Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=[C:9]([NH:16][C:17](=[O:25])OC3C=CC=CC=3)[CH:8]=2)[CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[NH:33][CH2:32][CH2:31]2>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=[C:9]([NH:16][C:17]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([O:27][CH3:26])=[C:36]([C:37]([F:39])([F:40])[F:38])[CH:35]=4)[CH2:31][CH2:32]3)=[O:25])[CH:8]=2)[CH:2]=1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: O=C(Nc1cc2c(c(-c3cccnc3)c1)OCC2)Oc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc3c(c(-c4cccnc4)c1)OCC3)CC2
Temperature: 25 °C
Yield: 25.6 %

Procedure:
Phenyl N-[2,3-dihydro-7-(pyrid-3-yl)benzofuran-5-yl]carbamate (D65) (0.20 g, 0.00060mole) in dry DMF (10 ml) was treated under argon with 5-methoxy-6 trifluoromethyl indoline (D11) (0.13 g, 0.00060 mole) and heated under reflux for 18 hours. The reaction was allowed to cool to ambient temperature and the solvent was removed in vacuo. The residue was dissolved in dichloromethane, washed with deionised water and 10% sodium hydroxide solution, dried (Na2SO4) and evaporated in vacuo. The resulting brown oil was purified by flash column chromatography on silica gel, eluting with 2% methanol/dichloromethane, followed by recrystallisation from ethyl acetate 60-80° petroleum ether to afford the title compound (0.07 g, 26%) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1.[CH3:40][O:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:47]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36]([C:46]3[CH:45]=[N:44][CH:43]=[C:42]([O:41][CH3:40])[CH:47]=3)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(Br)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cncc(-c2ccc([C@H](Oc3cc(-c4ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc4)nc(N)n3)C(F)(F)F)cc2)c1
Temperature: 150 °C
Yield: 40.8 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-pyridine (69 mg, 0.27 mmol), 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and purified by preparative HPLC to give 60 mg of (S)-3-[4-(2-amino-6-{(S)-2,2,2-trifluoro-1-[4-(5-methoxy-pyridin-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert butoxycarbonylamino-propionic acid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[O:7])CCC.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=2)=[O:7]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O
Reactant: COCCN
Product: COCCNC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and 2-methoxy-ethylamine in analogy to example B-5; MS-(+)-ion: M+1=339.0.
Reaction SMILES: CCCCCCC.C(OCC)(=O)C.C(OC(=O)NCC(CC(=O)NCCC#N)CC(C)C)(C)(C)C.[Br-].[Li+].C[O:39][C:40](=[O:54])[CH:41]([CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CC(C)=O>[C:46]([O:45][C:43](=[O:44])[CH2:42][CH:41]([CH2:50][CH:51]([CH3:52])[CH3:53])[C:40]([OH:54])=[O:39])([CH3:49])([CH3:48])[CH3:47]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)CC(C)C
Agent: CC(C)CC(CNC(=O)OC(C)(C)C)CC(=O)NCCC#N
Agent: [Br-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Yield: 95.4 %

Procedure:
Synthesis of Compound 1 Lithium aluminum hydride (69.4 mL of a 1 M solution in ether, 69.4 mmol) was added dropwise to a stirring solution of cis-cyclobutane-1,2-dicarboxylic acid (5 g, 34.7 mmol) in THF (60 mL) at 0° C. under argon. The mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was cooled to 0° C. and quenched by careful addition of water (2.7 mL), sodium hydroxide solution (2.7 mL of a 15% w/v solution), and water (8.1 mL). The mixture was stirred for 15 minutes, and the precipitate was removed by filtration. The solvent was evaporated under reduced pressure to give the alcohol 1 as a colorless oil (4.0 g, 98%); δH (400 MHz; CDCl3): 3.85 (2H, m), 3.6 (2H, m), 3.2 (2H, s), 2.7 (2H, m), 2 (2H, m); 1.55 (2H, m); δC (400 MHz; CDCl3): 63.15, 37.83, 20.40. Synthesis of Compound 2 Mesyl chloride (6.2 mL, 79.1 mmol) was added dropwise to a stirring solution of 1 (4.0 g, 34.4 mmol) in dichloromethane (150 mL) at −40° C. under argon. Triethylamine (12.0 mL, 86.0 mmol) was then added dropwise, and the mixture was allowed to warm slowly to room temperature. After stirring for 16 hours, the mixture was quenched by addition of dilute hydrochloric acid (50 mL). The organic layer was separated, and the aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 6:4) to give the mesylate 2 (6.1 g, 73%) as a white solid; Rf(heptane/ethyl acetate, 1:1) 0.18. δH (400 MHz; CDCl3): 4.3 (4H, m), 3.05 (6H, s), 2.9 (2H, m), 2.2 (2H, m), 1.8 (2H, m); δc(400 MHz; CDCl3): 69.51, 37.45, 35.28, 21.09. Synthesis of Compound 3 Anhydrous lithium bromide (10.6 g, 121.8 mmol) was added to a stirring mixture of 2 (5.95 g, 24.4 mmol) in acetone (50 mL) under argon, and the mixture was refluxed for 2 hours. After cooling, the acetone was evaporated under reduced pressure, and the residue was taken up in ether (50 mL), washed with water (50 mL), brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5) to give the dibromide 3 (5.36 g, 86%) as an orange liquid; Rf (heptane-ethyl acetate,
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([F:15])[C@@H:13]([CH2:16][CH:17]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)O[C@@H]1OC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:40]([O-:43])([OH:42])=O.[Na+].[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(O)(=O)C>[C:1]([O:9][C@@H:10]1[C@H:14]([F:15])[C@@H:13]([CH2:16][CH:17]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[S:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:42][C@H:40]1[O:43][C:45](=[O:47])[CH3:46])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CC(=O)OC(C)=O
Reactant: CCOP(=O)(OCC)C(C[C@H]1O[C@H](OC)[C@H](OC(=O)c2ccccc2)[C@@H]1F)Sc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C(C[C@H]1O[C@@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1F)Sc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Compound 35.13 (50 mg, 0.1 mmol) was dissolved in a 10% solution of acetic anhydride in acetic acid (2.2 mL). Concentrated sulfuric acid was added and the mixture was stirred at r.t. for 2 h. The mixture was then poured into a 5% aqueous solution of NaHCO3 (100 mL) containing 50 g of ice. The aqueous phase was then extracted with 2×100 mL CH2Cl2. The extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography to give compound 35.14 (60 mg, 95% yield).
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][N:7]=1.S(Cl)([Cl:15])=O>>[ClH:15].[Cl:15][CH2:2][C:3]1[N:4]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][N:7]=1
Reactant: OCc1nccn1CC(F)(F)F
Reactant: O=S(Cl)Cl
Product: Cl
Product: FC(F)(F)Cn1ccnc1CCl
Temperature: 90 °C

Procedure:
To 2-hydroxymethyl-1-(2,2,2-trifluoroethyl)imidazole (1.40 g) was added thionyl chloride (14 ml), and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature, the solvent was distilled off under reduced pressure and the obtained solid was washed with ethyl acetate, to give 2-chloromethyl-1-(2,2,2-trifluoroethyl)imidazole hydrochloride (1.63 g) as brown crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][NH:28][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=3)[CH2:11][N:12]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:32][CH:33]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CS(=O)(=O)N(CCc1ccccn1)Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CS(=O)(=O)N(CCc1ccccn1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 17 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 504. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.5 (d, 1H) 8.3 (d, 1H) 7.9 (m, 2H) 7.6 (m, 1H) 7.4 (m, 2H) 7.2 (m, 2H) 7.0 (d, 2H) 6.9 (d, 1H)-6.7 (d, 2H) 5.4 (s, br, 1H) 4.4 (s, 2H) 3.7 (m, 2H) 3.6 (m, 2H) 3.0 (m, 2H) 2.8 (m, 2H) 2.8 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.[Br:49][C:50]1[CH:51]=[N:52][C:53](Cl)=[N:54][CH:55]=1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[Br:49][C:50]1[CH:51]=[N:52][C:53]([N:33]2[CH2:34][CH2:35][CH:30]([C:10]3[C:9]([CH:36]([F:47])[C:37]4[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=4)=[C:8]([CH:5]4[CH2:6][CH2:7][C:2]([F:1])([F:48])[CH2:3][CH2:4]4)[C:17]4[CH:16]([O:18][CH2:19][C:20]5[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=4[N:11]=3)[CH2:31][CH2:32]2)=[N:54][CH:55]=1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: Clc1ncc(Br)cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To a solution of 1.0 g (1.5 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, in 5 ml of N,N-dimethylformamide, 0.58 g (3.0 mmol) of 5-bromo-2-chloropyrimidine and 0.27 ml (1.8 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene were added, and the reaction solution was stirred at 100° C. for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. 5% Ethyl acetate/n-hexane solution was added to the obtained residue and the precipitate was obtained by filtration to provide 0.78 g of 2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline as a white solid (yield: 64%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(O)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][S:18]([C:21]2[C:22](=[O:23])[O:10][C:5]3[C:6]([CH:7]=2)=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=3)(=[O:19])=[O:20])=[CH:25][CH:26]=1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1
Reactant: O=Cc1cc(Br)ccc1O
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3cc(Br)ccc3oc2=O)cc1
Yield: 78 %

Procedure:
A solution of 5-bromosalicylaldehyde (1 mmol) and 2-(4-methoxybenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 78% yield of the title compound; m.p. 231-232° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][C:25]1[C:30]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:26]5[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH:32]([CH3:33])[CH3:34])[C:25]=5[F:24])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC(C)Oc1cccc(B(O)O)c1F
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc(OC(C)C)c4F)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-fluoro-3-isopropoxyphenylboronic acid (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: tR 2.91 min (Method A); M+H=446 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.11-8.07 (m, 2H), 7.77-7.73 (m, 1H), 7.56-7.54 (m, 1H), 7.22-7.15 (m, 2H), 6.99-6.92 (m, 1H), 4.64 (hp, 1H), 3.87 (s, 3H), 3.58 (s, 3H), 1.94 (s, 3H), 1.33-1.28 (m, 6H))
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CNN>>[NH2:3][O:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: CNN
Product: CC(C)(C)OC(=O)N1CCC(ON)CC1
Yield: 73 %

Procedure:
Deprotection of tert-butyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]piperidine-1-carboxylate with methylhydrazine following the procedure described for the preparation of Reference Example 9 gave tert-butyl 4-(aminooxy)piperidine-1-carboxylate (1.3 g, 73%) as an amber oil: 1H NMR (500 MHz, CDCl3) δ 1.47 (9H, s), 1.48-1.54 (2H, m), 1.86-1.88 (2H, m), 3.04-3.10 (2H, m), 3.66-3.69 (2H, m), 4.20 (1H, br s), 5.30 (2H, br s).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.O>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:39])=[O:38])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL), cooled in an ice bath, was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of benzenesulfonyl chloride (0.155 g, 0.879 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was then diluted with water (15 mL) and the aqueous layer extracted with DCM (3×30 mL) and the combined organic extracts dried over a phase separating column and concentrated. MeOH (ca. 0.5 mL) was added to the residue which resulted in the precipitation of a solid. The solid was filtered, washed with MeOH (2 mL) and dried, to afford the title compound (88 mg). LCMS (A) m/z: 425 [M+1]+, Rt 1.40 min (basic).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.O1CCCC1.[Pd]>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:12]=[CH:11][C:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a solution of 5-nitro-2-(4-(trifluoromethyl)phenyl)pyridine (260 mg, 0.97 mmol) in ethanol (10 mL) and tetrahydrofuran (5 mL) was added 10 wt % palladium on carbon (100 mg). The reaction was pressurized to 50 psi hydrogen and stirred at room temperature for 4 hours. The reaction was filtered through Celite and concentrated to give 6-(4-(trifluoromethyl)phenyl)pyridin-3-amine (220 mg, 95%). 1H NMR (400 MHz, CD3OD, δ): 7.98 (s, 1H), 7.88 (d, 2H), 7.60 (d2, H), 7.54 (d, 1H), 7.09 (d, 1H).
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)C(=O)NC2SC(SC[C:16](O)=[O:17])=CN=2)CCCC1.[CH:28]1([NH:35][CH:36]2[CH2:41][CH2:40][CH:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C([O:50][C:51](=[O:62])[C:52]([S:55][C:56]1[S:60][C:59]([NH2:61])=[N:58][CH:57]=1)([CH3:54])[CH3:53])C>>[CH:28]1([N:35]([CH:36]2[CH2:41][CH2:40][CH:39]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:38][CH2:37]2)[C:16](=[O:17])[NH:61][C:59]2[S:60][C:56]([S:55][C:52]([CH3:54])([CH3:53])[C:51]([OH:50])=[O:62])=[CH:57][N:58]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: c1ccc(C2CCC(NC3CCCCCC3)CC2)cc1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(C2CCCCCC2)C2CCC(c3ccccc3)CC2)s1)C(=O)O

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (via cycloheptyl-(4-phenyl-cyclohexyl)-amine and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: FC(F)(F)C([O-])=O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[O:17])[NH:15][CH:14]=[C:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:34])=[C:23]([CH:33]=3)[C:24]([N:26]3CCC[NH2+]CC3)=O)[N:12]2[CH:35]=1.[Cl:36]C1C=C2C(=O)NC=C(CC3C=CC(F)=C(C=3)C#N)N2C=1.ClN1C(=O)CCC1=O>C1COCC1>[Cl:36][C:35]1[N:12]2[C:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:34])=[C:23]([CH:33]=3)[C:24]#[N:26])=[CH:14][NH:15][C:16](=[O:17])[C:11]2=[CH:10][C:9]=1[Cl:8]
Reactant: N#Cc1cc(Cc2c[nH]c(=O)c3cc(Cl)cn23)ccc1F
Reactant: O=C(c1cc(Cc2c[nH]c(=O)c3cc(Cl)cn23)ccc1F)N1CCC[NH2+]CC1
Agent: O=C([O-])C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: N#Cc1cc(Cc2c[nH]c(=O)c3cc(Cl)c(Cl)n23)ccc1F

Procedure:
A mixture of Example 6, F5 (1 eq) and N-chlorosuccinimide (2 eq) in THF was stirred at RT. The solvent was removed under reduced pressure and the resulting crude was used as such in the next step without purification. MS (ES) C15H8Cl2FN3O requires: 335, found: 336 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:26])[C:24]=2[CH3:25])[CH2:3]1.I[CH3:28].[Al]>C(#N)C.[Ag]=O>[CH3:28][O:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:26])[C:24]=2[CH3:25])[CH2:3]1
Reactant: CI
Reactant: CC1=C(N2CC(O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Agent: O=[Ag]
Agent: [Al]
Solvent: CC#N
Product: COC1CN(C2=C(C)C(=O)OC2)C(=O)C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 58 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (100 mg, 0.273 mmol) in acetonitrile (1 mL) was added iodomethane (171 μL, 2.73 mmol) and silver oxide (69.6 mg, 0.300 mmol). The vial was sealed, wrapped with aluminum foil, and stirred at 58° C. for 15 h. The reaction mixture was filtered through CELITE®, concentrated to give the crude product, which was purified by column chromatography (0-10% MeOH/DCM) to afford the title compound as a mixture of enantiomers. LC/MS: [(M+1)]+=381. The racemic mixture was separated by SFC-HPLC, using the following conditions: chiralcel AD-H, 2×25 cm, 15% MeOH, 60 mL/min to afford faster eluting Enantiomer A: LC/MS: [(M+1)]+=381; and slower eluting Enantiomer B: LC/MS: [(M+1)]+=381
Reaction SMILES: [OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20](Cl)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:37][C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([N:40]4[CH2:41][CH2:42][C@H:38]([F:37])[CH2:39]4)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: F[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(N3CC[C@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-trifluoromethyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoro-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (d, 1H), 4.72 (s, 1H), 3.80-3.58 (m, 3H), 3.26 (m, 2H), 2.59 (m, 1H), 2.22 (m, 1H), 2.08 (1H), 1.85-1.72 (m, 2H), 1.50 (m, 1H), 1.33-1.20 (m, 3H). m/z: 474 [M+H]
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(O)(=[O:15])C.O.[C:18]([NH:22][C:23](=N)SC)([O:20][CH3:21])=[O:19]>C(O)C>[OH2:15].[NH:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:23]1[NH:22][C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(=O)O
Reactant: Nc1cnc2ccccc2c1N
Reactant: COC(=O)NC(=N)SC
Solvent: CCO
Solvent: O
Product: COC(=O)Nc1nc2cnc3ccccc3c2[nH]1

Procedure:
To a solution of 6.6 g (0.041 mole) of 3,4-diaminoquinoline (from Example 39), 2.0 ml of glacial acetic acid, 35 cc of ethanol and 35 ml of water was added 9.3 g (0.045 mole) of N-carbomethoxy-S-methylisothiourea, and the mixture was heated at its reflux temperature for two hours. Evaporation provided a residue which was suspended in ethanol, separated by filtration and washed with water. Recrystallization from ethanol provided methyl 1H-imidazo[4,5-c]quinolin-2-carbamate hydrate, m.p. >250° C. Analysis: Calculated for C12H10N4O2. 0.75H2O: %C, 56.4; %H, 4.5; %N, 21.9; Found: %C, 56.1; %H, 4.4; %N, 22.4.