Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]=[C:9]=[O:10])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:30][C:31]([NH2:35])=[N:32]2)=[CH:27][CH:26]=1>CN(C=O)C>[NH2:35][C:31]1[CH:30]=[C:29]([N:36]2[CH2:37][CH2:38][N:39]([C:9]([NH:8][C:7]3[C:2]([F:1])=[C:3]([F:14])[C:4]([F:13])=[C:5]([F:12])[C:6]=3[F:11])=[O:10])[CH2:40][CH2:41]2)[C:28]2[C:33](=[CH:34][C:25]([Cl:24])=[CH:26][CH:27]=2)[N:32]=1
Reactant: O=C=Nc1c(F)c(F)c(F)c(F)c1F
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)Nc3c(F)c(F)c(F)c(F)c3F)CC2)c2ccc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of pentafluorophenyl isocyanate (0.03 mL, 0.23 mmol) and iPr2NEt (0.05 mL, 0.29 mmol) in DMF (1 mL), a hot solution of 7-chloro-4-(1-piperazinyl)-2-quinolinamine (50 mg, 0.19 mmol) in DMF (2 mL) was added. After stirring at rt overnight, the mixture was poured into ice-water. The solid was collected by filtration and re-dissolved in CH2Cl2-MeOH, then purified by preparative TLC (CH2Cl2-MeOH, 9:1) affording the product as a light yellow solid. LC-MS: 472 (M++1). 1HNMR (DMSO-d6) δ 3.02 (br.s, 4H), 3.70 (br.s, 4H), 6.28 (s, 1H), 6.50 (s, 2H), 7.10 (d, 1H), 7.39 (s, 1H), 7.78 (d, 1H), 8.80 (s, 1H).
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:11]=[CH:12][CH:13]=O.[C:19]([CH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)=[O:23])#[N:20]>C(O)C>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][NH:24][C:22](/[C:21](=[CH:13]/[CH:12]=[CH:11]/[C:10]1[CH:15]=[CH:16][C:17]([OH:18])=[C:8]([OH:7])[CH:9]=1)/[C:19]#[N:20])=[O:23]
Reactant: O=CC=Cc1ccc(O)c(O)c1
Reactant: N#CCC(=O)NCc1cccc(F)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#C/C(=C\C=C\c1ccc(O)c(O)c1)C(=O)NCc1cccc(F)c1

Procedure:
The compound was prepared as described in Example 37 by adding piperidine to a solution of 3,4-dihydroxycinnamaldehyde (35 mg, 0.2 mmol) and 2-cyano-N-(3-fluorobenzyl)acetamide (38 mg, 0.2 mmol) in ethanol. After recrystallization from ethanol-water a yellow solid was obtained (51 mg, 75%). The product gave the following analytical data:
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][OH:5].C(O)CCCCCCCCC/C=C\CC.Br[C:33]1[O:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][CH:34]=1.ClC1OC(C(O)=O)=CC=1>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][O:5][C:33]1[O:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CC(C)CCCC(C)CCCC(C)CCO
Agent: CC/C=C\CCCCCCCCCCO
Agent: O=C(O)c1ccc(Cl)o1
Product: CC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)O)o1

Procedure:
In the procedure of Example 4(A), 3,7,11-trimethyldodecanol was substituted for cis-11-tetradecenol and 5-bromo-2-furoic acid substituted for 5-chloro-2-furoic acid to yield 5-(3,7,11-trimethyldodecyloxy)-2-furancarboxylic acid, M.P. 70°-73° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]>CC(N(C)C)=O>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[CH:15][CH:16]=[C:7]([CH2:6][N:1]=[N+:2]=[N-:3])[CH:8]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cccc(CN=[N+]=[N-])c1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
Add sodium azide (0.3 g, 4.8 mmol) to a solution of methyl 3-bromomethylbenzoate (1.00 g, 4.4 mmol) in 10 mL of dimethylacetamide. Stir at room temperature for several h, pour mixture into ice water and extract with EtOAc. Wash combined extracts 4 times with H2O, brine and dry over sodium sulfate. Filter the mixture and concentrate to afford 0.81 g, 97% yield of 3-azidomethyl-benzoic acid methyl ester as an oil.
Reaction SMILES: Cl[C:2]1C=CC(C2N=C(C(C)(C)CNC)NC=2C2C=CN=CC=2)=CC=1O.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:34]=[C:35]([C:44]([CH3:60])([CH3:59])[CH2:45][NH:46][C:47]([N:49]3[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][O:57][CH3:58])[CH2:51][CH2:50]3)=[O:48])[NH:36][C:37]=2[C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)=[CH:29][C:28]=1[OH:61]>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:34]=[C:35]([C:44]([CH3:59])([CH3:60])[CH2:45][N:46]([CH3:2])[C:47]([N:49]3[CH2:50][CH2:51][N:52]([CH2:55][CH2:56][O:57][CH3:58])[CH2:53][CH2:54]3)=[O:48])[NH:36][C:37]=2[C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)=[CH:29][C:28]=1[OH:61]
Reactant: COCCN1CCN(C(=O)NCC(C)(C)c2nc(-c3ccc(Cl)c(O)c3)c(-c3ccncc3)[nH]2)CC1
Reactant: CNCC(C)(C)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Product: COCCN1CCN(C(=O)N(C)CC(C)(C)c2nc(-c3ccc(Cl)c(O)c3)c(-c3ccncc3)[nH]2)CC1
Yield: 41 %

Procedure:
The title compound (170 mg, 41%) was prepared from the product of Example 52 and the product of Example 49 Step 1 using the method described in Example 49 Step 2; MS(ES+) m/e 527/529 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl.CO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Reactant: NCc1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Fc1nc(NCc2ccncc2)c2nc[nH]c2n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
To a stirred solution of 6-chloro-2-fluoro-9H-purine (0.9 g, 5.22 mmol) in BunOH (60 mL) under Ar, cooled to −20° C., was added Pri2NEt (2.5 mL, 14.35 mmol) followed by 4-(aminomethyl)pyridine (0.58 mL, 5.69 mmol). The reaction mixture was stirred at-20° C. for 3 h, and then allowed to return to RT over 2 h and stirred at RT for a further 48 h, when TLC (9:1 CHCl3/MeOH) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3/MeOH (100:0→90:10), to afford the title compound as a white solid (0.69 g, 54%). Mp>340° C. 1H-NMR (d6-DMSO, 250 ME): δ 4.67 (d, 2H, J=6.35 Hz, —HNCH2-Pyr), 7.34, 8.50 (2×m, 4H, Pyr), 8.14 (s, 1H, —N═CH—NH—), 8.84 (bs, 1H, —HNCH2-Pyr), 13.13 (bs, 1H, —N═CH—NH—). FAB-MS m/z (relative intensity): 245 ([M+H]+, 27), 176 (15), 154 (100), 136 (77). Accurate Mass (M+H): Actual: 245.0951, Measured: 245.0942. Microanalysis (Expected:Measured) C11H9N6F.0.6H2O: C, 51.80:52.08; H, 4.03:3.84; N, 32.95:31.29.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[C:19]2[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=2[N:21]=[CH:22][N:23]=1>CS(C)=O.O>[CH3:32][Si:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][O:28][CH2:27][N:24]1[C:20]2[N:21]=[CH:22][N:23]=[C:18]([O:1][C@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)[C:19]=2[CH:26]=[CH:25]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.6 %

Procedure:
To a solution of (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0.4 g, 2.0 mmol) in DMSO (5 mL) under nitrogen, was added NaH (60% suspension in mineral oil, 79 mg, 2.0 mmol). After the reaction was stirred for 1.5 h at rt, a solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (564 mg, 2.0 mmol) in DMSO (5 mL) was added dropwise at rt and the mixture was heated at 50° C. for 2 h. The reaction mixture was cooled to rt, diluted with water (10 mL) and extracted with EtOAc (4×60 mL). The combined organic layer was washed with water (50 mL), dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography (silica gel, gradient EtOAc in Hexanes) to give (750 mg, 85%) of the titled intermediate.
Reaction SMILES: [O-]CC.[Na+].C([O:7][C:8](=O)[CH:9]([CH:16]=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])C.[NH2:19][C:20]([NH2:22])=[S:21].C(O)(=O)C>C(O)C>[O:7]=[C:8]1[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][NH:22][C:20](=[S:21])[NH:19]1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(C=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c[nH]c(=S)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
Sodium ethoxide (6.105 g, 89.71 mmol) was added to absolute ethanol (150 mL) under an atmosphere of nitrogen followed by diethyl-2-formylsuccinate (1105) (crude, 16.5 g) in absolute ethanol (30 mL) and thiourea (6.829 g, 89.71 mmol). The reaction mixture was heated at reflux for 1 hour then cooled to room temperature at which stirring was continued for 16 hours. The volatiles were evaporated under reduced pressure to give a brown oily solid. Cold aqueous acetic acid solution (15%; 120 mL) was added and the resulting mixture was sonicated and then stirred at 0° C. until all the residue was in suspension. The resulting precipitate was collected by filtration. The filter cake was washed with water (100 mL) and dried to give the title compound (I106) (6.31 g, 19% yield over 2 steps) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 7.44 (s, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.28 (s, 2H), 1.17 (t, J=7.1 Hz, 3H). LCMS Method C: rt 2.92 min; m/z 213.0 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH3:15][S:14][C:10]1[N:9]=[C:8]([C:7]2[C:2]([O:23][C:20]3[CH:21]=[CH:22][C:17]([NH2:16])=[CH:18][CH:19]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Nc1ccc(O)cc1
Reactant: CSc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Temperature: 130 °C

Procedure:
A resealable pressure bottle was charged with 4-(2-chloropyridin-3-yl)-2-(methylthio)pyrimidine (2.85 g, 12.00 mmol), 4-aminophenol (1.44 g, 26.5 mmol), and cesium carbonate (1.44 g, 13.20 mmol). These reagents were suspended in DMSO (24 ml, 0.50 M), and the vessel was sealed and mixture heated to 130° C. for 48 h. The reaction mixture was allowed to cool to RT, diluted with water and extracted with ethyl acetate. The organic layer was collected, dried with Na2SO4, filtered, and concentrated to give light brown residue, which was purified by silica gel chromatography (ISCO, 10% to 50% Ethyl Acetate/Hexanes) to afford 4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)benzenamine as a light yellow solid. MS m/z=311 [M+H]+. Calc'd for C16H14N4OS: 310.37.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:17]([NH2:18])=[N:16][C:10]2[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=2[CH:8]=1.[C:20]([N:24]=[C:25]=[O:26])([CH3:23])([CH3:22])[CH3:21].N>C>[NH2:15][C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:19])[C:17]([NH:18][C:25]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[N:16][C:10]=2[N:11]=1
Reactant: CC(C)(C)N=C=O
Reactant: Cc1ccccc1-c1cc2cnc(N)nc2nc1N
Agent: C
Agent: N
Product: Cc1ccccc1-c1cc2cnc(N)nc2nc1NC(=O)NC(C)(C)C

Procedure:
The title compound was prepared from 6-o-tolyl-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 90 and tert-butyl isocyanate according to Example 2. The product was purified by MPLC eluting with CHCl3 :EtOAc (1:1) afford the pure product; mp 195-197° C., CIMS (1% ammonia in methane): m/z (relative intensity) 351 (MH+ +1, 55), 352 (MH+ +2, 12), 84 (100).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[C:14]([O:18][C:19]([N:21]1[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][C@H:22]1[CH:23]=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].O>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][C@H:22]1[CH:23]([OH:24])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
2.0M Phenylmagnesium bromide-tetrahydrofuran solution (22.8 ml, 45.6 mmol) was added dropwise to a solution of (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (10 g, 30.4 mmol) in tetrahydrofuran (200 ml) at -78° C. in a nitrogen stream. The reaction solution was allowed to gradually warm and then stirred at room temperature for 3 hours. After addition of water, this reaction solution was concentrated in vacuo. The resulting residue was poured into a liquid mixture of ethyl acetate with water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The resulting oily residue was subjected to silica gel column chromatography (Wakogel™ C-300 heptane:ethyl acetate 4:1) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(α-hydroxybenzyl)pyrrolidine (11.98 g, yield: 96.8%) as a colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[O:11][N:10]=2)=[C:5]([F:17])[CH:4]=1)#[N:2].[C:18]([C:22]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([NH:33][CH:34]3[CH2:36][CH2:35]3)[CH2:29][CH2:28]2)[O:24][N:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[N:26]=[C:25]([N:27]2[CH2:28][CH2:29][CH:30]([N:33]([CH:34]3[CH2:36][CH2:35]3)[C:14]([C:12]3[O:11][N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[F:17])[CH:13]=3)=[O:16])[CH2:31][CH2:32]2)[O:24][N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: N#Cc1ccc(-c2cc(C(=O)O)on2)c(F)c1
Product: CC(C)(C)c1noc(N2CCC(N(C(=O)c3cc(-c4ccc(C#N)cc4F)no3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 3-(4-cyano-2-fluoro-phenyl)-isoxazole-5-carboxylic acid and [1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-cyclopropyl-amine following a procedure analogous to that described in Example 18. LC (method 18): tR=1.29 min; Mass spectrum (ESI+): m/z=479 [M+H]+.
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.[CH2:20]=[CH:21][CH:22]=[CH2:23]>C(OCC)(=O)C>[C:16]([C:7]1[C:8](=[O:15])[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]2([CH2:23][CH2:22][CH:21]=[CH:20][CH2:4]2)[CH:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC=C
Solvent: CCOC(C)=O
Product: CC(C)(C)C1=CC2(C=C(C(C)(C)C)C1=O)CC=CCC2
Yield: 100 %

Procedure:
Following the same general procedure as in Example I, 20 mmols of N,N-dimethyl-4-aminomethyl-2,6-di-t-butylphenol were reacted with approximately 222 mmols of 1,3-butadiene in 47 g of ethyl acetate at about 190° C. for 10 hours. As determined by GC analysis, the process resulted in a 100% yield of 2,4-di-t-butylspiro[5.5]undeca-1,4,8-trien-3-one.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8]2)C=C.O.C(OCC)(=O)C.CN(C)[C:27]1[CH:32]=CC=C[CH:28]=1>>[CH2:32]([C:6]1[C:5]([OH:4])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10]([CH3:16])([CH3:17])[C:11]2=[O:15])[CH:27]=[CH2:28]
Reactant: C=CCOc1ccc2c(c1)CCC(C)(C)C2=O
Reactant: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCc1c(O)ccc2c1CCC(C)(C)C2=O
Temperature: 25 °C

Procedure:
1.69 g of 6-(allyloxy)-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one was dissolved in 10 ml of N,N-dimethylaniline, and the obtained mixture was heated to reflux under nitrogen atmosphere for 7 hours. The reaction solution was cooled to a room temperature. Water and ethyl acetate were added to the reaction solution, so as to obtain an organic layer. The obtained organic layer was successively washed with 5 N hydrochloric acid (3 times), water (4 times), and a saturated sodium chloride solution. The resultant product was then dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. Hexane was added to the residue, and the precipitate was then collected by filtration, so as to obtain 1.06 g of the subject compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:24]=[C:23]([Cl:25])[S:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>>[Br:19][C:20]1[CH:24]=[C:23]([Cl:25])[S:22][C:21]=1[S:26]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1sc(Cl)cc1Br
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1sc(Cl)cc1Br

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene 1,2-diamine was reacted with 3-bromo-5-chlorothiophene-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.41 (dd, J=2.1 & 10.5 Hz, 1H), 7.35 (br m, 2H), 7.31 (dd, J=2.1 & 4.2 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.08 (dd, J=9.0 & 17.4 Hz, 1H), 6.02 (dt, J=2.1, 8.4 & 17.1 Hz, 1H), 5.59 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:26][C:27]2[N:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH:29]=O)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23].COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:29][C:28]2[C:27]([NH:26][C:18]3[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=3)=[N:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: COc1cc(Nc2ncccc2C=O)cc(OC)c1OC
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2cccnc2Nc2cc(OC)c(OC)c(OC)c2)cc1OC
Reaction time: 0.08 h
Yield: 81.7 %

Procedure:
To a solution of 3,4-dimethoxyacetophenone (124 mg, 0.692 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then 2-(3,4,5-trimethoxyphenylamino)nicotinaldehyde (200 mg, 0.692 mmol) added and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h then reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6w) (254.7 mg, 82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.FC(F)(C(F)(F)F)C([O:32][C:33](=O)[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=O>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([NH:16][C:33](=[O:32])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: N[C@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(N[C@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)C(F)(F)C(F)(F)F
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
To a solution of (R)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (15 mg, 0.038 mmol), prepared by method described in Procedures 5, 6 and 7, in anhydrous DCM (0.5 mL), was added pyridine (1 drop) and 2,2,3,3,3-pentafluoropropanoic anhydride (14 mg, 0.040 mmol) at room temperature. The reaction mixture was stirred for 5 mins and the solvents removed under a stream of nitrogen. The resulting residue was diluted with MeOH (0.5 mL) and purified by preparative HPLC (YMC Sunfire 30×100 mm column, eluting with 10-90% MeOH/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm); (R)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-2,2,3,3,3-pentafluoropropanamide (13.4 mg, 65% yield) was isolated as a colorless oil at a retention time of 12.44 min. LCMS: RT=2.12 min [M+H] 541.21 (LCMS Method 2); HPLC: RT=4.28 min, Purity 98% (HPLC Method 1) NMR: 400 MHz 1H (CDCl3) 9.60 ppm, 1 H, s; 8.36 ppm, 1 H, s; 7.75 ppm, 1H, d, J=8.0 Hz; 7.44 ppm, 1H, s; 7.34 ppm, 1H, d, J=8.0Hz; 7.30 ppm, 1H, d, J=8.0 Hz; 7.09 ppm, 4 H, m; 6.53 ppm, 2H, d, J=4.0 Hz; 3.38 ppm, 1H, d, J=12.0 Hz; 3.65 ppm, 1H, d, J=12.0 Hz.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])[N:3]=[CH:4][CH:5]=1.N1(C2C=CC(C(F)(F)F)=CC=2C(O)=O)C=CN=N1.N1NN=CC=1.[Cl:42]C1C=CC(I)=C(C=1)C(O)=O>>[Cl:42][C:12]1[CH:13]=[CH:14][C:6]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1I
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1-n1nccn1
Agent: O=C(O)c1cc(C(F)(F)F)ccc1-n1ccnn1
Agent: c1cn[nH]n1
Product: O=C(O)c1cc(Cl)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37a) and 2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37b) from 2H-1,2,3-triazole (CAS number 288-36-8; 1.0 g, 10.86 mmol) and 5-chloro-2-iodobenzoic acid (CAS number 13421-00-6; 2.00 g, 7.24 mmol). The crude solid was purified by column chromatography (silica, 0-3% methanol/DCM) to afford 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 38a; also commercially available CAS number 1293284-54-4). The mixed fractions were further purified by column chromatography (silica, 0-3% methanol/DCM) to afford 5-chloro-2-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 38b).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:3]1=2.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:39])C(=O)C1.O>C(Cl)(Cl)(Cl)Cl>[Br:39][CH2:12][C:10]1[CH:9]=[CH:8][C:4]2[B:5]([OH:7])[O:6][C:2]([CH3:13])([CH3:1])[C:3]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)C(C)(C)OB2O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(O)c2ccc(CBr)cc21
Temperature: 25 °C
Yield: 62.2 %

Procedure:
To a solution of 3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (5.0 g, 28.4 mmol) in CCl4 (50 mL) at rt was added benzoyl peroxide (0.7 g, 2.8 mmol) following by NBS (5.0 g, 28.4 mmol). The reaction mixture was refluxed overnight, cooled to rt and treated with water. The aqueous layer was extracted with EA (20 mL×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the product (4.5 g, yield 62%) as yellow oil. MS: 255 & 257 [M+H]+.