Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]1)[CH3:2].Br[C:33]1[N:37]=[C:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH:45]([CH3:47])[CH3:46])=[C:40]([Cl:48])[CH:39]=2)[S:35][N:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.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:48][C:40]1[CH:39]=[C:38]([C:36]2[S:35][N:34]=[C:33]([C:8]3[C:3]([CH2:1][CH3:2])=[C:4]([CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]4)[CH:5]=[CH:6][CH:7]=3)[N:37]=2)[CH:43]=[CH:42][C:41]=1[O:44][CH:45]([CH3:46])[CH3:47]
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Reactant: CCOC(=O)CCN1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CCC(Cc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2CC)CC1
Temperature: 120 °C
Yield: 37.4 %

Procedure:
To a solution of ethyl 3-(4-{[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinyl)propanoate (D140) (1.3 g, 3.03 mmol) in N,N-Dimethylformamide (DMF) (6 mL) and Water (1.500 mL) was added 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (1.010 g, 3.03 mmol), tripotassium phosphate (1.928 g, 9.08 mmol) and Pd(Ph3P)4 (0.350 g, 0.303 mmol). The reaction mixture was heated by Biotage Initiator to 120° C. for 20 min. The reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated and purified by ISCO column chromatography to afford ethyl 3-(4-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-1-piperidinyl)propanoate (D141) (0.63 g). MS (ES): C30H38ClN3O3S requires 555.2. found 556.2 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].ClCCl.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23].Cl>C1C=CC=CC=1.CCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
To a stirred solution of 13.43 g. (0.05 mole) of 3,5-di(t-butyl)-4-hydroxybenzoyl chloride in 50 ml. of dichloromethane is added dropwise 8.77 g. (0.12 mole) of t-butylamine. The mixture obtained is neutralized carefully with 10 percent hydrochloric acid and washed thrice with 200 ml. portions of water. The organic layer is dried, then evaporated under vacuum to provide a white residue. The residue is dissolved in hot benzene-hexane mixture and crystallized to provide 3,5-di(t-butyl)-4-hydroxy-N-t-butylbenzamide, m.p. 207°-208° C.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:27])[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:8]1.[OH-].[Na+].C(O[BH-](O[C:40](=O)[CH3:41])OC(=O)C)(=O)C.[Na+].CS(O)(=O)=O.CO[C:51](C)(C)[CH3:52]>CCCCCCC>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH:40]1([CH2:41][N:24]2[CH2:23][CH2:22][N:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:9]3[CH2:8][C:7]([CH3:27])([CH3:6])[CH2:12][C:11]([CH3:13])([CH3:14])[CH2:10]3)[CH2:26][CH2:25]2)[CH2:52][CH2:51]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: COC(C)(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Product: CC1(C)CC(c2ccccc2N2CCN(CC3CC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazine methanesulfonate (820 mg, 2.07 mmol) was suspended in t-butyl methyl ether (8.2 mL), and a 1N aqueous solution of sodium hydroxide (2.5 mL) was added thereto, followed by stirring at room temperature for 40 minutes. The organic layer was separated and washed twice with water (8 mL), and the solvent was removed under reduced pressure. To the resultant residue were added tetrahydrofuran (6.1 mL), acetic acid (0.116 mL) and cyclopropanecarbaldehyde (0.182 mL) in this order, followed by stirring at room temperature for 20 minutes. To the mixture was added sodium triacetoxyborohydride (606 mg, 2.86 mmol), followed by stirring at room temperature for 1.5 hours. To the reaction mixture were added a 1N aqueous solution of sodium hydroxide (8.1 mL) and t-butyl methyl ether (6.1 mL), followed by stirring at room temperature, and the organic layer was separated. The organic layer was washed twice with water (6 mL), and the solvent was removed under reduced pressure. To the resultant residue was added 4-methyl-2-pentanone (6 mL), followed by heating and stirring at an external temperature of 100° C. Methanesulfonic acid (0.121 mL, 1.86 mmol) was added thereto and dissolved. The mixture was further stirred at an external temperature of 100° C. for 2 minutes, heptane (3 mL) was added, and heating was stopped and stirring was carried out. The mixture was stirred at room temperature for 14 hours and the produced precipitate was collected by filtration under reduced pressure. The precipitate was washed with a mixture of 4-methyl-2-pentanone (3 mL) and heptane (3 mL), and dried under reduced pressure at 40° C. for 2 hour to give 670 mg of the title compound as white crystals (crystal α).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CCS(=O)(=O)Nc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CCS(=O)(=O)Nc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 34 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and N-(2-bromophenyl)ethanesulfonamide. MS (ESI): mass calcd. for C18H17FN4O2S, 372.11; m/z found, 372.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.43-8.36 (m, 1H), 8.04 (d, J=1.0, 1H), 7.93 (m, 1H), 7.46-7.28 (m, 6H), 6.72 (s, 2H), 2.91 (q, J=7.4, 2H), 1.07 (t, J=7.3, 3H).
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([Li])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCCCC)CCC.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C1COCC1.CO>[NH2:15][CH:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]1([N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#CC1(N(Cc2ccccc2)Cc2ccccc2)CCCC1
Reactant: [Li]c1ccccc1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Solvent: CO
Product: NC(c1ccccc1)C1(N(Cc2ccccc2)Cc2ccccc2)CCCC1
Yield: 38 %

Procedure:
The title compound (2.31 g; 38%) was prepared from 1-[bis(phenylmethyl)amino]cyclopentanecarbonitrile D32 (4.0 g; 13.8 mmol), and phenyllithium in di-n-butylether (8.4 ml of 1.8M solution; 15.2 mmol) in THF (80 ml), followed by reaction with sodium borohydride (1.57 g; 41.4 mmol) in methanol (80 ml) in a similar manner to that described in D2. Mass Spectrum (Electrospray LC/MS), API+: Found 371 (MH+). C26H30N2 requires 370. Ret. time 2.62 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[CH3:11][C:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=C.[C:19]1(C)C=CC=CC=1>>[OH:10][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:1]([CH3:19])([CH3:3])[CH2:2][C:12]2([CH3:11])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccccc1
Reactant: C=C(C)CC(C)(C)C
Reactant: C=C(C)c1ccc(O)cc1
Product: CC(C)(C)CC1(C)CC(C)(C)c2ccc(O)cc21

Procedure:
134 g (0.5 mol) of molten dimeric 4-isopropenylphenol and 120 g (1.07 mol) of diisobutylene are simultaneously added dropwise over a period of 4 hours at around 90° C to a suspension of 20 g of an acid-activated fuller's earth in 100 ml of toluene. The mixture is then left to react for another 2 hours at 90° C, after which the catalyst is filtered off and the solvent distilled off. Fractional distillation of the residue gives a fraction which distills over at 160°-170° C./12 Torr and subsequently solidifies in crystalline form. Recrystallisation from petroleum ether gives 41.2 g (34 % of the theoretical) of 5-hydroxy-1,1,3-trimethyl-3-neopentyl indane (IV) melting at 102° C. ##STR22##
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11]=1[CH2:12]O)=[CH:9][CH:8]=[CH:7][CH:6]=2.P(Br)(Br)Br.[CH3:24][NH:25][CH3:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11]=1[CH2:12][N:25]([CH3:26])[CH3:24])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: OCc1c(Cl)nc(-c2ccccc2)c2ccccc12
Reactant: CNC
Agent: BrP(Br)Br
Solvent: Cc1ccccc1
Product: CN(C)Cc1c(Cl)nc(-c2ccccc2)c2ccccc12

Procedure:
8.2 g 3-Chloro-4-hydroxymethyl-1-phenyl-isoquinoline are suspended in 300 ml toluene and 16.2 g phosphorus tribromide are added thereto while cooling with ice. After a 10 hours' stirring at room temperature dimethylamine is introduced until an alcaline reaction occurs. The reaction mixture is concentrated and water is added to the residue. Extraction with acetic acid ester gives a yellow oil, that crystallizes slowly. Melting point 75° to 77° C. Hydrochloride: 244° to 246° C.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:23]=2)=[O:20])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[CH:2]([CH3:4])[CH3:3].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:56]([NH2:60])(=[O:59])[CH:57]=[CH2:58].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH2:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:23]=2)=[O:20])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:58]=[CH:57]/[C:56]([NH2:60])=[O:59])[CH:14]=2)[CH2:9]1)[CH:2]([CH3:4])[CH3:3]
Reactant: C=CC(N)=O
Reactant: CCN(CC)c1ccc(NC(=O)C2(NC(=O)OCC(C)C)CCc3cc(Br)ccc3C2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(=O)C2(NC(=O)OCC(C)C)CCc3cc(/C=C/C(N)=O)ccc3C2)cc1
Temperature: 110 °C
Yield: 94.6 %

Procedure:
To a 10 ml pressure tube, the bromide from Example 42B (125 mg, 0.24 mmol), palladium(II)acetate (2.7 mg, 0.012 mmol), tri-o-tolylphosphine (110 mg, 0.36 mmol), acrylamide (34 mg, 048 mmol), triethylamine (0.12 ml, 0.8 mmol) and DMF (2 ml) were added. After purging with nitrogen, the reaction mixture was heated at 110° C. for overnight. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified on column of silica gel to provide the titled compound (115 mg, 95%) as a white solid. 1HNNMR (DMSO-d6, 300 MHz), δ 9.13 (b, 1H, NH), 7.45 and 7.30 (b, 2H, NH2), 7.01 (b, 1H, NH), 7.36, 7.32, 6.56 and 6.52 (AB, J=12 Hz, 2H, CH═CH), 7.32, 7.30, 6.61 and 6.58 (AB, 4H, J=9 Hz, Ar—H), 3.76–3.66 (m, 2H, OCH2), 3.27 (q, J=3.0 Hz, 4H, 2NCH2), 3.33, 3.29, 3.07 and 3.03 (AB, J=12 Hz, 2H, CH2), 2.80–2.71 (m, 2H, CH2), 2.35 and 2.09 (m, 2H, CH2), 1.79 (m, H, CH), 1.04 (t, J=3.0 Hz, 6H, 2CH3), 0.84 (d, J=6.0 Hz, 6H, 2 CH3). MS (ESI) (M+1)+ 507, (M−1)+ 505.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([CH3:15])=[O:14])=[CH:9][CH:10]=2)[C:5]([CH3:17])([CH3:16])[CH2:4][CH2:3]1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(Cl)(=O)C1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.Cl.[CH3:47][OH:48]>C(Cl)Cl>[CH3:1][C:2]1([CH3:18])[CH2:3][CH2:4][C:5]([CH3:17])([CH3:16])[C:6]2[CH:7]=[C:8]([NH:12][C:13]([C:15]3[CH:36]=[CH:37][C:38]([C:39]([O:48][CH3:47])=[O:40])=[CH:42][CH:43]=3)=[O:14])[CH:9]=[CH:10][C:11]1=2
Reactant: CO
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CC(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: -25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
First, 125 g (0.51 mole) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-acetaminonaphthalene was dissolved in 625 ml of CH2Cl2. To this solution, 206 ml of dimethylaniline and 116.6 g (0.51×1.1 mole) of phosphorus pentachloride were added in this order at -25° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1.5 hours. To this reaction mixture was added dropwise 2.06 l of methanol, after which the cooling bath was removed and the stirring of the mixture was continued for 2 hours (at -25° C. to room temperature). Furthermore, this reaction mixture was cooled to -25° C., and 306 ml of dimethylaniline and 101.1 g (1.01×0.51 mole) of terephthalic chloride were added thereto in this order. The mixture was stirred at -20° C. to -30° C. for 1 hour. After the reaction was completed, the reaction mixture was poured into 2.6 l of chilled 1N hydrochloric acid, and the mixture was extracted with 1.3 l of CH2Cl2. The CH2Cl2 layer was washed with 2.6 l of 1N hydrochloric acid, 4 l of water, 5% aqueous solution of sodium bicarbonate and 4 l of water in this order. After drying over MgSO4, the solution was evaporated to dryness. To this residue was added 740 ml methanol, and the mixture was allowed to stand overnight, resulting in 151 g (81%) of the above-described compound.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([O:15][Si](CC)(CC)CC)([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>Cl>[F:11][C:10]1[C:5]2[N:6]([C:2]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[C:25]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[CH:26]=3)=[CH:3][N:4]=2)[CH:7]=[CH:8][C:9]=1[C:12]([OH:15])([CH3:13])[CH3:14]
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2c1F
Agent: Cl
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2c1F
Reaction time: 18 h

Procedure:
3-Bromo-8-fluoro-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-α]pyridine was coupled with 4-fluoro-3-(pyridin-3-yl)phenylboronic acid as described in Example 1 and then deprotected by treatment with an ethanolic solution of 37% hydrochloric acid (5 drops in 2 ml of ethanol). After 18 h, the solution was concentrated in vacuo and purified by column chromatography on silica, to afford the title compound as a white amorphous solid: δH (360 MHz, CDCl3) 1.74 (6H, s), 7.20 (1H, t, J 7.0), 7.26-7.44 (2H, m), 7.54-7.62 (2H, m), 7.71 (1H, s), 7.90-7.93 (2H, m), 8.05 (1H, d, J 7.3), 8.65-8.66 (1H, m), 8.85 (1H, s); m/z (ES+) 366 (100%, [MH]+).
Reaction SMILES: [OH-].[Na+].COCCO.[Br:8][C:9]1[C:10](/[C:23](/[CH3:36])=[CH:24]/[C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=2)=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1>CCOCC>[Br:8][C:9]1[C:10](/[C:23](/[CH3:36])=[CH:24]/[C:25]2[CH:35]=[CH:34][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:19])([CH3:20])[C:17]=2[CH:18]=1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2Br)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of sodium hydroxide, 2-methoxyethanol and ether was added to 50 mg (0.11 mmol) of ethyl 4-[(E)-2-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphtha-len-2-yl)propen-1-yl]benzoate (Compound 14) and the resulting mixture stirred at room temperature for 17 hours. Solvent was removed in-vacuo and the resulting solid taken-up in water, acidified using 2N HCl, and extracted with ether. The ether extracts were washed with water, brine and dried (MgSO4). The solvent was removed in-vacuo to give the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=O)[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(OP(Cl)(OCC)=O)C.[CH2:40]([N:42](CC)[CH2:43]C)C.Cl.CNC>O1CCCC1>[CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([N:42]([CH3:43])[CH3:40])=[O:25])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCN(CC)CC
Reactant: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: CCOP(=O)(Cl)OCC
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccccc1CC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reaction time: 20 h

Procedure:
A mixture of 0.836 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid, 0.38 g of diethylchlorophosphate, 2.2 g of triethylamine, 1.8 g of dimethylamine hydrochloride and 25 ml of tetrahydrofuran was stored at room temperature for 20 hr. The solvent was removed in vacuo and the residual materials were taken up in 100 ml of methylene chloride and then washed with water (3×30 ml), dried (MgSO4) and the solvent removed in vacuo. The residual materials were crystallized from ethanol to yield (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]-N,N-dimethylbenzamide as an off-white colored solid, m.p. 125°-127° C. Anal. Calcd for C26H27N3O2S: C, 70.09; H, 6.11; N, 9.43. Found: C, 69.92; H, 6.25; N, 9.42.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1.[Br:13]N1C(=O)CCC1=O.Br>Br.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH:4]([Br:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccc(Cl)c1
Agent: Br
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Br)c1cccc(Cl)c1
Yield: 68.5 %

Procedure:
A mixture of (3-Chloro-phenyl)-acetic acid methyl ester (2.0 g, 10.8 mmol), N-bromosuccinimide (1.95 g, 11.0 mmol) and 3 drops of hydrobromic acid (48% solution) in chloroform (100 mL) was heated under reflux for three days. Additional amounts of N-bromosuccinimide and hydrobromic acid were added to drive the reaction to completion. The reaction mixture was concentrated to dryness, taken up in methylene chloride and loaded onto a column of silica gel. Elution with 10% ethyl acetate/hexanes gave Bromo-(3-chloro-phenyl)-acetic acid methyl ester (1.95 g, 69% yield) as a colorless oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[C:33]([O-:41])(=[O:40])[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.[Cs+].O>C(#N)C>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:41][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: O=C([O-])c1ccncc1
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)OC(=O)c1ccncc1
Temperature: 25 °C
Yield: 83 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (0.40 g, 0.81 mmol) and cesium isonicotinate (0.42 g, 1.64 mmol) in acetonitrile (20 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 83%. 1H NMR (400 MHz, DMSO-d6): δ 8.78-8.74 (m, 2H), 7.85 (dd, 1H), 7.79 (dd, 1H), 7.40-7.35 (m, 1H), 7.31 (t, 1H), 7.21-7.17 (m, 1H), 7.01-6.94 (m, 1H), 4.79-4.72 (m, 1H), 4.12-4.00 (m, 2H), 3.91-3.84 (m, 1H), 3.78-3.73 (m, 1H), 3.36-3.26 (m, partially obscured by water, 2H), 3.17-3.11 (m, 1H), 3.07-3.03 (m, 2H), 2.40 (d, 3H), 2.15-2.04 (m, 2H), 2.00-1.97 (m, 2H) 1.59 (dd, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:9](=O)[CH2:10][CH:11]([CH3:13])[CH3:12].C(O)(=O)C>O>[CH3:12][CH:11]([CH3:13])[CH2:10][CH:9]=[C:4]1[CH2:5][CH2:6][CH2:7][C:3]1=[O:8]
Reactant: CC(C)CC=O
Reactant: O=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CC=C1CCCC1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Water (1.9 L) and sodium hydroxide (NaOH, 40 g, 50% caustic) were charged in a flask and heated to 80° C. A premix of cyclopentanone (840 g, 10 mol) and isovaleraldehyde (1.05 Kg, 12 mol) was slowly fed for over 5 hours. The reaction mixture was aged at 80° C. for another 30 minutes, cooled to room temperature, and quenched with acetic acid (120 g, 2 mol). A rushover process provided the crude product 2-[3-methyl-butylidene]-cyclopentanone.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]([CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]2)=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C.CCCCCC.Cl>C1(C)C=CC=CC=1>[F:25][C:22]([F:23])([F:24])[C:10]1[CH:11]=[C:12]([CH2:13][NH2:14])[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C(F)(F)F)cc2CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: NCc1cc(C(F)(F)F)n[nH]1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl (1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (20 g, 0.052 mol) in toluene (300 mL) cooled to 0° C. was added aluminum chloride (17.34 g, 0.129 mol) portion wise for 30 min. The reaction mixture was slowly heated to 50-60° C. and allowed to stir for 2 h at the same temperature. Progress of the reaction was monitored by TLC (20% ethyl acetate/hexane, Rf˜0.1). On completion of the reaction, the reaction contents were treated with diluted HCl, ice cold water (300 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The aqueous layer was basified with sodium hydroxide solution and extracted with ethyl acetate and dried over sodium sulfate and concentrated under reduced pressure to give (3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine as a brown colored solid (4.6 g, crude). The crude product obtained was used directly for the next step.