Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:35][C:36](=[O:44])[NH:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:20][C@@H:21]3[O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(=O)CC>[CH3:33][N:31]([CH3:32])[C:30]([O:29][C@@H:21]1[C@@:22]2([CH3:23])[C:17](=[CH:16][CH:15]=[C:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH:5]=[O:4])[CH3:9])[CH2:18][C@@H:19]([O:35][C:36](=[O:44])[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:20]1)=[O:34]
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)Nc5ccccc5)C[C@H](OC(=O)N(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCC(C)=O
Product: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)Nc5ccccc5)C[C@H](OC(=O)N(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 10 h
Yield: 55 %

Procedure:
In 10 ml of 2-butanone was dissolved 95 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(N,N-dimethylcarbamoyl)oxy-3β-(N-phenylcarbamoyl)oxypregna-5,7-diene, followed by addition of 50 mg of pyridinium p-toluenesulfonate, and the mixture was stirred in an atmosphere of argon gas at a temperature of 50° C. for 10 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 45 mg of 1α-(N,N-dimethylcarbamoyl)oxy-3β-(N-phenylcarbamoyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=1)=[O:4].[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)=[CH:23][CH:22]=1.C(O)(=O)C.[Na].C([O-])(O)=O.[Na+]>ClC(Cl)C.C1CCCCC1.CCOC(C)=O.C(Cl)Cl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([S:27][C:28]2[CH:35]=[CH:34][C:31]([CH2:32][N:16]3[CH2:17][CH2:18][CH:13]([C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:19])[CH3:1])[CH:11]=[CH:10][C:9]=4[CH3:12])[CH2:14][CH2:15]3)=[CH:30][CH:29]=2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Reactant: O=Cc1ccc(Sc2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(Cc2ccc(Sc3ccc(F)cc3)cc2)CC1
Reaction time: 10 h
Yield: 36.2 %

Procedure:
2-methyl-N-(4-methyl-3-(4-piperidyl)phenyl)propanamide (130 mg, 0.500 mmol) and 4-(4-fluorophenylthio)benzaldehyde (116 mg, 0.500 mmol) were dissolved in dichloroethane (5.00 mL) and acetic acid (30.0 mg, 0.500 mmol), and sodium triacetoxborohydride (212 mg, 1.00 mmol) was added at room temperature. Stirring was continued under nitrogen at room temperature for 10 h, then a saturated aqueous NaHCO3 solution and CH2Cl2 was added. The phases were separated, and the organic phase was washed with water, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (eluent: cyclohexane:EtOAc (85:15 then 7:3)) gave N-[3-(1-{[4-(4-fluorophenylthio)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (86.3 mg, 36.2% yield) as a white solid. 1H NMR (CDCl3) δ 7.43-7.32 (m, 3H), 7.31-7.22 (m, 5H), 7.09-6.98 (m, 4H), 3.51 (s, 2H), 3.04-2.93 (m, 2H), 2.76-2.61 (m, 1H), 2.52-2.41 (m, 1H), 2.27 (s, 3H), 2.14-2.03 (m, 2H), 1.86-1.65 (m, 4H), 1.25 (d, 6H, J=7.026 Hz); ESMS m/e: 477.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1cccc(Br)n1
Reactant: C#CCCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1cccc(C=O)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 6-bromo-2-pyridinecarboxaldehyde (3.0 g) in tetrahydrofuran (10 ml), was added sequentially bis(triphenylphosphine)palladium(II)chloride (0.178 g), copper(I)iodide (0.024 g), 1-dodecyne (3.25 ml), and triethylamine (2.12 ml). The solution was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, charged again with bis(triphenylphosphine)palladium (II) chloride (0.024 g), copper (1) iodide (0.024 g), and triethylamine (2.12 ml), and 1-dodecyne (3.25 ml), and tetrahydrofuran (5.0 ml), and heated at 40° C. for 5 hrs. The reaction mixture was again cooled and recharged as above, and heated at 40° C. for 24 hrs. The cooled mixture was concentrated, taken up in ethyl acetate (100 ml), washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was taken up in ethyl acetate (100 ml) and filtered. The filtrate was combined with material from a similar reaction run 1.43 g of the carboxaldehyde and proportionate amounts of the catalysts, 1-dodecyne, and solvent. The filtrate was concentrated. The residue was purified by flash chromatography using 1.5% ethyl acetate/hexane followed by 1% ethyl acetate/hexane as eluents. The appropriate fractions were collected and concentrated to yield 2.24 g (29%) of product, as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]([CH2:14][CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH2:27])=[O:4].[F:28][C:29]1[CH:34]=[C:33]([Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=1OS(C(F)(F)F)(=O)=O.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.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[CH3:1][O:2][C:3]([C:5]1[N:13]([CH2:14][CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:18]([CH3:20])[CH3:19])[CH:21]([CH3:23])[CH3:22])[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:27][C:30]1[CH:31]=[CH:32][C:33]([Si:35]([CH3:37])([CH3:36])[CH3:38])=[CH:34][C:29]=1[F:28])=[O:4]
Reactant: C[Si](C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: COC(=O)c1c(N)c2cnccc2n1CCO[Si](C(C)C)(C(C)C)C(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cnccc2n1CCO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
A degassed solution of 3-amino-1-(2-triisopropylsilanyloxy-ethyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (1.41 g, 3.61 mmol), trifluoro-methanesulfonic acid 2-fluoro-4-trimethylsilanyl-phenyl ester (1.48 g, 4.69 mmol), Pd2dba3 (165 mg, 0.18 mmol), Xantphos (208 mg, 0.36 mmol) and Cs2CO3 (2.35 g, 7.21 mmol) in toluene (30 ml) was heated to reflux then stirred for 16 hours. The reaction mixture was cooled to ambient temperature then diluted with EtOAc and filtered through a pad of celite. The resultant solution was concentrated in vacuo to give a black oil. The oil was purified by flash chromatography (Si-PPC, pentane:ether, gradient 100:0 to 0:100) to provide the title compound as a yellow oil (1.78 g, 88%). LCMS (method B): RT=3.76 min, M+H+=558.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1.[F:28]C1C(F)=CC2C3C(C(=O)N(C4C=CC=CC=4F)N=3)=CNC=2C=1.N1CCNCC1>>[F:1][C:2]1[C:11]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[N:20]=[C:5]3[C:4]=2[CH:3]=1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1F
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Agent: C1CNCCN1
Product: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1F

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27c and piperazine. 1H-NMR (CD3OD) δ (ppm): 3.01 (4H, brm), 3.34 (4H, brm), 7.05 (1H, d, J=7.7 Hz), 7.16 (2H, m), 7.31 (1H, m), 7.40 (1H, m), 7.66 (1H, d, J=13.1 Hz), 8.44 (1H, s). m/z 382.2
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)[CH2:2][CH2:3][CH:4]=[CH2:5].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.B(F)(F)F.CCOCC.O>C1(C)C=CC=CC=1>[C:7]1([C:1]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:2][CH2:3][CH:4]=[CH2:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CCCC(=O)c1ccccc1
Reactant: C1CCNC1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: C=CCC=C(c1ccccc1)N1CCCC1
Yield: 78.9 %

Procedure:
In 50 ml of toluene, 1.60 g of 4-pentenophenone, 2.13 g of pyrrolidine and 0.14 g of boron trifluoride etherate were dissolved. The mixture was refluxed for 46 hours using a Cope water separator and molecular sieve 4A as the dehydrating agent. After having distilled out the solvent under a reduced pressure, the residue was subjected to a distillation under a reduced pressure to obtain 1.68 g of the desired enamine (yield: 79%).
Reaction SMILES: Cl([O-])=O.[Na+].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[CH:11][C:10]=1[NH:18][C:19](=[O:37])[CH2:20][CH:21]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH3:8])([CH3:7])[CH3:6].P([O-])(O)(O)=[O:39].[Na+].Cl>O.CS(C)=O.C(Cl)Cl.C(OCC)(=O)C>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[CH:11][C:10]=1[NH:18][C:19](=[O:37])[CH2:20][CH:21]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:39])=[O:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH3:6])([CH3:7])[CH3:8]
Reactant: O=P([O-])(O)O
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(C(=O)O)cc1OC
Yield: 89 %

Procedure:
A solution of 650 mg (7.19 mmol) of sodium chlorite in 7 ml of water was added dropwise over a period of 15 minutes to a solution of 1.44 g (3.18 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(4-formyl-2-methoxyphenyl)octanamide (prepared as described in Example 110) in a mixture of 15 ml of dimethyl sulfoxide and a 1 M aqueous solution of sodium dihydrogenphosphate, and the resulting mixture was stirred for 4.5 hours. At the end of this time, the reaction mixture was acidified with 1 N aqueous hydrochloric acid, and methylene chloride was added thereto to separate out crystals, which were collected by filtration. The crystals were washed with water and then with ethyl acetate to give 1.32 g (yield 89%) of the title compound as a powdery substance, melting at 204-206° C. (from methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]#[CH:22])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C(C2C=C(O)C(Cl)=CC=2F)=NC=C(C(F)(F)[F:31])C=1.C(Br)C#C>>[Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[C:14]([O:19][CH2:20][C:21]#[CH:22])[C:15]([Cl:18])=[CH:16][C:17]=2[F:31])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: C#CCOc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Agent: C#CCBr
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Yield: 67 %

Procedure:
In a preparation similar to that described above for 3-chloro-2-(4-chloro-3-propargyloxyphenyl)-5-trifluoromethylpyridine, reaction of 1.4 g (4.5 mmol) of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-trifluoromethylpyridine and 0.6 g (5 mmol) of propargyl bromide resulted in 1.1 g of colorless crystals. Yield: 67%; melting point: 97°-98° C.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].[K+].[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH2:16][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: NC(=O)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccccc1OCC1CC1

Procedure:
Salicylamide (15.22 g), potassium hydroxide (85%, 7.73 g) and cyclopropylmethyl bromide (16.024 g) were heated together under reflux in absolute ethanol (100 ml) for 91/2 hours. The cooled mixture was filtered to remove inorganic products and the filtrate was evaporated to an oil. The oil was dissolved in 1:1 toluene:ethyl acetate (200 ml) and the solution was washed with 10% potassium hydroxide solution (2×30 ml), water (50 ml) and saturated brine (50 ), dried (Na2SO4), and concentrated under reduced pressure, leaving 2-(cyclopropylmethoxy)benzamide as an oil which crystallised (17.606 g, 83%), mp 95°-100° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH2:7]2.[BH4-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:7][OH:8])[C:10]=1[CH2:9][OH:11]
Reactant: Cc1cccc2c1C(=O)OC2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cccc(CO)c1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
A solution of the 7-methyl-1(3H)-isobenzofuranone obtained above in tetrahydrofuran (80 ml) was cooled to 0° C., and lithium borohydride (1.90 g, 87.2 mmol) was added thereto. The mixture was stirred at 60° C. for 2 hours, then cooled to 0° C., and a 2N aqueous solution of hydrochloric acid (50 ml) was added dropwise. The product was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give an oily residue. The residue was subjected to chromatography on a silica gel (75 g) column (eluent; ethyl acetate:hexane=2:1˜1:0) to afford the title compound (4.17 g, 19% total yield from methyl 2,6-dimethylbenzoate) as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=1.C1COCC1>CO.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Yield: 91.3 %

Procedure:
A solution of 2-(4-methyl-1H-imidazol-1-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (0.73 g, 2.46 mmol) in MeOH (10 mL)/THF (10 mL) was treated with 10% Pd/C (50% wet, 0.261 g, 0.122 mmol) and the mixture was hydrogenated (50 psi) for 16 h at RT. The mixture was filtered through diatomaceous earth and washed with 10% methanol-DCM (3×10 mL). The combined filtrate was concentrated to afford 5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.6 g, 91%) as an off-white solid. MS (ESI) m/z: 268.2 (M+H+).
Reaction SMILES: [CH:1]([OH:3])=[O:2].F[C:5]1[CH:13]=[C:12]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[C:24]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])=[N:25][CH:26]=[CH:27][CH:28]=3)[C:18]([C:35]([F:38])([F:37])[F:36])=[CH:17][N:16]=2)[CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8].NC1C=CC(C(N)=O)=CC=1[F:49]>C(O)=O>[CH:1]([OH:3])=[O:2].[F:49][C:13]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:14][C:15]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[C:24]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])=[N:25][CH:26]=[CH:27][CH:28]=2)[C:18]([C:35]([F:36])([F:38])[F:37])=[CH:17][N:16]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1ccc(N)c(F)c1
Reactant: CN(c1ncccc1CNc1nc(Nc2ccc(C(N)=O)c(F)c2)ncc1C(F)(F)F)S(C)(=O)=O
Solvent: O=CO
Product: CN(c1ncccc1CNc1nc(Nc2ccc(C(N)=O)cc2F)ncc1C(F)(F)F)S(C)(=O)=O

Procedure:
Compound 14 was prepared in a manner similar to that described Example 13 for the preparation of 13 except that 4-amino-3-fluorobenzamide (1.5 equ/189 μM) was used instead of 4-amino-2-fluorobenzamide to provide the formic acid salt of 14 as a cream colored solid. Yield: 26 mg, 37%. LC-MS M+1=514. NMR (d6-DMSO) δ: 2.98 (3H, s), 3.09 (3H, s), 4.65 (2H, s), 7.35-7.66 (7H, m), 7.87 (1H, s), 8.23 (1H, s), 8.38 (1H, s), 9.19 (1H, s). FAK IC50: <0.000595 μM (Table 1, Example 322)
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (1 g, 2.99 mmol) was treated with Dioxane.HCl (30 mL) at 0° C. The reaction mixture was stirred at rt for 1 h. After completion of the reaction mixture, the solvent was removed under vacuo and the residue was dissolved in H2O (10 mL). The aqueous layer was treated with solid Na2CO3 until effervescence ceases and the solution was extracted with EtOAc (3×25 mL). The combined organic layer was dried over Na2SO4, concentrated to yield titled intermediate (700 mg, 92%), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 7.41-7.25 (m, 5H), 5.08 (s, 2H), 3.95-3.78 (m, 2H), 3.22 (bs, 2H), 2.82-2.75 (m, 1H), 2.61-2.45 (m, 2H), 1.82-1.78 (m, 1H), 1.69-1.59 (m, 1H), 1.40-1.33 (m, 1H), 1.22-1.10 (m, 1H). ES-MS: m/z [M+1]=235.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:9](=O)/[CH:10]=[CH:11]/[CH3:12]>Cl.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([CH:9]=[CH:10][C:11]([CH3:12])=[N:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: C/C=C/C=O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1ccc2ccc(Cl)cc2n1

Procedure:
To a solution of m-chloroaniline (25.51 g, 0.2 mol) in 100 mL of 6N HCl kept at reflux is added dropwise with stirring 85% aqueous crotonaldehyde (14.7 g, in 2.6 g of water). After an additional 45 minutes at reflux, the mixture is cooled and extracted with ethyl ether to remove tars. To the vigorously stirred solution is added ZnCl2 (27.2 g, 0.20 mol). A tan gum ball is formed. The mixture is then refluxed for a total of three hours to give a clear brown solution. Upon cooling, a gummy solid is formed which is filtered and triturated with 2-propanol followed by ethyl ether and dried in vacuo to give the quinaldine HCl-ZnCl2 complex. The 7-chloroquinaldine is then isolated by dissolving the complex into 150 mL of water and 50 mL of NH4OH, and concentrated to yield the crude product (tan solid 15.77 g, 44.4%). Purification of the crude product is achieved by flash chromatography, (silica Merck 60, methylene chloride:ethyl acetate 98:2). Removal of the solvent affords a light tan solid (11.1 g, 31.3%), m.p. dec. 68°-70° C. (lit: 42%, m.p. 75°-77° C.).
Reaction SMILES: C(O[C:4]([N:6]1[CH2:27][CH2:26][C:9]2[N:10]([CH3:25])[C:11]3[C:12]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:4][N:6]1[CH2:27][CH2:26][C:9]2[N:10]([CH3:25])[C:11]3[C:16]([C:8]=2[CH2:7]1)=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1
Reactant: CCOC(=O)N1CCc2c(c3cccc(Nc4ccc(C)cc4)c3n2C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(Nc2cccc3c4c(n(C)c23)CCN(C)C4)cc1
Reaction time: 0.17 h
Yield: 23 %

Procedure:
Ethyl-5-methyl-6-(4-toluidino)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (73 mg, 0.214 mmol) was dissolved in anhydrous THF (1 mL) under N2 and LAH (1M in THF, 0.42 mmol) was added slowly. The reaction was brought to reflux for 2 hours. The reaction was quenched by the addition of water (16 μL), 15% aq. NaOH (16 μL) and then water (49 μL). The reaction was allowed to stir for 10 minutes between each addition. The aluminum salts were removed by filtration. The filtrate was evaporated and purified by silica gel column chromatography (10%, then 20% EtOAc-Hex) to give 2,5-dimethyl-N-(4-methylphenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-amine (15 mg, 23%). 1H NMR (CDCl3, 300 MH2) δ 7.23-7.27 (m, 1H), 6.89-7.03 (m, 3H), 6.88 (d, 1H, J=7.3 Hz), 6.54 (d, 2H, J=8.4 Hz), 3.70 (s, 5H), 2.79-2.89 (m, 4H), 2.58 (s, 3H), 2.23 (s, 3H) ppm.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:11]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH2:3][CH2:4]2
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)CCCN2
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (100 mg) in N,N-dimethylformamide (1 ml), a solution of N-bromosuccinimide (134 mg) in N,N-dimethylformamide (1 ml) was added dropwise under ice cooling and stirred at the same temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracted organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure to give 6-bromo-1,2,3,4-tetrahydroquinoline (137 mg) as a yellow oil.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]2[C:27]([Cl:28])=[CH:26][N:25]=[C:24](Cl)[N:23]=2)(=[O:14])=[O:13])[CH2:8]1)(C)(C)C.[NH2:32][C:33]1[CH:34]=[CH:35][C:36]2[CH2:42][CH:41]([NH:43][CH2:44][CH2:45][OH:46])[CH2:40][CH2:39][CH2:38][C:37]=2[C:47]=1[O:48][CH3:49]>>[Cl:28][C:27]1[C:22]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:12]([N:9]2[CH2:10][CH2:11][C@@H:7]([OH:6])[CH2:8]2)(=[O:13])=[O:14])=[N:23][C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]3[CH2:42][CH:41]([NH:43][CH2:44][CH2:45][OH:46])[CH2:40][CH2:39][CH2:38][C:37]=3[C:47]=2[O:48][CH3:49])=[N:25][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1c(N)ccc2c1CCCC(NCCO)C2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@@H](O)C3)n2)ccc2c1CCCC(NCCO)C2

Procedure:
The title compound was prepared from {2-[(R)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine (150 mg, 0.30 mmol) and 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)-ethanol (75 mg, 0.30 mmol) in an analagous manner to Example 946 to afford an off-white foam. Mp: 90-2° C. LCMS (m/e) 603 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.37 (s, 1H), 8.49 (d, J=8 Hz, 1H), 8.16 (s, 1H), 7.98 (m, 2H), 7.61 (t, J=8 Hz, 1H), 7.52 (br s, 1H), 7.28 (m, 1H), 6.81 (m, 1H), 4.37 (m, 1H), 3.74 (s, 3H), 3.61 (m, 2H), 3.42 (m, 3H), 3.29 (m, 1H) 2.98-2.68 (m, 7H), 2.09-1.73 (m, 8H), 1.60 (m, 1H).