Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)(=[O:4])=[O:3].[H-].[Na+].I[CH3:20]>C1COCC1>[CH3:20][N:5]([CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: CI
Reactant: CS(=O)(=O)NC1CCCOc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C1CCCOc2ccccc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
1.54 g (13.4 mmol) of methanesulfonyl chloride were added dropwise with ice cooling to a solution of 2.0 g (12.2 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine (Example 6b) and 3.7 g (36.6 mmol triethylamine in 40 ml of THF. The mixture was allowed to come to RT and was stirred overnight and treated with 50 ml of water, and the THF was distilled off in vacuo. The residue was diluted with a further 50 ml of water and stirred for 3 h, and the deposited product was filtered off with suction. After drying in vacuo, 2.2 g of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine were obtained, m.p. 105-106° C. b) A solution of 1.1 g (6.2 mmol) of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF was added dropwise to a suspension of 0.23 g (6.2 mmol) of 80 percent sodium hydride in 10 ml of THF. After 2 h at RT, 0.94 g (6.7 mmol) of iodomethane were added and the mixture was stirred overnight at RT. After distilling off the solvent in vacuo, the residue was taken up in EA, and the solution was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated. Subsequent recrystallization of the product from isopropanol yielded 0.5 g of 5-(N-methyl-N-methylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine, m.p. 143-145° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:6])[CH2:5][CH2:4]1.[Br:7][C:8]1[CH:9]=[CH:10][C:11](F)=[N:12][CH:13]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:6][CH:3]2[CH2:5][CH2:4]2)=[N:12][CH:13]=1
Reactant: Fc1ccc(Br)cn1
Reactant: SC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(SC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in mineral oil, 2.40 g) in THF (100 mL) was added dropwise cyclopropanethiol (0.25 M in Et2O, 160 mL) at 0° C. After stirring for 30 min, 5-bromo-2-fluoropyridine (3.52 g) was added in portions at 0° C. and then warmed to r.t. slowly. The reaction mixture was stirred at r.t. overnight. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. After filtration and evaporation of the solvent, the crude product was obtained and used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][NH2:4].C(N(C(C)C)CC)(C)C.Cl[C:19]([O:21][CH3:22])=[O:20].O>C(Cl)Cl>[CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][NH:4][C:19](=[O:20])[O:21][CH3:22]
Reactant: C=CCC(C)(C)CN
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C=CCC(C)(C)CNC(=O)OC
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A 1 L round-bottom flask under nitrogen was charged with 2,2-Dimethylpent-4-en-1-amine (9.86 g, 87 mmol), diisopropylethylamine (16.73 ml, 96 mmol), and DCM (100 mL) and cooled to 0° C. A solution of methyl chloroformate (7.08 mL, 91 mmol) in DCM (50 mL) was added dropwise. The reaction mixture was warmed to RT, stirred for 24 hours and poured into water. The mixture was extracted with EtOAc (3×). The combined organic portions were washed with brine, dried with anhydrous MgSO4 and filtered, and the solvent was removed from the filtrate by rotary evaporation. The crude product was purified by silica gel chromatography eluting with 70 hexane/30 EtOAc, to give the title compound. 1H NMR (CDCl3): δ 5.85-5.79 (m, 1H), 5.06-5.02 (m, 2H), 4.46 (s, 1H), 3.67 (s, 3H), 3.02-3.00 (m, 2H), 1.98-1.96 (m, 2H), 0.88 (s, 6H) ppm.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:19])[CH:3]=1.[O:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=3)[CH2:26][CH2:25]2)[CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:19][C:4]1[CH:3]=[C:2]([NH:36][C:33]2[CH:32]=[CH:31][C:30]([N:27]3[CH2:28][CH2:29][N:24]([CH:22]4[CH2:21][O:20][CH2:23]4)[CH2:25][CH2:26]3)=[CH:35][N:34]=2)[C:10]2[N:9]=[CH:8][N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[CH:5]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(Br)cc(Cl)cc21
Reactant: Nc1ccc(N2CCN(C3COC3)CC2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cnc2c(Nc3ccc(N4CCN(C5COC5)CC4)cn3)cc(Cl)cc21
Temperature: 120 °C
Yield: 84.7 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 116a (600 mg, 1.65 mmol), 5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-amine (390 mg 1.67 mmol), cesium carbonate (1.09 g, 3.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (152 mg, 0.167 mmol), Xantphos (193 mg, 0.334 mmol), and dioxane (10 mL). After bubbling nitrogen through the suspension for 10 minutes, the reaction was heated at 120° C. overnight. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with a mixed solvent of petroleum ether and ethyl acetate (15 mL, 2:1) to afford 116b as a yellow solid (720 mg, 85%). MS-ESI: [M+H]+ 515.2
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[S:25](Cl)(=[O:27])=[O:26].O>O1CCCC1>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[S:25]([N:8]1[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cn(S(=O)(=O)c2cc3ccccc3s2)c(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (700 mg) in tetrahydrofuran (70 mL) was added sodium hydride (60% in oil, 244 mg), and the mixture was stirred for 30 min. 1-Benzothiophene-2-sulfonyl chloride (1.04 g) was added to the reaction mixture, and the mixture was stirred for 1.5 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:3) to give the title compound as a colorless oil (yield 1.25 g, 83%).
Reaction SMILES: P(Cl)(Cl)(OC1C=CC=CC=1)=O.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.N1C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:30]=[N+:31]=[N-:32])=[O:19])=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(=O)O)cc1N1CCN(C)CC1
Agent: O=P(Cl)(Cl)Oc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N=[N+]=[N-])cc1N1CCN(C)CC1
Reaction time: 12 h

Procedure:
At ambient temperature, add a solution of 5.3 g (0.025 mol) of phenyl dichlorophosphate in 100 ml of dichloromethane to a solution of 5 g (0.02 mol) of 4-methoxy-3-(4-methyl piperazin-1-yl)benzoic acid [J. Med. Chem., 37 (15), 2255 (1994)] and 3.25 g (0.05 mol) of sodium azide in 4.05 ml of pyridine. After stirring for 12 hours, wash the organic phase with 100 ml of water, separate off the organic phase, dry it over magnesium sulphate and evaporate off the solvent in vacuo at 30° C.
Reaction SMILES: BrC(F)(F)C(Cl)(F)C=C.[F:10][C:11]([F:25])([C:21]([F:24])([F:23])[F:22])[C:12]([F:20])([F:19])[C:13]([O:16][CH2:17]C)([F:15])[F:14]>>[F:10][C:11]([F:25])([C:21]([F:22])([F:24])[F:23])[C:12]([F:19])([F:20])[C:13]([O:16][CH3:17])([F:15])[F:14]
Reactant: CCOC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C=CC(F)(Cl)C(F)(F)Br
Product: COC(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Solvency tests with 50% by volume 4-bromo-3-chloro-3,4,4-trifluorobutene and 50% by volume ethyl nonafluorobutyl ether were performed. The solvency characteristics of these mixtures matched or exceeded that of CFC-113with Krytox and Jet Lube. The solvency of the individual components was inferior to that of CFC-113toward Krytox and Jet Lube, illustrating the effectiveness of using mixtures as taught by this invention. Similarly, mixtures of 4-bromo-3,3,4,4-trifluorobutene and methyl nonafluorobutyl ether produced solvency characteristic that met or exceeded those of CFC-113.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH:3]=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C.[Pd]>[CH3:15][C:2]([CH3:1])([CH3:16])[CH2:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)C(=CC(C)(C)C)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CC(C)(C)C)C(=O)OCC

Procedure:
In 2-liter stainless steel pressure reactor, to a solution of 114 g (0.50 mol) of diethyl (2,2-dimethylpropylidene)malonate in 650 ml of ethanol 1.60 g of 10% Pd/C was added. Hydrogenation was carried at 5 atm of hydrogen gas for 6 h at 40° C. The following GC analysis showed that conversion of the starting material into the title product was almost quantitative. The reaction mixture was added to 1500 cm3 of cold water, and the product was extracted by 3×300 ml of dichloromethane. The combined organic extract was passed through short layer of silica gel 60 (40-63 um), evaporated in vacuum, and then used without an additional purification. Yield of the title material was almost quantitative.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11](=[O:28])[C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:4].CO.O.[OH-].[Li+]>C1COCC1>[C:24]([O:23][C:21]([NH:20][C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:11]([N:6]1[CH2:7][C@H:8]([OH:10])[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])=[O:28])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester (4.7 g, 11.8 mmol) was dissolved in THF (80 mL), methanol (20 mL), and water (40 mL). Powdered lithium hydroxide (5.6 g, 233 mmol) was added. The light yellow slurry was stirred at rt under N2 for 16 h, and then concentrated in vacuo. The residue was partioned between ether and water. The ether phase was discarded, and the aqueous phase was treated with 1N HCl until the pH was 4. This acidic solution was extracted with EtOAc (3×). The combined EtOAc extracts were dried (MgSO4) and concentrated in vacuo to give 4.36 g (96%) of 1-(2(S)-tert-butoxycarbonylamino-8-nonenoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid as a white solid. This acid was then dissolved in 150 mL of DMF and (1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester hydrochloride (2.61 g, 13.6 mmol), N-methyl morpholine (2.5 mL, 22.6 mmol), and HATU (5.2 g, 13.7 mmol) was added. The reaction mixture was stirred at rt under N2 for 16 h, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (60%-80% ethyl acetate/hexane) gave 6.0 g (98%) of 1-{[1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)carbonyl]-(1R)-amino}-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester as a white solid: 1H NMR (500 MHz, CD3OD) δ 1.25 (t, J=7.2 Hz, 3H), 1.33-1.80 (m, 10H), 1.46 (s, 9 H), 2.09 (m, 3H), 2.25 (m, 2H), 3.76 (m, 2H), 4.14 (m, 2H), 4.27 (dd, J=8.5, 5.2 Hz, 1H), 4.50 (m, 2H), 4.94 (d, J=10.1 Hz, 1H), 5.01 (dd, J=17.1, 1.8 Hz, 1H), 5.11 (dd, J=10.4, 1.8 Hz, 1H), 5.30 (d, J=15.6 Hz, 1H), 5.80 (m, 2H), 8.57 (s, 1H); MS m/z 522 (M++1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:12][Br:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)cc(C(C)(C)C)c1

Procedure:
5-tert-butyl-m-xylene (15g) was dissolved in carbon tetrachloride (80ml), N-bromosuccinimide (16.45g) and a catalytic amount of azoisobutyronitrile were added and the reaction was heated at reflux for 4h. The reaction was cooled and the mixture filtered to remove the succinimide. The solvent was removed in vacuo to afford a light brown oil. Purification was carried out by chromatography on silica gel (eluting silica with 100% petroleum ether, bp 60°-800° C.) to afford 3-t-butyl-5-methylbenzyl bromide as a clear oil (15.3g). 1H NMR (360MHz, CDCl3) d 1.31 (9H; s; t-Bu), 2.34 (3H; s; CH3), 4.47 (2H; s; CH2Br), 7.04 (1H; s; Ar H), 7.13 (1H; s; Ar H), 7.25 (1H; s; Ar H). m/z (CI+)=258 (M+NH4+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][O:15][S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1oc(-c2ccc(Cl)nc2)nc1CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(Cl)nc3)oc2C)cc1
Reaction time: 8 h

Procedure:
The crude 2-[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethanol from step C is dissolved in methylene chloride (50 mL), then TsCl, DMAP and triethyl amine are added and stirred overnight. The reaction mixture is washed with water, brine and concentrated. Column chromatography on silica gel gave the title compound (0.5 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([CH3:11])[CH2:9][C@@H:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])[CH2:7][C@H:6]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:3])[CH3:2].[Br:27][C:28]1[N:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[CH:30][C:29]=1[F:37]>CCOC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([CH3:11])[CH2:9][C@@H:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH:18][C:34](=[O:35])[C:32]2[CH:31]=[CH:30][C:29]([F:37])=[C:28]([Br:27])[N:33]=2)[CH2:7][C@H:6]1[NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](C)C[C@@H](c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(F)c(Br)n1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C[C@H]1NC(=O)OC(C)(C)C

Procedure:
Following Method 9, (1R,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-(tert-butoxycarbonylamino)-6-methylcyclohexyl acetate and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, (1R,2R,4R,6S)-4-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-2-(tert-butoxycarbonylamino)-6-methylcyclohexyl acetate was obtained. LCMS (m/z): 567.2 (MH+), Rt=0.82 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([Cl:16])[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[Cl:16][C:4]1[N:3]=[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=1
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)c2)cc1Cl
Reactant: C1COCCN1
Product: Fc1ccc(-c2cc(Cl)nc(N3CCOCC3)c2)cc1Cl

Procedure:
Stir a solution of 2,6-dichloro-4-(3-chloro-4-fluoro-phenyl)-pyridine (100 mg) in morpholine (2 mL) 3 h at 80° C., concentrate, partition between H2O and EtOAc, dry over Na2SO4, and concentrate under vacuum. Purify by preparative TLC (3:1 hexanes/EtOAc) to give the title compound.
Reaction SMILES: [CH:1]12[CH:8]([N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.CC1C=CC(S(O[CH2:29][CH2:30][CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][CH2:31][CH2:30][CH2:29][N:3]2[CH2:4][CH:5]3[CH:8]([N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:34][CH:35]=1)#[N:40]
Reactant: CN(C(=O)OC(C)(C)C)C1C2CCC1CNC2
Reactant: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Yield: 59 %

Procedure:
A mixture of tert-butyl 3-azabicyclo[3.2.1]oct-8-yl(methyl)carbamate (Preparation D; 2.90 g, 12.1 mmol), 3-(4-cyanoanilino)propyl 4-methyl-benzenesulfonate (see step (ii) above; 3.98 g, 12.1 mmol), and potassium carbonate (1.67 g, 12.1 mmol) in DMF (50 mL) was heated at 90° C. under nitrogen for 4 h. The mixture was partitioned with water (50 mL) and diethyl ether (50 mL). The aqueous layer was separated and then extracted with diethyl ether (2×50 mL). The combined organic extracts were washed with saturated brine (2×30 mL), dried (Na2SO4), filtered and then concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane:methanol (98:2), to afford 2.85 g (59%) of the sub-title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[C:29]([F:34])([F:35])[C:30]([F:33])([F:31])[F:32])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCn2c(C(F)(F)C(F)(F)F)nc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(Cc1ccc(OCCn2c(C(F)(F)C(F)(F)F)nc3ccccc32)cc1)C(=O)O

Procedure:
The ethyl ester (200 mg, 0.4 mmol) from Step B was hydrolysed using NaOH (64 mg, 1.6 mmol) in ethanol (10 ml) and water (5 ml) by the procedure described in Step C of Example 1 (141 mg, 75%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[C:15][Si](C(C)C)(C(C)C)C(C)C)=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)[C@H](Nc1ccc(C)cn1)C[C@H](C)N2C(C)=O
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A solution of (2S,4R)-1-acetyl-2-methyl-N-(5-methyl-2-pyridinyl)-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 109) (135 mg, 0.284 mmol) in tetrahydrofuran (THF) (3 mL) at room temperature was treated with TBAF (1N in THF, 0.341 mL, 0.341 mmol) and the resulting mixture was stirred at this temperature for 30 min then most of the solvent was removed in vacuo. The residue was partitioned between AcOEt and water and the layers were separated. The organic phase was washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 10 G silica cartridge (gradient:5 to 25% (20% MeOH in DCM) in DCM) gave (2S,4R)-1-acetyl-6-ethynyl-2-methyl-N-(5-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine (70 mg, 0.219 mmol, 77% yield) as an orange foam.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:31])[CH:11]([N:15]1[C:19](=[O:20])[CH:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[NH:17][C:16]1=[O:30])[CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1>CO.[Pd]>[Br:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH:18]2[C:19](=[O:20])[N:15]([CH:11]([CH:12]([CH3:14])[CH3:13])[C:10]([NH:9][OH:8])=[O:31])[C:16](=[O:30])[NH:17]2)=[CH:28][CH:27]=1
Reactant: CC(C)C(C(=O)NOCc1ccccc1)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)C(C(=O)NO)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Yield: 52 %

Procedure:
The oil obtained in step i above (22i) (271 mg, 0.571 mmol) and 10% Pd/C (31 mg) were stirred in MeOH (25 mL) at room temperature for 3 h under H2 atmosphere, the mixture was filtered through celite, washed with MeOH for several times and then concentrated. The residue was purified by silica gel column chromatography which gave the title compound as an oil (118 mg, 52% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:25])[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>N1C=CC=CC=1>[OH:25][C:8]1([C:4]2[CH:3]=[C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH:7]=[CH:6][CH:5]=2)[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:12]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN2CC3CCC(C2)C3(O)c2cccc(N)c2)cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(CN2CC3CCC(C2)C3(O)c2cccc(NS(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
8-(3-Amino-phenyl)-3-(4-methoxy-benzyl)-3-aza-bicyclo[3.2.1]octan-8-ol (2.11 g, 6.23 mmol) in pyridine (15 mL) at 0° C. was charged with methanesulfonylchloride (0.72 mL, 9.35 mmol) dropwise. The reaction was warmed to room temperature and judged complete by TLC after 3 h. Following a water addition (20 mL), the product was extracted with EtOAc (4×30 mL), the organic layer was washed with saturated aqueous NaCl solution (6×50 mL), dried over Na2SO4, filtered and concentrated to give a crude orange liquid. Flash chromatography provided the title compound as a yellow semi-solid (1.28 g, 49%). (TLC 50% EtOAc/Hexanes Rf 0.24); 400 MHz 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J=8.7 Hz, 2H), 7.27 (m, 3H), 7.14 (dd, J=7.1, 2.1 Hz, 1H), 6.83 (d, J=8.7 Hz, 2H), 3.77 (s, 3H), 3.53 (m, 2H), 2.96 (s, 3H), 2.82 (m, 2H), 2.60 (m, 2H), 2.36 (br s, 2H), 1.78 (m, 2H), 1.36 (m, 2H); APCI MS m/z 417.1 (M+1)+; LCMS m/z 417.1 (M+1)+.