Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([O:17]CC=C(Cl)Cl)=[C:6]([Cl:16])[CH:7]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([Cl:15])[Cl:14])[CH:9]=1)(=[O:3])[CH3:2].O>C1(C)C=CC=CC=1.C(OCC)C>[C:1]([C:4]1[C:5]([OH:17])=[C:6]([Cl:16])[CH:7]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([Cl:15])[Cl:14])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCC=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Temperature: 85 °C
Reaction time: 6 h

Procedure:
6.1 g of 3-acetyl-2,5-bis-(3,3-dichloroprop-2-enyloxy)-1-chlorobenzene were dissolved in 160 ml of toluene. 7.79 g of magnesium dibromide/diethyl ether complex, dissolved in 25 ml of diethyl ether, were added to this solution, and the mixture was then stirred at 85° C. for 6 hours. After the reaction had ended according to TLC, the mixture was allowed to cool, about 300 ml of water were added and the organic phase was separated off. The aqueous phase was re-extracted twice with ethyl acetate, and the combined organic phases were then washed with saturated sodium chloride solution. After drying and concentration of the organic phase, the crude product was purified chromatographically. Yield: 2.86 g (64%)
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:29]=[CH:28][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=O)(C)(C)C.[ClH:30]>C(O)C>[ClH:30].[ClH:30].[NH2:8][CH2:9][C:10]1[CH:29]=[CH:28][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:16]2)=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN2CCC(Cc3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: NCc1ccc(CN2CCC(Cc3ccccc3)CC2)cc1
Reaction time: 1 h

Procedure:
To 5.77 g (14.6 mM) of 1-[4-[N-(tert-butoxycarbonyl)aminomethyl]benzyl]-4-benzylpiperidine was added 10 ml (120 mM) of 12N-hydrochloric acid at room temperature and the mixture was stirred at the prevailing temperature for one hour. After addition of ethanol, the mixture was concentrated under reduced pressure and ethanol and diethyl ether were added to the residue. The resulting crystal crop was harvested by filtration and rinsed with ethanol and diethyl ether to provide the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]([O:34][CH2:35][CH2:36][CH2:37]Br)(=[O:33])[CH3:32]>CN(C=O)C>[C:31]([O:34][CH2:35][CH2:36][CH2:37][O:19][C:15]1[CH:14]=[C:13]([C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OCCCBr
Reactant: CCOC(=O)c1cc(-c2cccc(O)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cccc(OCCCOC(C)=O)c2)n(-c2cccc(Cl)c2)n1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
100 mg (0.292 mmol) of the compound of Example 44A are provided in 1 ml of dry DMF, 242 mg (1.75 mmol) of potassium carbonate and 158 mg (0.875 mmol) of 1-acetoxy-3-bromopropane are added, and the mixture is stirred at 90° C. for 4 h. The reaction mixture is subsequently purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with the addition of 0.1% formic acid) and 109 mg (84% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([SH:8])=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Br>CC(C)=O>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][S:8][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: COC(CBr)OC
Reactant: Cc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(CSc1ccccc1C)OC
Yield: 89.6 %

Procedure:
To a solution of o-thiocresol (16.89 g, 136 mmol) in acetone (130 ml) is added potassium carbonate (20.5 g, 148 mmol) and a solution of bromoacetaldehyde dimethylacetal (19.93 g, 123 mmol) in acetone (20 ml) and the reaction mixture is stirred at ambient temperature overnight. The solids are filtered and washed with diethyl ether. The filtrate is concentrated and dissolved into ethyl acetate, washed successively with water, 0.5 N NaOH, and 2N NaOH. The combined aqueous fractions are extracted with dichloromethane. The combined organic fractions are dried over anhydrous MgSO4, filtered and concentrated to afford 1-[(2,2-dimethoxyethyl)thio]-2-methyl-benzene as a brown oil (23.4 g, 90%) that is used without further purification. 1H NMR (CDCl3): δ=7.33 (1H, brd), 7.19-7.08 (3H, m), 4.56 (1H, t), 3.38 (6H, s), 3.10 (2H, d), 2.42 (3H, s).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)C=C1>>[CH2:6]1[C:1]2[NH:7][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[CH2:3][CH2:4][CH2:5]1
Reactant: NNc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Product: c1ccc2c3c([nH]c2c1)CCCC3

Procedure:
In Scheme XVII, Step A, a phenylhydrazine salt (for example the hydrochloride salt) of formula (4), is reacted with a cyclic ketone of formula (3), wherein Z=OBn, in a Fischer indole reaction to provide a tetrahydrocarbazole of formula (5). The hydrazine and ketone are reacted in acetic acid and heated at about 60 to 110° C., for about 4 to 48 hours. The product is isolated by removal of the acetic acid under reduced pressure and trituration of the material in an inert solvent, preferably dichloromethane. After filtration, the filtrate is concentrated and the resulting material purified using standard techniques such as recrystillization or silica gel chromatography.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]([NH2:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CC(O)C>[C:10]([NH:13][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1)([CH3:12])([CH3:11])[CH3:9]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
251 mg of 4,6-dichloropyrimidine, 123 mg of 2-methylpropan-2-amine and 260 mg of DIPEA were dissolved in 2.5 mL of i-PrOH and charged into a screw cap vial and the vial obtained was kept overnight in a heating block at 90° C. The reaction was monitored by TLC and was completed after 12 hours. The mixture obtained was cooled to r.t., solvent was evaporated and pure N-tert-butyl-6-chloropyrimidin-4-amine was obtained by column chromatography using PE:EtOAc 10:1.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16]([C@@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[C:24](=[O:43])[C@@H:25]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C@H:26]([CH3:34])[CH2:27][CH:28]([CH3:33])[CH2:29][CH2:30][CH:31]=C)=[O:17])[CH2:12][C@H:11]2[CH:13]=C)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH:1]1([S:4]([NH:7][C:8]([C@@:10]23[CH2:12][C@H:11]2[CH:13]=[CH:31][CH2:30][CH2:29][CH:28]([CH3:33])[CH2:27][C@@H:26]([CH3:34])[C@H:25]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[C:24](=[O:43])[N:19]2[CH2:20][C@H:21]([OH:23])[CH2:22][C@H:18]2[C:16](=[O:17])[NH:15]3)=[O:9])(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CC1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Solvent: ClCCCl
Product: CC1CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A solution of tert-butyl ((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (9.50 g, 15.2 mmol) in DCE (2.5 L) was sparged with nitrogen for 30 min. To the solution was added Hoveyda-Grubbs 2nd Generation Catalyst (0.574 g, 0.912 mmol). The solution was heated at 80° C. for 2 h; then cooled to 45° C. and stirred for 2 days. The reaction solution was concentrated in vacuo and the resulting solid residue was then subjected to flash chromatography on silica gel (hexanes:acetone, 80:20 to 40:60) to afford tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-hydroxy-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate as a solid foam (7 g). MS: MS m/z 597.35 (M++1).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:36]4[C:35](=[C:34]([CH3:33])[CH:39]=[CH:38][CH:37]=4)[NH:40][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 508.3 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3]1.[Br:20]Br>C(O)(=O)C.S(=O)(=O)(O)O>[Br:20][C:12]1[CH:11]=[CH:10][C:6]2[NH:7][C:8](=[O:9])[CH:2]([CH3:1])[N:3]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH:13]=1
Reactant: BrBr
Reactant: CC1N=C(c2ccccc2)c2ccccc2NC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1N=C(c2ccccc2)c2cc(Br)ccc2NC1=O
Yield: 78.7 %

Procedure:
To a stirred solution of 131 (66.5 g, 265 mmol) in glacial acetic acid (400 mL), sulfuric acid (80 mL) was added to the solution. Bromine (28 mL, 530 mmol) dissolved in acetic acid (150 mL) was added dropwise into the mixture. The reaction mixture was allowed to stir until analysis by NMR spectroscopy indicated that all of the starting material 131 had been consumed. The solution was concentrated under reduced pressure and then brought to pH 7 by addition of 1N aq NaOH solution and then extracted with EtOAc. The crude product 132 was purified by recrystallization from CH2Cl2 to afford 132 (68.66 g, 79%). mp 210-212° C.; IR (KBr, cm−1) 2931, 1692, 1603, 1563, 1475, 1445, 1375, 1259, 1235, 1130, 1090; 1H NMR (CDCl3) δ 9.36 (s, 1H), 7.63 (dd, J=2.22, 8.58 Hz, 1H), 7.54-7.39 (m, 6H), 7.12 (d, J=8.611H), 3.76 (q, J=6.3 Hz, 1H), 1.76 (d, J=6.45 Hz, 3H). MS (EI) m/e (relative intensity) 330 (M++1, 21), 329 (M+, 50), 328 (22), 327 (48), 289 (44), 288 (46), 287 (100), 286 (45), 285 (60) 205 (25), 77 (49).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.Br[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:13]([N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: CC1(C)CC(O)CC(C)(C)N1
Product: CCCCN1C(C)(C)CC(O)CC1(C)C
Temperature: -78 °C
Yield: 46.9 %

Procedure:
Into a 400-milliliter Hastalloy pressure tube are placed 62.8 grams of 2, 2, 6, 6-tetramethyl-4-hydroxypiperidine and 35.6 grams of 1-bromobutane. The tube and contents are cooled to -78°C., evacuated and filled with nitrogen. The tube is sealed, shaken and warmed to 100°C. for 1 hour, 120°C. for 1 hour and 150°C. for 30 hours. The tube is cooled and the solid charge is removed and placed in a Sohlet extraction apparatus. The material is extracted for 8 hours with diethyl ether. The resulting ether solution is treated with activated charcoal, filtered and concentrated under vacuum. The residue is distilled at 120°-125°C. at 1 torr to give 26 grams of 1-(1-butyl)-2, 2, 6, 6-tetramethyl-4-hydroxypiperidine, a white solid melting at 29°-33°C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:10]([CH2:14][CH3:15])[C:11](O)=[O:12])=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:10]([CH2:14][CH3:15])[C:11]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=2)=[O:12])=[CH:5][C:4]=1[C:21]([F:22])([F:24])[F:23])#[N:2]
Reactant: CCC(C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: Nc1ccc(F)cc1
Product: CCC(C(=O)Nc1ccc(F)cc1)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 91C using 2-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]butanoic acid and 4-fluoroaniline:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.Br[C:25]1[CH:37]=[CH:36][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]2)=[CH:27][CH:26]=1.CO.CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:25]3[CH:37]=[CH:36][C:28]([CH2:29][N:30]4[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]4)=[CH:27][CH:26]=3)[S:10][C:3]=12
Reactant: O[C@H]1CCN(Cc2ccc(Br)cc2)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H]1CCN(Cc2ccc(-c3cc4nccc(Cl)c4s3)cc2)C1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a solution of 98 (2.44 g, 5.30 mmol) and bromide 97 (1.3 g, 5.07 mmol) in dry toluene (30 mL) was added Pd(PPh3)4 (290 mg, 0.25 mmol). The reaction mixture was heated to reflux for 1.5 h, cooled to room temperature and the solvent was removed under reduced pressure. The resultant solid was purified by column chromatography, eluents EtOAc-Hexane (1:1) then MeOH/EtOAc (20:80), to afford title compound 99 (1.24 g, 71% yield) as a white solid. MS (m/z): 345.1/347.1 (M+H).
Reaction SMILES: [CH3:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].O.[C:14]([OH:18])(=[O:17])[CH:15]=O.P(=O)(O)(O)O>C(OCC)C.ClCCl>[O:12]=[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:1]=[CH:15][C:14]([OH:18])=[O:17]
Reactant: O=CC(=O)O
Reactant: CCCCCCCCCC(C)=O
Agent: O=P(O)(O)O
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC(=O)C=CC(=O)O
Temperature: 25 °C

Procedure:
A mixture of 2-undecanone (10 g, 58.7 mmol), glyoxylic acid monohydrate (5.15 g, 56 mmol) and 85% phosphoric acid (10 ml) was warmed at 80° for 18 hours. On cooling to room temperature, the mixture was diluted with ethyl ether/dichloromethane (50 ml each) and washed thoroughly with brine. Evaporation of the dried (magnesium sulphate) organic phase gave a yellow oil which on crystallization from ethyl ether/petroleum ether gave 4-ketotridec-2-enoic acid as colorless prisms.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:45])[CH2:7][C:8]1([CH2:11][CH2:12][CH:13](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=2)[CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C>C1COCC1.O>[C:6]([CH2:7][C:8]1([CH2:11][CH2:12][CH:13](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][C:41]([F:42])([F:44])[F:43])=[CH:38][CH:39]=2)[CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)([OH:45])=[O:5]
Reactant: CCOC(=O)CC1(CCC(/C=C/c2ccccc2OCc2ccc(OC(F)(F)F)cc2)Cc2ccc(C(=O)O)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1(CCC(/C=C/c2ccccc2OCc2ccc(OC(F)(F)F)cc2)Cc2ccc(C(=O)O)cc2)CC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
4 mg (0.17 mmol) of lithium hydroxide are added to a solution of 50 mg (0.08 mmol) of 4-[(3E)-2-{2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}-4-(2-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-but-3-en-1-yl]benzoic acid (enantiomer 1) in 2 ml of THF and 1 ml of water, and the mixture is stirred at 50° C. for 12 hours. After cooling, the THF is removed under reduced pressure, and the aqueous phase is adjusted to pH 4 using 1 M hydrochloric acid. The product precipitates out and is filtered off, washed with water and dried. This gives 38 mg (79% of theory) of a slightly white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1.[F:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1.CC#N.O>C(O)=O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:4]([CH2:5][C:6]3[NH:7][C:8](=[O:16])[C:9]4[CH2:15][O:14][CH2:13][CH2:12][C:10]=4[N:11]=3)[CH2:3][C:2]([F:1])([F:17])[F:18])=[O:34])[CH2:30][CH2:31]2)=[O:25])=[CH:36][CH:37]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c(CNCC(F)(F)F)nc2c1COCC2
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC(F)(F)F)CC1

Procedure:
Following the general procedure of Example 1, the title compound was prepared (0.015 g) from 2-((2,2,2-trifluoroethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. 1H NMR (400 MHz, MeOD) δ ppm 8.04-8.18 (m, 2H), 7.21-7.33 (m, 2H), 4.62-4.70 (m, 2H), 4.36-4.53 (m, 5H), 4.17-4.30 (m, 1H), 3.87-4.00 (m, 2H), 3.66-3.80 (m, 2H), 3.38-3.59 (m, 1H), 3.08-3.26 (m, 2H), 2.54-2.69 (m, 2H), 1.93-2.27 (m, 4H). HRMS calculated for C24H27F4N4O4 511.1968. found (ESI, [M+H]+) 511.1963. MS (ESI) m/z 511.2. (M+H)+. Retention time: 3.02 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:31])[NH:13][C:14]1[S:15][C:16]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:17]([CH3:19])[N:18]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12](=[O:31])[NH:13][C:14]1[S:15][C:16]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]([CH3:28])([CH3:27])[CH2:29][NH2:30])[CH:21]=2)=[C:17]([CH3:19])[N:18]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C(C)(C)C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C(C)(C)CN)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
LiAlH4 (1M in THF, 3.06 mL, 3.06 mmol, 1.5 eq) is added to a solution of {5-[2-(cyano-dimethyl-methyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-carbamic acid tert-butyl ester (Step 21.4) (0.73 g, 2.04 mmol) in THF (10 mL), under an argon atmosphere. The reaction mixture is stirred for 2 h at rt, quenched by addition of H2O (20 mL) and extracted with EtOAc (2×75 mL). The organic phase is washed with a saturated solution of NaHCO3 (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH/NH3aq, 99:0:1→94:5:1) to afford 318 mg of the title compound as a brown solid: ESI-MS: 363.1 [M+H]+; TLC: Rf=0.11 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J15) (290 mg, 1.0 mmol) and 3-(3-imidazol-1-yl-phenyl)-3-oxo-propionic acid tert-butyl ester (Example K16) (286 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (380 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:13])[CH3:12].Br[C:15]1[CH:16]=[C:17]([CH:21]2[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22]2)[CH:18]=[N:19][CH:20]=1.[C@H]1(N)CCCC[C@@H]1N.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I.O>[C:26]([N:23]1[CH2:24][CH2:25][CH:21]([C:17]2[CH:16]=[C:15]([N:6]3[C:5]([CH3:13])([CH3:12])[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[C:7]3=[O:11])[CH:20]=[N:19][CH:18]=2)[CH2:22]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCC(c2cncc(Br)c2)C1
Reactant: CC1(C)NC(=O)c2ccc(Cl)cc21
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCC(c2cncc(N3C(=O)c4ccc(Cl)cc4C3(C)C)c2)C1
Yield: 10 %

Procedure:
A mixture of 5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediate A-12, 160 mg, 0.82 mmol), 1-[3-(5-bromo-pyridin-3-yl)-pyrrolidin-1-yl]-ethanone (160 mg, 0.6 mmol), CuI (34 mg, 0.8 mmol), (1S,2S)-cyclohexane-1,2-diamine (41 mg, 0.36 mmol) and Cs2CO3 (390 mg, 1.2 mmol) were dissolved in dioxane (5 mL). The reaction mixture was subjected to microwave reaction at 150° C. for 2.5 hours before it was poured into H2O (50 mL) and extracted with EtOAc (25 mL×2). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by Prep-HPLC to yield the title compound (23 mg, 10%) as a white solid. MS: 384.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:30](=[O:32])[CH3:31])[CH:25]2[CH2:26][CH2:27][CH2:28]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CCC2)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)C2CCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-cyclobutylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: O=C([O-])CCCO
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCCO)OCc1ccccc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
Sodium 4-hydroxybutyrate (25 g, 0.2 mol) and benzyl bromide (37 g, 0.22 mol) were dissolved in a mixed solvent of DMF (40 ml) and ethyl acetate (50 ml), and the reaction mixture was heated and refluxed for 4 hours. Then, the reaction mixture was allowed to cool to room temperature, diluted with a proper amount of ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily product. The resulted product was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=4/1) to give 34.9 g of benzyl 4-hydroxybutyrate. Yield: 90%.