Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[N:4][C:3]=1[C:17](O)=[O:18].B.O1CCCC1.Cl>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[N:4][C:3]=1[CH2:17][OH:18]
Reactant: Cc1sc(-c2cccc(C(F)(F)F)c2)nc1C(=O)O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Cc1sc(-c2cccc(C(F)(F)F)c2)nc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (5 mL) of the compound (310 mg, 1.1 mmol) obtained in Example 71a in tetrahydrofuran was added borane-tetrahydrofuran complex (1.1 M tetrahydrofuran solution, 3.0 mL, 3.3 mmol), and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=65/35) to give the title compound (82 mg, 27%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22]12([CH2:32][C:33](Cl)=[O:34])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:22]12([CH2:32][C:33]([N:1]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:34])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: C1COCCOCCOCCOCCOCCOCCN1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)N1CCOCCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16,19-hexaoxacycloheneicosane and (1-adamantyl)acetyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(N(C(C)C)CC)(C)C.ON1C2N=CC=CC=2N=N1.Cl.[CH3:48][C:49]1[C:53]([NH2:54])=[CH:52][O:51][N:50]=1.C(Cl)CCl>CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([NH:54][C:53]1[C:49]([CH3:48])=[N:50][O:51][CH:52]=1)=[O:8]
Reactant: Cc1nocc1N
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nocc1NC(=O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}-4-(4-morpholinylmethyl)benzoic acid (may be prepared as described in Description 22; 150 mg, 0.34 mmol) in N,N-dimethylformamide (4 ml) was added diisopropylethylamine (0.12 ml, 0.68 mmol), 1-hydroxy-7-azabenzotriazole (55.4 mg, 0.41 mmol), 3-methyl-4-isoxazolamine hydrochloride (39.9 mg, 0.41 mmol) and EDC (98 mg, 0.51 mmol). The reaction was stirred for 18 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2; ethyl acetate) to yield the title compound as a solid. 162 mg.
Reaction SMILES: Cl.[CH:2]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(O[CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C([O-])(=O)C.[Na+]>C(O)C>[CH2:17]([O:16][C:14]([C:13]1[CH:12]=[N:8][N:7]([CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[C:19]=1[NH2:20])=[O:15])[CH3:18]
Reactant: NNC1CCCC1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCC2)c1N
Temperature: 70 °C
Yield: 79.3 %

Procedure:
Cyclopentyl-hydrazine hydrochloride (1.000 g; 7.32 mmol), ethyl (ethoxymethylene)-cyanoacetate (1.026 g, 6.61 mmol) and anhydrous sodium acetate (0.644 g, 7.85 mmol) were combined in ethanol (10 mL) and heated at 70° C. for 20 hours. After cooling to room temperature, ethanol was removed in vacuo and the residue was partitioned between methylene chloride and water. The organic phase was washed sequentially with water and brine. Each aqueous phase was back extracted with a single portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated. Purification by flash chromatography, eluting with 10-40% EtOAc/hexanes yielded 5-amino-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.170 g, 73%). Mass spectrum: m/z: 224.1 (M+H).
Reaction SMILES: [CH:1]1([C:5]2[CH:6]=[N+:7]([O-])[CH:8]=[CH:9][C:10]=2[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:4][CH2:3][CH2:2]1.C[Si]([C:22]#[N:23])(C)C.CN(C)C(Cl)=O>ClCCl>[CH:1]1([C:5]2[C:10]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]([C:22]#[N:23])=[N:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccc(OCC(F)(F)F)c(C2CCC2)c1
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: N#Cc1cc(OCC(F)(F)F)c(C2CCC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
To a solution of 3-cyclobutyl-4-(2,2,2-trifluoroethoxy)pyridine 1-oxide (Example 108d, 3.5 g, 14.2 mmol) in dichloromethane (55 ml) under argon atmosphere was added trimethylsilylcyanide (1.83 g, 2.47 ml, 18.4 mmol) followed by addition of dimethylcarbamoyl chloride (CAN 79-44-7, 2.28 g, 1.95 ml, 21.2 mmol). The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (2.95 g, 77%) as light yellow solid. MS (ESI, m/z): 257.5 (M+H+).
Reaction SMILES: [Cl-].C[N:3]([CH3:14])[CH:4]=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:6]=[N+:7](C)C.Cl.[CH2:16]([N:23]1[CH2:28][CH2:27][N:26](C(N)=N)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:14]2[N:3]=[CH:4][C:5]([C:10]([F:11])([F:12])[F:13])=[CH:6][N:7]=2)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)C=C(C=[N+](C)C)C(F)(F)F
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of (3-Dimethylamino-2-trifluoromethyl-allylidene)-dimethyl-ammonium chloride ([176214-18-9], 0.60 g) in acetonitrile (10 mL) was added 4-Benzyl-piperazine-1-carboxamidine hydrochloride ([7773-69-5], 0.66 g) and triethylamine (0.87 mL), and the reaction mixture was stirred for 3 hours at room temperature. After such time, the reaction mixture was concentrated in vacuo and purified by column chromatography to yield the title compound as a light yellow solid (0.79 g). MS (m/e): 323.4 (M+H+).
Reaction SMILES: O[N:2]1C(=O)C2=CC=CC=C2C1=O.[C@H:13]1([CH2:21][OH:22])[CH2:18][CH2:17][C@H:16]([CH2:19][OH:20])[CH2:15][CH2:14]1>>[NH2:2][O:20][CH2:19][C@H:16]1[CH2:17][CH2:18][C@H:13]([CH2:21][OH:22])[CH2:14][CH2:15]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OC[C@H]1CC[C@H](CO)CC1
Product: NOC[C@H]1CC[C@H](CO)CC1

Procedure:
Prepared by a similar procedure as described for preparation 31. Starting materials: N-hydroxyphthalimide and trans-1,4-cyclohexanedimethanol (Acros). 13C-NMR (CDCl3) δ 81.6, 68.2, 40.3, 36.8, 29.0, 28.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Cl)ccc2o1
Reactant: CN1CCNCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(c2nc3cc(Cl)ccc3o2)CC1
Reaction time: 12 h

Procedure:
A 300 mg portion of 5-chloro-2-mercaptobenzoxazole was suspended in 50 ml of anhydrous benzene, and the suspension was mixed with 404 mg of phosphorus pentachloride and heated under reflux for 3 hours. The reaction solution was cooled in an ice bath and, with stirring, 1.6 g of 1-methylpiperazine was added thereto. After 30 minutes of stirring, the ice bath was removed to carry out 12 hours of stirring at room temperature, and then the reaction solution was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate and then the solvent was evaporated under a reduced pressure. Thereafter, the thus obtained mixture was purified by a silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound (121 mg) in light yellow color.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH2:22])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1.[CH3:31][C:32]1[O:36][C:35]([C:37](O)=[O:38])=[N:34][N:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH:22][C:37]([C:35]5[O:36][C:32]([CH3:31])=[N:33][N:34]=5)=[O:38])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(N)CC2)n1
Reactant: Cc1nnc(C(=O)O)o1
Product: Cc1nnc(C(=O)NC2(C(=O)NC3CSc4cc(-c5cc(Cl)cc(F)c5-c5nnn(C)n5)ccc43)CC2)o1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-2,3-dihydro-benzo[b]thiophen-3-yl}-amide (example 61) has been coupled with 5-methyl-[1,3,4]oxadiazole-2-carboxylic acid to yield the title compound as light yellow amorphous solid. MS: 555.1 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].[CH3:37][N:38]([CH3:45])[CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:42]3[CH2:43][CH2:44][CH:39]([N:38]([CH3:45])[CH3:37])[CH2:40][CH2:41]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27]
Reactant: CN(C)C1CCNCC1
Reactant: O=C1c2c(-c3ccc(F)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C)C1CCN(c2cc(-c3ccc(F)cc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Yield: 36.2 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (53.3 mg) was reacted with 4-(dimethylamino)piperidine (15.4 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(dimethylamino)piperidine-1-yl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (22.6 mg, 36%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23].C(N(CC)CC)C.C(OCC)(=O)C>C(#N)C.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.[Cu]I>[CH3:21][Si:22]([C:25]#[C:26][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2)([CH3:24])[CH3:23]
Reactant: CCOC(=O)C1=Cc2cc(I)ccc2NC1C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2cc(C#C[Si](C)(C)C)ccc2NC1C(F)(F)F
Yield: 38.4 %

Procedure:
The ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example 160, Step 1)(750 mg, 1.89 mmol), trimethylsilylacetylene (925 mg, 9.44 mmol), dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmol), copper(I)iodide (9.5 mg, 0.05 mmol), and triethylamine (953 mg, 9.44 mmol) were mixed at room temperature for 2 h in acetonitrile (10 mL). The resulting black heterogeneous mixture was poured into ethyl acetate(50 mL) and extracted with water (2×25 mL), 1 N aqueous hydrochloric acid (25 mL), and saturated aqueous ammonium chloride (2×25 mL). The organic layer was dried over sodium sulfate and solvent removed at reduce pressure. The product was purified by flash chromatography (0-25% ethyl acetate/hexanes, silica gel). A black semisolid was isolated which upon trituration with hexanes afforded ethyl 6-trimethylsilylethynyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid(267 mg,38%): mp 117-119° C. 1H NMR (CDCl3, 300 MHz) 7.65 (s, 1H), 7.24-7.32 (m, 2H), 6.55 (d, 1H, J=8.0 Hz), 5.08-5.18 (m, 1H), 4.66 (brs, 1H), 4.24-4.64 (m, 2H), 1.34 (t, 3H, J=7.1 Hz) 0.22 (s, 9H). ESHRMS m/z 368.1306 (Calc'd for M+H 368.1293).
Reaction SMILES: [CH3:1][C@@:2]([S:26]([CH3:29])(=[O:28])=[O:27])([CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[N:16]1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl>C1COCC1>[OH:6][NH:5][C:3](=[O:4])[C@:2]([CH3:1])([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[N:16]1
Reactant: C[C@@](CCn1cc(-c2ccccc2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@](CCn1cc(-c2ccccc2)cn1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-pyrazol-1-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.685 g, 1.62 mmol, 1 eq) in THF (20 mL) was added HCl (4M aq. sol.) and the reaction was allowed to stir at RT overnight. The reaction mixture was concentrated and azeotroped with MeOH to remove water to give (2R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-pyrazol-1-yl)butanamide (497 mg, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.85-10.73 (m, 1H), 10.30-10.18 (m, 1H), 8.19 (s, 1H), 7.86 (s, 1H), 7.60-7.50 (m, 2H), 7.32 (t, J=7.7 Hz, 2H), 7.15 (s, 1H), 4.27-4.14 (m, 1H), 4.10-3.95 (m, 1H), 3.04 (s, 3H), 2.79-2.63 (m, 1H), 2.32-2.18 (m, 1H), 1.46 (s, 3H). LC-MS M+H+338.0.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]21[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([O:19][CH:16]1[CH2:17][CH2:18][C:6]2([CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]2[NH:4][C:1](=[O:3])[CH3:2])[CH2:14][CH2:15]1)(=[O:29])=[O:28]
Reactant: CC(=O)NC1c2ccccc2CC12CCC(O)CC2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NC1c2ccccc2CC12CCC(OS(C)(=O)=O)CC2
Temperature: 0 °C

Procedure:
To an ice cold solution of 1.21 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol (isomer B)[27] (prepared in Example 61B) in 12 ml. of pyridine, 1.2 ml. of methane sulfonyl chloride is added. After about 5 hours in the cold the mixture is poured into ice: water. The solid that precipitates is recrystallized from acetone: Skellysolve B to give 1.21 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan-4-ol methanesulfonate (isomer B)[28], melting at 161° to 163° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)[CH:33]=O>>[CH2:1]([N:3]([CH2:33][C:32]1[CH:35]=[CH:36][C:37]([O:38][CH:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)=[C:30]([F:29])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:15]2[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN1CCC(Oc2ccc(C=O)cc2F)CC1
Product: CCN(Cc1ccc(OC2CCN(C)CC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 28.3 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 3-fluoro-4-(1-methylpiperidin-4-yloxy)benzaldehyde (55 mg) according to an analogous synthetic method to Example 264 described below and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])=[C:4]([CH2:20][CH3:21])[CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O.CN(C)C=O>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[O:11][C:10]([CH3:17])([CH3:18])[C:9]3=[O:19])=[C:4]([CH2:20][CH3:21])[CH:3]=2)=[C:25]([F:30])[CH:24]=1
Reactant: CCc1cc(Br)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: Oc1ccc(Br)cc1F
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1cc(Oc2ccc(Br)cc2F)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C

Procedure:
A mixture of 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.42 g, 1.19 mmol), 4-bromo-2-fluorophenol (0.27 g, 1.43 mmol), cesium carbonate (0.78 g, 2.38 mmol), copper(II) trifluoromethanesulfonate (0.02 g, 0.06 mmol) and ethyl acetate (0.004 g, 0.06 mmol) in dry toluene (10 ml) are heated to reflux for 21 hours. The mixture is cooled to room temperature and N,N-dimethylformamide (2 ml) is added. The mixture is partitioned between 2M aqueous hydrochloric acid (10 ml) and ethyl acetate (3×10 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue is purified by preparative reverse phase HPLC to give 4-[4-(4-bromo-2-fluorophenoxy)-2-ethylphenyl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>ClCCl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Nc1ccccn1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Iodo-benzenesulfonyl chloride, (52.3 g, 0.17 mol) was dissolved in dichloromethane (300 ml) and 2-aminopyridine (65 g, 0.69 mol) was added. The solution was stirred at room temperature for 3 days, washed with 2M sulfuric acid (2×200 ml) and water (100 ml), dried with Na2SO4 and evaporated to dryness. Yield 46.9 g (76%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11](O)=O)([O-])=O.[CH3:14][N-:15][CH3:16].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:14][N:15]([CH3:16])[CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: C[N-]C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(C)CCc1ccccc1N

Procedure:
The title compound was prepared from 2-nitrophenylacetic acid by conversion to the N,N-dimethylamide, hydrogenation then reduction with lithium aluminium hydride.
Reaction SMILES: [CH:1]1([NH:4][C@@H:5]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]2)[CH2:3][CH2:2]1.Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([N:4]([CH:1]2[CH2:2][CH2:3]2)[C@@H:5]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]2)=[N:19][CH:20]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC2CC2)C1
Reactant: N#Cc1ccc(Br)nc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N(c2ccc(C#N)cn2)C2CC2)C1

Procedure:
The title compound was prepared according to the procedures of Intermediate 2 (A) using (R)-tert-butyl 3-(cyclopropylamino)pyrrolidine-1-carboxylate and 6-bromonicotinonitrile under similar conditions MS (m/z): 329 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[CH:36]=[N:37][CH:38]=[C:33]([F:32])[CH:34]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: OB(O)c1cncc(F)c1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3cncc(F)c3)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (5-fluoropyridin-3-yl)boronic acid gave 239. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 9.15 (t, J=1.7 Hz, 1H), 8.74 (d, J=2.7 Hz, 1H), 8.55 (s, 1H), 8.37 (dt, J=9.5, 2.3 Hz, 1H), 7.84 (s, 1H), 4.87 (dd, J=10.5, 3.9 Hz, 1H), 4.58-4.36 (m, 1H), 4.34-4.20 (m, 1H), 4.16-3.92 (m, 1H), 3.79 (s, 3H), 3.37-3.23 (m, 2H), 2.15-2.05 (m, 1H), 1.91-1.67 (m, 5H). LCMS (ES+) m/z 435 (M+1).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH:14]2[CH2:20][CH:19]3[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]([CH2:17][CH2:18]3)[CH2:15]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:43]3[CH:52]=[CH:51][N:50]([CH3:53])[C:44]=3[N:45]=[C:46]([C:48]#[N:49])[N:47]=2)=[CH:38][C:37]=1[C:54]([F:57])([F:56])[F:55]>CC(N(C)C)=O>[C:48]([C:46]1[N:47]=[C:42]([C:39]2[CH:40]=[CH:41][C:36]([O:11][CH2:12][CH2:13][CH:14]3[CH2:15][CH:16]4[N:21]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH:19]([CH2:18][CH2:17]4)[CH2:20]3)=[C:37]([C:54]([F:57])([F:56])[F:55])[CH:38]=2)[C:43]2[CH:52]=[CH:51][N:50]([CH3:53])[C:44]=2[N:45]=1)#[N:49]
Reactant: Cn1ccc2c(-c3ccc(O)c(C(F)(F)F)c3)nc(C#N)nc21
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC3CCC(C2)N3C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cn1ccc2c(-c3ccc(OCCC4CC5CCC(C4)N5C(=O)OC(C)(C)C)c(C(F)(F)F)c3)nc(C#N)nc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
tert-Butyl 3-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (150 mg) and potassium carbonate (100 mg) were added to a solution of 4-[4-hydroxy-3-(trifluoromethyl)phenyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (100 mg) in DMAc (2 mL) at room temperature, and the mixture was stirred at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=80:20 to 50:50), whereby tert-butyl 3-{2-[4-(2-cyano-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy]ethyl}-8-azabicyclo[3.2.1]octane-8-carboxylate (146 mg) was obtained as a white solid.