Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][CH2:23][CH2:24][N:25]([CH3:29])[C:26](=[O:28])[CH3:27].[F:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C@H:37]([CH:41]([CH3:43])[CH3:42])[C:36](=[O:44])[CH2:35][CH2:34]2>CCCCCC.O1CCCC1.C1(C)C=CC=CC=1.O.CCCCC>[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][CH2:23][CH2:24][N:25]([CH3:29])[C:26](=[O:28])[CH2:27][C@@:36]1([OH:44])[CH2:35][CH2:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([F:30])[CH:32]=2)[C@@H:37]1[CH:41]([CH3:42])[CH3:43]
Reactant: CC(C)[C@@H]1C(=O)CCc2cc(F)ccc21
Reactant: CC(=O)N(C)CCCc1nc2ccccc2[nH]1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: CCCCC
Product: CC(C)[C@H]1c2ccc(F)cc2CC[C@]1(O)CC(=O)N(C)CCCc1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under a dry nitrogen atmosphere, a 2.5 molar solution of butyllithium in hexane, 8.4 mL (21 mmol) was added by syringe to 20 mL pentane. The solution was cooled to 0° C. and 2.75 mL (2.13 g, 21 mmol) diisopropylamine was added by syringe over six minutes. The solution was warmed to 25° C. and stirred for three hours, then volatiles were removed in vacuo. Tetrahydrofuran, 20 mL, was added via syringe to the residue, and the resulting yellow solution cooled to 0° C. A solution of 2.42 g (10.5 mmol) N-[3-(1H-benzimidazol-2-yl)propyl]-N-methylacetamide in 10 mL tetrahydrofuran was added by syringe over nine minutes. The yellow solution was stirred at 0° C. for fifteen minutes, then cooled to -78° C. (S)-6-Fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one, 2.166 g, 87.2% pure, 97.6:2.4 S:R, in 2 mL toluene was added by syringe over twelve minutes, and a further 2 mL toluene was used to complete the transfer. After stirring at -78° C. for two hours, the viscous yellow mixture was added to 50 mL water at less than 10° C. The suspension that formed was extracted with 50 mL diethyl ether, then with a further 25 mL diethyl ether; and the combined ether extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3.74 g of impure (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide as a yellow foam. The foam was recrystallized from 6-8 mL toluene, and washed on the filter with 5 mL of toluene at -30° C. to afford 2.69 g of (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide as a colorless solid, m.p. 132°-138° C. This material may be recrystallized a second time from toluene to remove residual (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one if necessary and desired.
Reaction SMILES: C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.Cl.NO.C[O-].[Na+].[OH:31][N:32]=[C:33]([C:39]([CH2:41]Br)=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35].[NH2:43][C:44]([NH2:46])=[S:45]>CO.C(O)C>[OH:31][N:32]=[C:33]([C:39]1[N:43]=[C:44]([NH2:46])[S:45][CH:41]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)C(=NO)C(=O)CBr
Reactant: NC(N)=S
Agent: C[O-]
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: CCOC(=O)C(=NO)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phenolphthalein indicator (3 drops) was added to a solution of hydroxylamine hydrochloride (4.2 g.) in dry methanol (60 ml.). To the solution was dropwise added with stirring at ambient temperature 1N methanol solution of sodium methoxide (60 ml.) until the color of the solution was changed to purplish red. Hydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The mixture was stirred for 30 minutes at ambient temperature. After precipitating sodium chloride was filtered off, 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylic acid (12.5 g.) was added to the filtrate and the mixture was refluxed with stirring for 1.5 hours. The reaction mixture was cooled to precipitate crystals. The crystals were collected by filtration and dried to give crude 2-hydroxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid (a mixture of syn and anti isomers) (5.5 g.). The filtrate was concentrated to the volume of 1/4 and ether was added thereto. Precipitating crystals were collected by filtration, washed with ether and dried to give the same compound (8.78 g.). Total yield (14.3 g.). (3) A mixture of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (2.4 g) and thiourea (0.76 g) in ethanol (15 ml) was stirred for 1 hour at 60° C. Ethanol was distilled off under reduced pressure and water was added to the residue. The resultant mixture was adjusted to pH 1.0 and washed with ethyl acetate. The aqueous layer was adjusted to pH 4.5 with triethylamine and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography on silica gel using a mixture of ethyl acetate and benzene (1:3) as developing solvent. The eluates containing syn isomer were collected and concentrated to give ethyl 2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (0.3 g).
Reaction SMILES: C1(C)C=CC=CC=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[S:13][CH2:14][CH2:15][C:16]([OH:18])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC.O>[S:8]1[C:9]2[S:13][CH2:14][CH2:15][C:16](=[O:18])[C:10]=2[CH:11]=[CH:12]1
Reactant: O=C(O)CCSc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1CCSc2sccc21
Reaction time: 1.5 h

Procedure:
In a 2-L three-neck round-bottom flask fitted with an overhead mechanical stirrer, thermometer, addition funnel, reflux condenser, and nitrogen bubbler vented through an acid-vapor scrubber was placed the toluene solution of 11 (130.7 g, 695 mmol). The reaction mixture was brought to an initial temperature of 20° C. and trifluoroacetic anhydride (161 g, 765 mmol) was added over 5 minutes to the stirred solution of 11. The reaction was then heated to 35°-38° C. and stirred for about 1.5 hours. The reaction was then slowly added to water (500 mL) maintaining the temperature at <25° C. A pH probe was placed in the vessel and the mixture was titrated to pH 7.0 with 50% sodium hydroxide (123 g, 1.53 mole). The layers were separated and the aqueous phase was extracted once with toluene (200 mL). The combined organic extracts were then concentrated under vacuum (43 mbar) to a volume of 200 mL and then diluted to 1.2 L with ethyl acetate for the next step (oxidation). A small sample was chromatographed to obtain the following data: Rf =0.29 (85:15 hexane:ethyl acetate). m.p. 61°-62° C. IR (CHCl3): 3120 w, 3090 m, 3010 m, 2930 w, 1660 s (C=O), 1500 m, 1390 s, 1315 w, 1280 w, 1265 m, 1190 w, 1035 w, 890 w. 1H NMR: δ7.42 (d, J=5.4, H2); 6.98 (d, J=5.4, H3); 3.33 (m, C5H2); 2.82 (m, C6H2). 13C NMR: δ188.9 (C4), 150.9, 135.0 (C3a, C7a), 126.1, 121.8 (C2, C3), 38.1 (C6), 30.0 (C5).
Reaction SMILES: [ClH:1].[C:2]([O:5][CH:6]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:7][O:8][CH:9]([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][CH3:24])C)(=[O:4])[CH3:3].[CH3:29][CH2:30][CH2:31]CC>>[ClH:1].[C:2]([O:5][CH:6]([CH2:25][N:26]([CH3:27])[CH3:28])[CH2:7][O:8][CH2:9][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][CH2:29][CH2:30][CH3:31])(=[O:4])[CH3:3]
Reactant: CCCCCCCCCCCCCCC(C)OCC(CN(C)C)OC(C)=O
Reactant: CCCCC
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCOCC(CN(C)C)OC(C)=O

Procedure:
1 l) (±)-3-dimethylamino-1-(2-hexadecyloxy)-2-propyl acetate hydrochloride; m.p. 78°-89° C. from n-pentane; yield 83.6%; and
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[N+]=[N-].CCOCC>C(O)C.[Pd]>[NH2:1][CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
A suspension of 5-(azidomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (10.3 g, 34 mmol, e.g. which can be as prepared in Intermediate 6) in ethanol (200 ml) was added to 10% palladium on carbon (1 g) and stirred under an atmosphere of hydrogen for 3 hours at room temperature. The catalyst was removed by filtration under nitrogen and washed well with ethanol. The filtrate was evaporated to dryness to give a dark oil. Ether was added and then evaporated to give the title compound as a foamy semi-solid (9.35 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([CH2:12][OH:13])[CH:5]=[CH:4][C:3]1=2.[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O>C(Cl)Cl>[C:18]([O:17][C:15](=[O:14])[NH:1][CH:2]1[C:3]2[C:8](=[CH:7][C:6]([CH2:12][OH:13])=[CH:5][CH:4]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NC1CCCc2cc(CO)ccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanol (2.0 g, 11.28 mmol) in CH2Cl2 (20 mL) was added (BOC)2O (2.7 g, 12.41 mmol). The resulting mixture was stirred at RT under N2 gas for 2 h. Reaction mixture was quenched with sat. NH4Cl, the organic layer was isolated and washed with water, brine, dried over MgSO4 and evaporated in vacuo to give the final product. MS m/z: 278.12 (M+H). Calc'd. for C16H23NO3-277.36.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10](=[O:40])[CH2:11][N:12]2[C:17](=[O:18])[C:16]3[CH:19]=[C:20]([CH2:22][CH3:23])[S:21][C:15]=3[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)[C:13]2=[O:39])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:41]B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:22]([C:20]1[S:21][C:15]2[N:14]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][CH:30]=3)[C:13](=[O:39])[N:12]([CH2:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([CH3:41])[CH:3]=3)=[O:40])[C:17](=[O:18])[C:16]=2[CH:19]=1)[CH3:23]
Reactant: CB(O)O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(Br)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(C)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 48 h
Yield: 80.8 %

Procedure:
A mixture of 4′-{[3-[2-(3-bromo-4-methoxyphenyl)-2-oxoethyl]-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.3 g), methylboronic acid (0.25 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.086 g), potassium carbonate (0.88 g), tetrahydrofuran (50 mL) and water (5 mL) was stirred under argon atmosphere at 50° C. for 2 days. The reaction mixture was diluted with ethyl acetate, and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.94 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([Br:21])=[CH:14][N:13]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([Br:21])=[CH:14][N:13]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Product: O=C(Nc1ncc(Br)cc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2-amino-5-bromo-3-nitropyridine as a light yellow solid as described in Example 1. 1H NMR (CDCl3): 10.56 (s, 1H), 9.00 (d, J=2.7, 1H), 8.82 (d, J=2.1, 1H), 8.69 (d, J=2.1, 1H), 8.27-8.23 (m, 1H), 7.53 (d, J=8.1, 1H).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C@@:25]3([N:30]=[C:29]([NH2:31])[CH2:28][O:27][CH2:26]3)[C:24]3[C:19](=[CH:20][CH:21]=[C:22](I)[CH:23]=3)[O:18][C:15]2=[N:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[Br:11][C:12]1[CH:13]=[C:14]2[C:25]3([N:30]=[C:29]([NH2:31])[CH2:28][O:27][CH2:26]3)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:7]4[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=4)[CH:23]=3)[O:18][C:15]2=[N:16][CH:17]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cccnc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: NC1=NC2(COC1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Temperature: 80 °C
Yield: 132 %

Procedure:
A vial charged with 2-fluoropyridin-3-ylboronic acid (0.078 g, 0.556 mmol), PdCl2(dppf)-CH2Cl2 (0.022 g, 0.026 mmol), (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine, and potassium carbonate (0.293 g, 2.118 mmol) was treated with 2.5 mL dioxane and 1 mL water. The vial was then flushed with argon, sealed and heated to 80° C. for 1 hr. The reaction mixture was diluted with EtOAc, dried over MgSO4 and concentrated under reduced pressure to yield 3-bromo-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.309 g, 0.700 mmol, 132% yield). This material was used without further purification. Step 2: A vial charged with Pd(PPh3)4 (0.079 g, 0.068 mmol), copper(I) iodide (0.013 g, 0.068 mmol), 18-crown-6 (0.045 g, 0.170 mmol), potassium fluoride (0.118 g, 2.040 mmol), trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.229 g, 1.360 mmol), and 3-bromo-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.300 g, 0.680 mmol) was treated with 3 mL DMF, sealed under argon, and heated to 110° C. overnight. The reaction mixture was then poured onto water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification of the crude residue by column chromatography [0-50% (9:1 DCM/MeOH)/DCM] gave (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.079 g, 0.094 mmol, 25.46% yield).
Reaction SMILES: [CH3:1][C@@H:2]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5]1.[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:1][C@@H:2]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:28]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:29])[CH2:3][N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:9]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: C[C@H](CN1CC=C(c2cccs2)CC1)Nc1ccccn1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: C[C@H](CN1CC=C(c2cccs2)CC1)N(C(=O)C1CCCCC1)c1ccccn1
Yield: 82.4 %

Procedure:
The title compound was prepared from (R)-[1-methyl-2-(4-thiophen-2-yl-3,6-dihydro-2H-pyrid-1-yl)-ethyl]-pyrid-2-yl-amine (2.4 g, 8 mmol) and cyclohexanecarbonyl chloride (1.173 g, 8 mmol) in the manner described in Example 5 above to yield 2.7 g of title compound as the dihydrochloride, m.p. 103°-6° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][C:24]=3[N:25]2[CH3:28])=[CH:21][CH:20]=1>>[CH3:28][N:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=4)=[CH:10][C:11]3=[O:15])[CH:27]=2)[C:23]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][C:24]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 57.9 %

Procedure:
4-(4-(Trifluoromethyl)phenyl)pyridin-2(1H)-one (86 mg, 0.36 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (120 mg, 0.32 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (97 mg, 58%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.74 (s, 4H), 7.58-7.52 (m, 2H), 7.36 (s, 1H), 7.08 (dd, J=8.2, 1.8 Hz, 1H), 6.92 (d, J=1.9 Hz, 1H), 6.50 (dd, J=7.2, 2.0 Hz, 1H), 4.65 (br m, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.81 (br m, 2H), 1.52 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]#[C:16][CH2:17][CH2:18][O:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:13][CH2:14]1)=[O:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.66 g (9.44 mmol) of trans-[4-(4-Hydroxy-but-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 75 ml CH2Cl2 was treated at 0° C. with 0.81 ml (10.38 mmol) methanesulfonylchloride, 1.14 ml (14.16 mmol) pyridine and 1.15 g (9.44 mmol) DMAP. The reaction mixture was stirred at RT for 3 h, water (19 ml) was added and the reaction was stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×) the organic phases were washed with aqueous saturated NaHCO3 (2×), aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 3.57 g (quantitative) of trans-Methanesulfonic acid 4-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-but-3-ynyl ester, MS: 360 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[C:3]=1[NH:10][C:11]([C:13]1[S:17][C:16]([NH:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:15][CH:14]=1)=[O:12].CN1CCOCC1.[CH3:45][C:46]([CH3:51])([CH3:50])[C:47](Cl)=[O:48].[NH4+].[Cl-]>C1COCC1.O>[C:47]([O:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:10][C:11]([C:13]1[S:17][C:16]([NH:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:15][CH:14]=1)=[O:12])(=[O:48])[C:46]([CH3:51])([CH3:50])[CH3:45]
Reactant: O=C(Nc1c(Cl)cccc1CO)c1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)C(=O)OCc1cccc(Cl)c1NC(=O)c1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Temperature: 25 °C
Yield: 104.2 %

Procedure:
To a solution of compound 7a (7.36 g, 14 mmol) in THF (200 mL) at 5° C. were added N-methylmorpholine (3.1 mL, 28 mmol) followed by slow addition of trimethylacetyl chloride (8a, 1.8 mL, 21 mmol). The reaction mixture was allowed to warm to room temperature over a period of 3 h. A solution of saturated NH4Cl in H2O (500 mL) was added. The mixture was extracted with EtOAc (2×250 mL). The combined extracts were washed with 1N HCl (500 mL), saturated NaHCO3 (500 mL), dried over MgSO4. The solution was filtered and concentrated in vacuo to give compound 9a as a white solid (8.90 g, 100% yield). 1H NMR (500 MHz, CDCl3) δ 1.16 (s, 9H), 5.01 (s, 2H), 7.20-7.40 (m, 18H), 7.79 (s, 1H), 8.30 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:32]([CH3:34])[CH3:33])[C:15]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([CH3:31])=[CH:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)=[O:16])[C@H:10]([CH:35]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]1([NH2:40])[CH2:39][CH2:38]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:32]([CH3:34])[CH3:33])[C:15]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([CH3:31])=[CH:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)=[O:16])[C@H:10]([CH2:35][NH:40][CH:37]2[CH2:39][CH2:38]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CC1
Reactant: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C=O)C(C)C)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3CNC3CC3)C(C)C)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,4R)-3-formyl-4-({isopropyl-[1-(3-methoxy-propyl)-3-methyl-1H-indole-6-carbonyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (6 g, 10.9 mmol) in dichloroethane (100 mL), cyclopropylamine (0.85 mL, 12 mmol) and NaBH(OAc)3 (4.32 g, 15.3 mmol) are added. The solution is stirred at RT overnight, then diluted with CH2Cl2. A saturated solution of NaHCO3 is added, the layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluent: AcOEt/MeOH 100:0 to 85:15) to give the title compound. TLC, Rf (AcOEt)=0.1. MS (LC-MS): 541.3 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.52 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([O:32]CC)=[O:31])[CH:24]=3)[NH:19]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[CH2:27][C:26]([CH3:28])([CH3:29])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=3)[NH:19]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(=O)(=O)c1ccc(F)cc1)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccc(F)cc2)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 2-(2-(4-fluorophenylsulfonamido)phenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous Sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-[2-(4-fluoro-benzenesulfonylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid. LC/MS m/e obsd. (ESI+) [(M+H)+] 455.20.