Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N2C3C(=NC(OC)=CC=3)C(NC(=O)C)CC2C)CCCC1.[CH:23]([O:26][C:27]([N:29]1[CH:38]([CH2:39]C)[CH:37]([CH3:41])[CH:36]([NH:42][C:43]2[CH:44]=[N:45][C:46]3[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=3[CH:52]=2)[C:35]2[N:34]=[C:33]3[CH2:53][CH2:54][CH2:55][CH2:56][C:32]3=[CH:31][C:30]1=2)=[O:28])([CH3:25])[CH3:24].[F:57][C:58]([F:72])([F:71])[C:59]1[CH:60]=[C:61]([CH:64]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:66]=1)[CH2:62]Br.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH:23]([O:26][C:27]([N:29]1[CH:38]([CH3:39])[CH:37]([CH3:41])[CH:36]([N:42]([CH2:62][C:61]2[CH:64]=[C:65]([C:67]([F:69])([F:70])[F:68])[CH:66]=[C:59]([C:58]([F:57])([F:71])[F:72])[CH:60]=2)[C:43]2[CH:44]=[N:45][C:46]3[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=3[CH:52]=2)[C:35]2[N:34]=[C:33]3[CH2:53][CH2:54][CH2:55][CH2:56][C:32]3=[CH:31][C:30]1=2)=[O:28])([CH3:24])[CH3:25]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCC1C(C)C(Nc2cnc3c(c2)CCCC3)c2nc3c(cc2N1C(=O)OC(C)C)CCCC3
Agent: COc1ccc2c(n1)C(NC(C)=O)CC(C)N2C1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)OC(=O)N1c2cc3c(nc2C(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cnc4c(c2)CCCC4)C(C)C1C)CCCC3
Yield: 20 %

Procedure:
Prepare the title compound by essentially following the procedure described in Example 49, Step 2, by replacing (+/−)-N-(1-cyclopentyl-6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]napthyridin-4-yl)-acetamide, with 2-ethyl-3-methyl-4-(5,6,7,8-tetrahydro-quinolin-3-ylamino)-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,5]napthyridine-1-carboxylic acid isopropyl ester (0.175 g, 0.378 mmol), and using 3,5-bis trifluoromethyl benzyl bromide and lithium hexamethyldisilazide. Purify using silica gel column chromatography (gradient eluent, 50:50 ethyl acetate in hexane) to afford the title compound (0.052 g, 20%). MS (ES+): 689 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:31]5[C:26]([C:25]([F:36])([F:35])[F:24])=[N:27][CH:28]=[CH:29][CH:30]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: OB(O)c1cccnc1C(F)(F)F
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccnc3C(F)(F)F)cc1-2
Yield: 25 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-(trifluoromethyl)pyridin-3-ylboronic acid were reacted to give 265 (0.058 g, 25%). 1H NMR (400 MHz, DMSO) δ 9.30 (d, J=2.2, 1H), 8.28 (d, J=8.0, 1H), 8.19 (t, J=7.9, 1H), 8.12 (s, 1H), 8.04 (dd, J=8.5, 2.3, 1H), 7.82 (t, J=17.9, 1H), 7.23 (d, J=8.5, 1H), 5.93 (dt, J=13.2, 6.7, 1H), 4.45 (t, J=4.9, 2H), 3.50 (t, J=4.8, 2H), 1.57 (d, J=6.6, 6H). MS (ESI(+)): m/z 458.1 (M+H)
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([CH3:16])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:3]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([CH3:16])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:3]1=[S:32]
Reactant: CCOC(=O)c1c(C)c2ccc(C(F)(F)F)cc2n(C)c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)c2ccc(C(F)(F)F)cc2n(C)c1=S
Temperature: 120 °C
Yield: 80 %

Procedure:
A solution of 460 mg (1.5 mmol) ethyl 1,4-dimethyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylate in toluene (10 ml) was treated with 2.4 g (5.9 mmol) Lawesson's reagent at RT, followed by heating to 120° C. for 16 h. After cooling to RT the RS was quenched with a sat. aq. Na2CO3 solution (30 ml). The mixture was then extracted with EtOAc (3×30 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. CC (EtOAc/hexane 1:4) of the residue provided 400 mg (1.2 mmol, 82%) ethyl 1,4-dimethyl-2-thioxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylate.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1)C.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([CH:21]([NH2:23])[CH3:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:13][C:11]1[CH:10]=[C:9]([NH:23][CH:21]([CH3:22])[C:20]2[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:8]=[C:7]([S:6][CH2:5][C:4]([OH:3])=[O:15])[N:12]=1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Reactant: CC(N)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(Nc1cc(Cl)nc(SCC(=O)O)n1)c1ccc(Cl)cc1

Procedure:
A stirred mixture of 2.7 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 1.6 g of p-chloro-α-methylbenzylamine and 1.1 g of sodium carbonate in 120 ml. ethanol was heated under reflux for 2 hr. The reaction mixture was filtered and the filtrate taken to dryness in a rotary evaporator in vacuo. The residual oil was treated with 100 ml. of 30% sodium hydroxide solution containing a few ml. of ethanol. After a few minutes the clear solution was acidified with concentrated hydrochloric acid and the mixture thus formed was extracted with ether (3 × 50 ml.). The ether solution was dried over magnesium sulfate, filtered and the filtrate evaporated to dryness. The residue was dissolved in 50 ml. of benzene and petroleum ether was added until the solution became cloudy. On cooling in ice a precipitate was deposited. Recrystallization of this material from 50% aqueous ethanol afforded the product, mp. 155°-160°C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:16]/[S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1ccc(Br)cc1
Reaction time: 24 h
Yield: 97.2 %

Procedure:
To a solution of 2.0 g (10 mmol) 4-bromobenzaldehyde in 20 ml CH2Cl2 at rt was added 1.3 g (10 mmol) (S)-(−)-2-methylpropane-2-sulfinamide and 2.4 g (10 mmol) copper (II) sulfate. After 24 h at room temperature, the reaction mixture was filtered through celite and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 0-40% EtOAc:hexane) afforded 2.8 g (90%) N-[(1E)-(4-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide. ES-MS [M+1]=289.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][CH2:11][CH2:10][C:9]#[C:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCC#Cc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCC#Cc2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
5-(4-Chlorophenyl)pent-4-yn-1-ol (35.7 g, 182 mmol), 4-dimetylamino- pyridine (8.9 g, 73 mmol), p-toluenesulfonyl chloride (34.7 g, 182 mmol), and 62 ml of triethylamine were combined in 330 ml of dichloromethane at 0° C. The mixture was stirred for 30 min. at 0° then 18 hours at room temperature. Dilution with 200 ml of dichloromethane followed by washing with brine, drying over magnesium sulfate, filtration through silica gel with hexane-ethyl acetate, 8:1, gave a yellow solid on evaporation. Crystallization from ether gave 5-(4-Chlorophenyl)pent-4-yn-1-ol p-toluenesulfonate as colorless crystals (31.7 g, 49% yield). This was converted to the title compound by reaction with sodium iodide in acetone, and was used in subsequent reactions with no further purification; MS m/z 303.9.
Reaction SMILES: [C:1]([N:11]([CH3:22])[C@H:12]([C:19]([OH:21])=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:23][C@H:24]([C:37]([NH2:39])=[O:38])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([N:11]([CH3:22])[C@H:12]([C:19]([NH:23][C@H:24]([C:37]([NH2:39])=[O:38])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([C:33]([CH3:36])([CH3:34])[CH3:35])[CH:27]=1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O
Reactant: CN(C(=O)OCc1ccccc1)[C@H](C(=O)O)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)[C@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of 3.28 g (11.0 mmol) of Z-N-Me-Phg-OH, 2.16 g (9.17 mmol) of Tyr(3-tBu)-NH2 and 1.40 g (9.17 mmol) of HOBT in 60 ml of DMF, 1.42 ml (9.17 mmol) of DIC was added dropwise under cooling with ice and the mixture was stirred for 4 hours under cooling with ice. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of methylene chloride, methanol and aqueous ammonia at a ratio of 100:5:1) to give Z-N-Me-Phg-Tyr(3-tBu)-NH2 in the amount of 4.03 g (85%).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17]([C@@H:19]3[CH2:23][C@@H:22]([F:24])[CH2:21][N:20]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[F:24][C@H:22]1[CH2:21][N:20]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C@H:19]([C:17](=[O:18])[NH:16][C@@H:13]2[C@@H:11]3[C@@H:10]([CH2:9][NH:8][CH2:12]3)[CH2:15][CH2:14]2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: [H][H]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21

Procedure:
To a solution of (2S,4R)-tert-butyl 2-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate (4.59 g, 10.64 mmol) from Step 1 in ethanol (45 mL) was added to 20% Pd(OH)2—C, wet (0.918 g, 6.54 mmol) in a 250 mL stainless steel pressure bottle. The mixture was shaken under 30 psi of hydrogen at 50° C. for 45 minutes. The mixture was filtered through a nylon membrane and the solvent removed in vacuo to give (2S,4R)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate: 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 7.87 (s, 1H), 5.21 (dd, J=53.6, 3.0, 1H), 4.61 (t, J=7.8, 1H), 4.24-4.14 (m, 1H), 3.91 (dd, J=11.6, 3.1, 2H), 3.66 (ddd, J=34.5, 12.8, 3.6, 1H), 3.15-3.05 (m, 2H), 2.96 (dd, J=10.7, 7.3, 1H), 2.68 (dd, J=10.7, 3.7, 1H), 2.64-2.57 (m, 1H), 2.57-2.31 (m, 3H), 2.10-2.00 (m, 1H), 1.95-1.85 (m, 1H), 1.70-1.58 (m, 1H), 1.49 (s, 9H), 1.41-1.30 (m, 1H); MS (ESI+) m/z 342 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][CH:8]([CH3:17])[CH:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>ClC1C=CC=CC=1Cl>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]([CH3:17])[N:7]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CC(NC(=O)c1cccc(I)c1)C(O)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1cc2ccccc2c(-c2cccc(I)c2)n1
Temperature: 25 °C
Yield: 62 %

Procedure:
A mixture of amide 3b, 11.54 g, 30.3 mmol) and P2O5 (43 g) in o-dichlorobenzene (150 mL) was refluxed for 20 h. After it was cooled to room temperature, it was cooled to 0° C. by application of an external ice-water bath. To this cooled mixture was cautiously added 300 mL of H2O. After the vigorous reaction had subsided, the dark solution was washed with toluene (2×50 mL). The aqueous layer was cooled to 0° C. and made to pH >11 with 50% aqueous NaOH. The resulting mixture was extracted with toluene (4×50 mL). The organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from benzene, thereby affording a white solid (6.5 g, 62%) mp 77-78° C. 1H NMR (CDCl3) d 2.72 (s, 3 H, CH3), 7.23 (t, J=7.8 Hz, 1 H, aromatic), 7.40-7.52 (m, 2 H, aromatic), 7.57-7.66 (m, 2 H, aromatic), 7.71-7.85 (m, 2 H, aromatic), 7.92 (d, J=8.7 Hz, 1 H, aromatic), 8.02 (s, 1 H, aromatic). 13C NMR (CDCl3) d 24.31 (q, CH3), 94.31 (s, =CI--, aromatic), 118.36 (d, aromatic), 126.39 (d, 2C, aromatic), 126.92 (d, aromatic), 129.08 (d, aromatic), 129.83 (d, aromatic), 129.99 (d, aromatic), 137.34 (d, aromatic), 137.47 (s, aromatic), 138.53 (d, aromatic), 141.70 (s, aromatic), 150.80 (s, aromatic), 158.36 (s, =CCH3 --, aromatic). Anal. Calcd for C16H12IN: C, 55.67; H, 3.50; N, 4.06. Found: C, 55.53; H, 3.56; N, 4.05.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([C:10]2[C:11]([F:17])=[N:12][C:13]([F:16])=[CH:14][CH:15]=2)[OH:9])[CH:7]=1.N1C=CN=C1.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].O>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([O:9][Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30])[C:10]2[C:11]([F:17])=[N:12][C:13]([F:16])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(Br)cc1C(O)c1ccc(F)nc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COc1ccc(Br)cc1C(O[Si](C)(C)C(C)(C)C)c1ccc(F)nc1F
Temperature: 70 °C

Procedure:
(5-Bromo-2-methoxyphenyl)(2,6-difluoropyridin-3-yl)methanol (13.77 g, 41.7 mmol) and imidazole (3.41 g, 50.1 mmol) were dissolved in dry DMF (20 mL) under nitrogen. t-Butyl(chloro)dimethylsilane (6.92 g, 45.9 mmol) was added and the solution heated to 70° C. After 1 hour the mixture was cooled to RT. Water (200 mL) and diethyl ether (200 mL) were added and the phases mixed and separated. The organic was washed with water (200 mL) one more time then dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to 1:1 DCM: hexane gradient) gave 3-((5-bromo-2-methoxyphenyl)(tert-butyldimethylsilyloxy)methyl)-2,6-difluoropyridine as a thick oil that solidified on standing.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[C:35]([F:37])[CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:31]1[CH:32]=[C:33]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1, 100 mg, 1.0 eq.), anhydrous copper(II) acetate (90 mg, 2.0 eq.), 3,5-difluorophenylboronic acid (123 mg, 3 eq.) and pyridine (80 uL, 4 eq.) in dichloromethane (2.5 mL) was stirred at room temperature for 2 days, evaporated to dryness and purified on silica gel, eluting with a 98:2 to 95:5 gradient of dichloromethane/methanol, to yield 79 mg (61%) from the desired product as light yellow foam. MS (m/e): 518.4 (MH+, 100%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7](O)(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC>CN(C=O)C.ClCCl>[C:2]([Cl:4])(=[O:3])[CH2:1][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
Oxalyl chloride (2.67 ml, 0.0191 mol) was added drop-wise to a mixture of Arachidic acid (6.0 g, 0.0211 mol) and DMF (4 drops) in dichloromethane (50 ml) at 0° C. After the addition was completed, the reaction mixture was stirred at 0° C. for 30 minutes and then stirred at 25° C. for 1 hour, the reaction mixture was partitioned between dichloromethane and water, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine, then dried with sodium sulphate and concentrated in vacuo to provide the desired product (6.35 g, 100% yield) as a solid which was not purified any further.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[C:5]#[N:6].S(Cl)([Cl:19])=O.O>N1C=CC=CC=1>[Cl:19][CH2:2][CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[C:5]#[N:6]
Reactant: O=S(Cl)Cl
Reactant: N#CC(CCO)c1ccccc1C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: N#CC(CCCl)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h

Procedure:
4-Hydroxy-2-(2-trifluoromethylphenyl) butyronitrile (2.6 g) was dissolved in pyridine (10 mL). Thionyl chloride (2.1 mL) was carefully added and the mixture was heated with stirring at 60° C. for four hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.3 g). The property values of the compound are as follows.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:27]([OH:29])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[H][H].C(N(CC)CC)C>[Pd].O.CO>[NH2:1][C@H:2]([C:27]([OH:29])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: N[C@@H](CCC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O

Procedure:
A suspension of 10.4 g of Z-Gln(Trt)-OH (20 mmol) in 180 ml of a 9:1 mixture of methanol and water and 20 ml of one-normal aqueous hydrochloric acid is hydrogenated at room temperature and under atmospheric pressure in the presence of 0.5 g of a 10% palladium on charcoal catalyst; after the uptake of hydrogen is complete the starting material has dissolved. The catalyst is filtered off and washed with methanol; the filtrate is concentrated to 200 g and, at 60°, 2.8 ml of triethylamine (20 mmol) are added, whereupon the product immediately starts to crystallize. The mixture is concentrated to 100 g and left to stand at about 4° for some time, and the crystals are filtered off and washed with a mixture of methanol and water until free of chloride. The H-Gln(Trt)-OH obtainable in this way contains 0.5 mole of water and melts at 233° (with decomposition).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][C@H:33]([CH3:35])[O:32][C@H:31]([CH3:36])[CH2:30]5)=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].CO.Cl>O.O1CCCC1>[CH3:35][C@H:33]1[O:32][C@@H:31]([CH3:36])[CH2:30][N:29]([C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:14]4[CH:15]=[CH:16][C:11]([C:8]5[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=5)=[CH:12][CH:13]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)[CH2:34]1
Reactant: COC(=O)c1ccc(-c2ccc(N3CCN(c4ccc(N5C[C@@H](C)O[C@@H](C)C5)cc4)CC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(c2ccc(N3CCN(c4ccc(-c5ccc(C(=O)O)cc5)cc4)CC3)cc2)C[C@H](C)O1
Temperature: 25 °C
Yield: 102.4 %

Procedure:
A mixture of 4′-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]-1,1′-biphenyl-4-carboxylic acid methyl ester (3.70 g) and 1.0 mol/l sodium hydroxide solution (30 ml) in a mixed solvent of methanol (75 ml) and tetrahydrofuran (185 ml) was refluxed for 15.5 hours. After cooling to ambient temperature, the reaction mixture was poured into cold water, and the mixture was adjusted to pH 2 with 1.0 mol/l hydrochloric acid. The resulting precipitates were filtered, washed with water and diisopropyl ether and dried to give 4′-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]-1,1′-biphenyl-4-carboxylic acid (3.68 g).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.CO[CH:13](OC)[N:14]([CH3:16])C.C[NH:20]N>C(OCC)C.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([C:6]([OH:8])=[O:7])=[CH:13][N:14]([CH3:16])[N:20]=2)[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: CNN
Reactant: COC(=O)CC(=O)C1CC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cn1cc(C(=O)O)c(C2CC2)n1
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A mixture of methyl 3-cyclopropyl-3-oxopropanoate (10.0 g, 70.4 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (10.1 g, 84.4 mmol) was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in diethyl ether (25 mL). A solution of methylhydrazine (3.56 g, 77.4 mmol) in diethyl ether (25 mL) was added dropwise with stirring under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (35 mL) and 8N aqueous sodium hydroxide solution (17.5 mL) were added to the residue, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give a mixture (8.71 g, 75%) of 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid (1) and 5-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid (2) as a white solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]2[O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[C:4]=2[N:3]=1.[Cl:22]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[O:14][C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[C:4]=3[N:3]=[C:2]2[Cl:22])=[CH:7][CH:8]=1
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Reactant: COc1ccc2c(c1)c(O)nc1c3cc(Cl)ccc3oc21
Product: COc1ccc2c(c1)c(Cl)nc1c3cc(Cl)ccc3oc21

Procedure:
The procedure was similar to step S19C, while the starting material was 28B in stead of 19B.