphenyl in 40 ml of toluene was treated with 4 ml of formic acid and stirred at room temperature overnight. The formic acid phase was separated and the toluene phase was washed neutral with water, dried over sodium sulphate, filtered and concentrated. For the ring isomerization, the resulting crude 4-[(4'-fluoro-4-biphenylyl)ethynyl]cyclohexanecarboxaldehyde was dissolved in 35 ml of ethanol, treated with 8.2 ml of 0.1N alcoholic potassium hydroxide solution and stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether, washed with saturated sodium hydrogen carbonate solution and with water, dried over sodium sulphate, filtered and concentrated. 0.80 g of trans-4-[(4'-fluoro-4-biphenylyl)ethynyl]cyclohexanecarboxaldehyde was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35]>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)COC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 25 °C
Yield: 7 %

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of dichloromethane. 85 μl (2 molar equivalent) of triethylamine and 78 μl (2 molar equivalent) of isobutyl chloroformate were respectively added. The reaction mixture was maintained at room temperature for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5) to provide 92 mg (yield=7%) of the desired product (formula shown hereinabove) as an orange powder which was characterized as follows:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34]>>[CH3:29][O:30][CH2:31][CH2:32][N:33]([CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1)[CH3:34]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reactant: CNCCOC
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Yield: 55 %

Procedure:
Conversion of 4-cloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (84 mg, 0.20 mmol) with N-(2-methoxyethyl)-methylamin (178 mg, 2.0 mmol) using the general procedure C affords the product as white solid in 55% yield.
Reaction SMILES: C1(S([NH:10][C:11]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:12]=2/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])(=O)=O)C=CC=CC=1.Br[CH2:28][C:29]([C:31]1[CH:36]=[C:35]([CH2:37][CH3:38])[CH:34]=[CH:33][N:32]=1)=[O:30]>>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[C:12]2[C:11](=[CH:22][CH:21]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:19]=2)[NH:10][C:28]=1[C:29]([C:31]1[CH:36]=[C:35]([CH2:37][CH3:38])[CH:34]=[CH:33][N:32]=1)=[O:30]
Reactant: COC(=O)/C=C/c1cc(C(F)(F)F)ccc1NS(=O)(=O)c1ccccc1
Reactant: CCc1ccnc(C(=O)CBr)c1
Product: CCc1ccnc(C(=O)c2[nH]c3ccc(C(F)(F)F)cc3c2CC(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-2-phenylsulfonylamino-5-(trifluoromethyl)cinnamate (step 2 of Example 151) and 2-bromoacetyl-4-ethylpyridine (Preparation is described in Example 57).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[Br:1][C:2]1[C:3]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:4][N:5]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:6]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(-c2n[nH]cc2Br)cc1
Product: CC(C)(C)OC(=O)Cn1cc(Br)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 3 with 4-bromo-3-(4-nitrophenyl)-1H-pyrazole and dimethylethyl bromoacetate furnished the title compound. ESMS [M+H]+: 382.0
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]([C:18]1[N:19]=[N:20][C:21]([NH:24][C:25]3[N:26]=[CH:27][C:28]4[CH:33]=[C:32]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[N:31]([CH:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[C:29]=4[N:30]=3)=[CH:22][CH:23]=1)=[O:17])[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][N:35]([CH3:37])[C:34]([C:32]1[N:31]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:29]2[N:30]=[C:25]([NH:24][C:21]3[N:20]=[N:19][C:18]([C:16]([N:11]4[CH2:10][CH:9]5[NH:8][CH:13]([CH2:14][CH2:15]5)[CH2:12]4)=[O:17])=[CH:23][CH:22]=3)[N:26]=[CH:27][C:28]=2[CH:33]=1)=[O:38]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)nn3)nc2n1C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)nn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a solution of 3-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (110 mg, 0.187 mmol) in DCM (1 ml) at −78° C. was added TFA (1 mL, 13.0 mmol). After warming to room temperature and stirring for 1 h, the reaction was concentrated under reduced pressure. The resulting oily residue was dissolved in 2 mL MeOH, flushed through a PL-HCO3 MP-Resin cartridge to remove TFA, then purified by HPLC which gave a white solid (55 mg, 0.112 mmol). 1H NMR (400 MHz, DMSO): δ, 10.71 (s, 1H), 8.88 (s, 1H), 8.60 (d, J=8 Hz, 1H), 7.82 (d, J=8 Hz, 1H), 6.68 (s, 1H), 4.81-4.72 (m, 1H), 4.22 (d, J=12 Hz, 1H), 3.53 (d, J=12 Hz, 1H), 3.48 (br s, 1H), 3.29 (br s, 1H), 3.27 (d, J=12 Hz, 1H), 3.06 (s, 3H), 3.05 (s, 3H) 2.93 (d, J=12 Hz, 1H), 2.42-2.33 (m, 2H), 2.01-1.96 (m, 4H), 1.72-1.58 (m, 6H); HRMS calcd for C25H31N9O2.H+ (M+H)+ 490.2679. found 490.2676 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:38][C@H:39]1[NH:45][CH2:44][C@@H:43]([CH3:46])[CH2:42][NH:41][C:40]1=[O:47]>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([N:45]1[CH2:44][C@@H:43]([CH3:46])[CH2:42][NH:41][C:40](=[O:47])[C@H:39]1[CH3:38])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CNC(=O)[C@@H](C)NC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCCl
Product: C[C@H]1CNC(=O)[C@@H](C)N(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 120 mg, 0.36 mmol) in acetonitrile (10 mL) was added HOBT (60 mg, 0.43 mmol) and EDC (75 mg, 0.4 mmol). The reaction was stirred at room temperature for 1 h and then treated with (3R,6R)-hexahydro-3,6-dimethyl-2H-1,4-diazepin-2-one (Intermediate 23, 50 mg, 0.35 mmol). The reaction was stirred at room temperature overnight. After removal of solvent, the crude product was purified by flash chromatography on a Biotage® system (silica, 6% methanol in dichloromethane) to yield the title compound as white solid. MS (M+1−Boc): 358.0
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:66]([O:73][C:74](=[O:80])[CH2:75][CH2:76][CH2:77][CH2:78][NH2:79])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>CN(C=O)C.C(N(CC)CC)C>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([NH:79][CH2:78][CH2:77][CH2:76][CH2:75][C:74]([O:73][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:80])=[O:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])=[O:4]
Reactant: NCCCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)NCCCCC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Boc-Gly-Gly-Phe-Gly-OH (SEQ ID NO. 1) (575 mg), HOSu (182 mg), and DCC (326 mg) were dissolved in DMF (20 ml), and the solution was stirred for 30 minutes. The resulting solution was added with a solution of p-toluenesulfonic acid salt of 5-aminopentanoic acid benzyl ester (500 mg) and triethylamine (0.184 ml) dissolved in DMF (10 ml), and the mixture was stirred at room temperature for three days. The reaction mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=20:1) to obtain 560 mg of Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOBzl (SEQ ID NO. 1). The Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOBzl (SEQ ID NO. 1) (560 mg) was dissolved in methanol (60 ml) containing 50% of water, and the solution was added with 5% Pd—C (water content; 50%, 1.5 g) and stirred overnight under hydrogen at ordinary pressure. After the catalyst was removed from the reaction mixture by filtration, the mixture was concentrated to dryness to obtain 300 mg of Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOH (SEQ ID NO. 1).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[F:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]([CH2:17]C(OCC)=O)=O)=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]2[N:1]=[C:2]3[CH:6]=[CH:5][S:4][C:3]3=[C:7]([OH:9])[CH:17]=2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: Nc1ccsc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1cc(-c2ccc(F)cc2)nc2ccsc12
Temperature: 25 °C
Yield: 16.6 %

Procedure:
A mixture of 3-amino-2-thiophenecarboxylic acid (8 g, 49 mmol), ethyl 4-fluorobenzoylacetate (9.6 g, 49 mmol), and p-toluenesulfonic acid monohydrate (0.2 g, 1 mmol) in toluene (100 mL) is refluxed for 20 hours with a Dean-Stark water trap to remove produced water. The mixture is cooled to room temperature. The resulting precipitate is filtered and washed with diethyl ether. The solid is dissolved in diphenyl ether (80 mL) and heated at 220° C. for 2 hours. The reaction solution is then cooled to room temperature and diluted with diethyl ether; the precipitate is filtered and washed with diethyl ether to give 5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (2 g, 17% yield) as brown crystalline needles, m.p. 316-318° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][CH2:34][CH2:35]O.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.O1CCCC1>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:35][CH2:34][O:33][CH3:32])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: COCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1ccc(C(=O)OC)c(O)c1
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a 50 ml tetrahydrofuran solution of 4.0 g (23.8 mmol) of methyl 2,4-dihydroxybenzoate, 7.49 g (28.5 mmol) of triphenylphosphine, 2.25 ml (28.5 mmol) of 2-methoxyethanol, and 4.5 ml (28.5 mmol) of diethyl azodicarboxylate were slowly added at 0° C. The mixture was brought to room temperature, and stirred for 1 hour. Then, the reaction mixture was diluted with ethyl acetate, and washed with water and a saturated aqueous solution of sodium chloride. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. To the residue, 100 ml of a solution of ethyl acetate/hexane (=1/4) was added, and insoluble solids were removed by filtration. Then, the mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to obtain 4.71 g (87%) of the captioned compound.
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([C:36]([F:39])([F:38])[F:37])([OH:35])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[H][H]>CO.[C].[Pd]>[CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([C:31]([F:34])([F:32])[F:33])([OH:35])[C:36]([F:38])([F:37])[F:39])=[C:24]([CH3:40])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:17])([CH3:18])[C:14]([CH3:19])([CH3:20])[O:13]2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Yield: 94 %

Procedure:
10% palladium-carbon (50 mg) was added to a solution of 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-butyn-2-ol (Example 27-(1); 142 mg, 0.249 mmol) in methanol (6 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for five hours. Then, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the target product as a colorless oil (134 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:44])[F:45])[CH:35]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc(C(F)(F)F)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-(trifluoromethyl)-benzenesulfonyl chloride. Purity (ELSD, based on MW=629.6)=97%.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:15]([CH3:17])=O)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][O:20][NH2:21]>CO>[CH2:1]([O:8][N:9]=[C:10]([C:15](=[N:21][O:20][CH3:19])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=NOCc1ccccc1)C(C)=O
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C(C)C(=NOCc1ccccc1)C(=O)OC
Yield: 83.2 %

Procedure:
To a solution of 4.0 g (17 mol) of methyl 2-benzyloxyiminoacetoacetate in 50 ml of methanol, 1.56 g (18.7 mmol) of methoxyamine hydrochloride was added and the mixture was heated under reflux for 3 hours. After distilling the solvent off under reduced pressure, 50 ml of water was added and the mixture was extracted twice with 50 ml of diethylether and then washed with water and a saturated aqueous sodium chloride. The organic layer was dried over with anhydrous magnesium sulfate and the solvent was distilled off to obtain a residue, which was then purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 4.11 g (yield:91%) of methyl 2-benzyloxyimino-3-methoxyiminobutyrate as a colorless oil. 1H-NMR(CDCl3) δ ppm:1.99(3H, s), 3.86(3H, s), 3.94(3H, s), 5.21(2H, s), 7.33(5H, m).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])=[O:14].ClS([N:28]=[C:29]=[O:30])(=O)=O.O>ClCCl>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[NH:15][C:13]([C:3]1[O:4][C:5]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=2[C:2]=1[NH:1][C:29]([NH2:28])=[O:30])=[O:14]
Reactant: COc1ccc2c(N)c(C(=O)Nc3ccc(Cl)cc3Cl)oc2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(NC(N)=O)c(C(=O)Nc3ccc(Cl)cc3Cl)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
3-Amino-N-(2,4-dichlorophenyl)-6-methoxybenzofuran-2-carboxamide ¼ hydrate (0.9 g) obtained in Example 1 was dissolved in dichloromethane (10 ml) and chlorosulfonyl isocyanate (0.4 g) was added under ice-cooling. The mixture was further stirred at room temperature for 1 hr. Then water was added and the precipitated crystals were recrystallized from water-containing dimethylformamide to give the title compound (0.3 g). melting point: >260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:31])([F:30])[C:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[N:24][CH:25]=1)[CH2:16][C:13]1([C:12]([F:11])([F:30])[F:31])[CH2:15][CH2:14]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=451.1, tR (minutes, Method G)=2.50. [α]D20=+33.55 (c=3.07 mg/mL,CHCl3)
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.C1C=C(O[C:26](OC2N=CC=CC=2)=[S:27])N=CC=1>C(Cl)Cl>[C:15]([O:14][C:12]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:1]=[C:26]=[S:27])[C:10]=2[CH3:11])[CH2:6][CH2:7]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1c(N)ccc2c1N(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c1N(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
6-Amino-1-t-butoxycarbonyl-2,3-dihydro-7-methylindole (0.5 g, 2.13 mmol) is dissolved in methylene chloride (10 mL). To this solution is added N,N-dimethylaminopyridine (0.052 g, 0.42 mmol) and di-2-pyridyl thionocarbonate (0.496 g, 2.13 mmol). The solution is allowed to stir for 20 minutes. The solution is diluted with methylene chloride and washed first with four 75-mL portions of aqueous citric acid solution followed by three 100-mL portions of aqueous potassium carbonate. The organic extracts are dried over anhydrous potassium carbonate, filtered and the solvent is removed by rotary evaporation to yield 0.59 g of crude 1-t-butoxycarbonyl-2,3-dihydro-6-isothiocyanato-7-methylindole as an orange, oily solid. The crude product is taken on to the next reaction without further purification.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:6].O.[CH:19]1(CO)[CH2:21][CH2:20]1>>[CH:19]1([CH2:2][O:3][C:4](=[O:17])[CH:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=2)[CH3:6])[CH2:21][CH2:20]1
Reactant: COC(=O)C(C)c1ccc(CC(C)C)cc1
Reactant: OCC1CC1
Agent: [Na]
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)OCC2CC2)cc1
Temperature: 50 °C

Procedure:
A mixture of 0.05 g of sodium in 20 ml of cyclopropylmethyl alcohol was heated at 50° C. for 5 hours. To the mixture was added 2.2 g of 2-(p-isobutylphenyl)propionic acid methyl ester and the whole was refluxed for 10 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure to leave a residue, to which was added water. The resulting mixture was extracted with ether, and the extract was washed sufficiently with water and then dehydrated. The ether was removed by distillation to leave a residual oily product. This product was then distilled under reduced pressure to yield 1.38 g of 2-(p-isobutylphenyl)propionic acid cyclopropylmethyl ester as a colorless oil, boiling at 109°-111° C./1 mmHg. Analysis-Calculated for C17H24O2 : C, 78.42; H, 9.29. Found: C, 78.19; H, 9.22.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C@@H:7]1[CH2:27][N:10]2[C:11](=[O:26])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=3)[CH2:13][C@H:9]2[CH2:8]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][C@@H:7]1[CH2:27][N:10]2[C:11](=[O:26])[N:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:18][CH:19]=3)[CH2:13][C@H:9]2[CH2:8]1
Reactant: CC(C)(C)[Si](O[C@H]1C[C@@H]2CN(c3ccc(OCC(F)(F)F)cc3)C(=O)N2C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)C[C@H]2C[C@H](O)CN12
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
To a solution of (6S,7aR)-6-(tert-Butyl-diphenyl-silanyloxy)-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (250 mg, 0.451 mmol) in THF (3 mL) was added TBAF (1M in THF, 0.55 ml, 0.541 mmol) at 0° C. and stirred for 4 h at room temperature. The mixture was concentrated under reduced pressure and the residue was taken up with DCM. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified through column chromatography over silica (elution with 20% ethyl acetate in hexane) to afford 130 mg (90%) of the title compound. LC-MS: 317.4 [M+1]+.