Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:13]([O:14]C(=O)C(C)(C)C)=[CH:12][C:8]2[CH:9]=[CH:10][O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>CCCCCC>[C:1]([C:5]1[C:13]([OH:14])=[CH:12][C:8]2[CH:9]=[CH:10][O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Oc1cc2ccoc2cc1C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: CC(C)(C)c1cc2occc2cc1O
Reaction time: 8 h
Yield: 84.1 %

Procedure:
Under a nitrogen stream, 0.12 g of 6-t-butyl-5-trimethylacetoxybenzofuran was dissolved in 5 ml of n-hexane at room temperature and 1.31 ml of diisobutylaluminium hydride (1M in n-hexane) was added dropwise and the mixture was stirred overnight. After the reaction was quenched with 5% hydrochloric acid, the mixture was extracted with water and ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified on a short column of silica gel (in n-hexane containing 5% ethyl acetate) to give 0.07 g of 6-t-butyl-5-hydroxybenzofuran as a reddish brown oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:11]=2[O:10][CH2:9][C:8]1=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1COc2c(Br)cccc2N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C1COc2c(Br)cccc2N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
To a solution of 8-bromo-4H-benzo[1,4]oxazin-3-one (343 mg, 1.5 mmol) in 10 ml anhydrous dimethylformanide was added sodium hydride (120 mg of a 60% suspension in mineral oil, 3.0 mmol) portionwise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 20 minutes, at which time the initial gas evolution ended. Benzyl bromide (0.22 ml, 1.8 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for 30 minutes. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (2×25 ml) and the combined organic fractions were washed with water (2×25 ml) and brine (2×25 ml). After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography (5%–15% Ethyl acetate/Hexane in 30 minutes) to give 402 mg of 4-benzyl-8-bromo-4H-benzo[1,4]oxazin-3-one as a yellow solid (84%). MS: 318 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:13]1([NH2:20])[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.C(N(CC)CC)C.O>CN(C)C=O>[CH2:11]([C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:19][CH:16]3[CH2:17][CH2:18][CH:13]([NH2:20])[CH2:14][CH2:15]3)[C:3]=2[CH:10]=1)[CH3:12]
Reactant: NC1CCC(N)CC1
Reactant: CCc1cc2c(Cl)ncnc2s1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1cc2c(NC3CCC(N)CC3)ncnc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
Into a 50-mL round-bottom flask, was placed 4-chloro-6-ethylthieno[2,3-d]pyrimidine (200 mg, 1.01 mmol, 1.00 equiv), cyclohexane-1,4-diamine (600 mg, 5.25 mmol, 5.22 equiv) in anhydrous N,N-dimethylformamide (5 mL) at room temperature. Then triethylamine (300 mg, 2.96 mmol, 2.95 equiv) was added via syringe and the resulting solution was stirred overnight at ambient temperature. After completion of the reaction, the resulting solution was diluted H2O, extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This desired 1-N-[6-ethylthieno[2,3-d]pyrimidin-4-yl]cyclohexane-1,4-diamine (0.3 g, crude) was obtained as a off-white solid which was used for next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].O1CCCC1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[O:23])=[CH:18][CH:17]=1>CC(=O)C.C(=O)=O.C(O)(=O)C.CC1C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[OH:23])=[CH:3][CH:4]=1
Reactant: O=C(c1ccncc1)c1ccc(F)cc1
Reactant: Fc1ccc(Br)cc1
Agent: O=C=O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A Grignard-complex was previously prepared starting from 22.75 parts of 1-bromo-4-fluorobenzene, 3.2 parts of magnesium and 45 parts of anhydrous tetrahydrofuran. The whole was cooled in 2-propanone/CO2 to a temperature of -20° to -25° C. A solution of 20.1 parts of (4-fluorophenyl)(4-pyridinyl)methanone in 45 parts of anhydrous methylbenzene was added dropwise, during a 30 minutes-period, at -20° C. Upon completion, the whole was stirred overnight at room temperature. After cooling to 0° C., the reaction mixture was decomposed by the dropwise addition of 50 parts of acetic acid. After stirring for 1 hour at room temperature, the precipitated product was filtered off and set aside. From the filtrate, the organic layer was separated, washed with 50 parts of water, dried, filtered and evaporated. The solid residue and the precipitated product, which was set aside (see above), were washed with water and distilled azeotropically with 180 parts of methylbenzene. The solid distillate was suspended in 80 parts of acetonitrile. The product was filtered off and dried, yielding 28 parts (94%) of α,α-bis(4-fluorophenyl)-4-pyridinemethanol (intermediate 26).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=O)[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:20])[NH:42][S:39]([CH3:38])(=[O:41])=[O:40])[CH:16]=1)[C:9]([CH3:24])([CH3:25])[CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NS(C)(=O)=O)c1)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 111.9 %

Procedure:
A solution of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (150 mg, 0.44 mmol) and 1,1′-carbonyldiimidazole (214 mg, 1.32 mmol) in tetrahydrofuran (3 mL) was heated to 60° C. for 2 h, then was cooled to room temperature and treated with methanesulfonamide (54.2 mg, 0.57 mmol, 1.3 eq.). After stirring for 10 min, the reaction mixture was treated with dropwise addition of a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (221 mg, 1.45 mmol) in tetrahydrofuran (1 mL). Upon completion of addition, the resultant mixture was stirred overnight. Thin layer chromatography (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The reaction mixture was quenched with brine and acidified with 1N hydrochloric acid solution to pH=5, extracted with ethyl acetate (twice). The combined organic layers were washed with brine for 3 times, dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 205 mg of methyl3,3-dimethyl-2-(3-(methylsulfonylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid, which was purified by column chromatography (petroleum ether:ethyl acetate=2:1 to 1:1) to afford 58 mg of white solid, which was used in next step.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:11])=[C:8]([OH:10])[CH:9]=1.I[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[N:21]=2)[N:18]=1>CN(C)C=O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:11])=[C:8]([CH:9]=1)[O:10][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([NH:22][C:23]([CH:25]3[CH2:26][CH2:27]3)=[O:24])[N:21]=2)[N:18]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Cc1ccc(N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
To a suspension of sodium hydride (56 mg, 1.40 mmol) in N,N-dimethylformamide (2.0 mL) was added a solution of 5-amino-2-methylphenol (173 mg, 1.40 mmol) in N,N-dimethylformamide (1.0 mL), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (306 mg, 0.933 mmol) in N,N-dimethylformamide (1.5 mL), and the mixture was stirred at 110° C. for 24 hr. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue. The aqueous layer was extracted three times with ethyl acetate. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=17/83→90/10) to give the title compound (94 mg, 31%) as a brown powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:22])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:23][NH2:24])=[CH:9][CH:8]=1)[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29].O.[OH-].[Na+]>N1C=CC=CC=1>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:22])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:23][NH:24][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:9][CH:8]=1)[CH3:26]
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccc(Br)cc3c(=O)c12
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)CCNc1ccc(CNS(C)(=O)=O)c2sc3ccc(Br)cc3c(=O)c12
Temperature: 25 °C
Yield: 86.5 %

Procedure:
1-[[2-(Diethylamino)ethyl]amino]-4-(aminomethyl)-7-bromothioxanthen-9-one (1 g, 2.3 mmol) in 11.5 mL of dry pyridine under nitrogen was stirred in an ice bath for 15 min and 0.2 mL (2.6 mmol) of methanesulfonyl chloride in chilled pyridine was added dropwise and the mixture was stirred at room temperature. The reaction mixture was poured into 200 mL of water, added 0.19 g of sodium hydroxide in ice/water, and extracted into chloroform. The organic layer was washed with water (2x) and brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated in vacuo and the residue was stirred in ether, filtered, and dried to afford 1.02 g of N-[[1-[[2-(diethylamino)ethyl]amino]-7-bromo-9-oxothioxanthen-4-yl]methyl]methanesulfonamide, m.p. 134°-139° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[C:13](OC(=O)C)(=[O:15])[CH3:14].Cl>CN(C)C=O>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([OH:10])=[C:2]([O:1][C:13](=[O:15])[CH3:14])[CH:3]=1)=[O:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,4-dihydroxybenzaldehyde (5.0 g) in N,N-dimethylformamide (36 mL) was added 60% sodium hydride (1.45 g) under ice-cooling, followed by stirring the reaction mixture at room temperature for 10 minutes. Then, after addition of acetic anhydride (3.6 mL), the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2N aqueous hydrochloric acid solution under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:2 to 1:1) to give acetic acid 5-formyl-2-hydroxyphenyl ester (4.9 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:32]2[CH:31]=[CH:30][N:29]=[C:28]([F:27])[CH:33]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(Br)c1
Reactant: OB(O)c1ccnc(F)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2ccnc(F)c2)c1
Yield: 52 %

Procedure:
By carrying out the operation analogously to example 3, starting from 3-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 2-fluoro-4-pyridineboronic acid, the expected product is obtained in the form of a white solid with a yield of 52%.
Reaction SMILES: [CH3:1][C:2]1[C:10]([S:11]([CH2:13][CH3:14])=[O:12])=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[OH:19][C:20]1[N:21]([CH3:25])[N:22]=[CH:23][CH:24]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C(OCC)(=O)C.O>[CH2:13]([S:11]([C:10]1[C:2]([CH3:1])=[C:3]([C:4]([C:24]2[CH:23]=[N:22][N:21]([CH3:25])[C:20]=2[OH:19])=[O:6])[CH:7]=[CH:8][C:9]=1[S:15]([CH3:18])(=[O:17])=[O:16])=[O:12])[CH3:14]
Reactant: CCS(=O)c1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reactant: Cn1nccc1O
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCS(=O)c1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Temperature: 0 °C
Yield: 95.1 %

Procedure:
305 mg of 2-methyl-3-ethylsulfinyl-4-methylsulfonylbenzoic acid and 106 mg of 3-hydroxy-2-methylpyrazole are suspended in 2 ml of ethyl acetate and 407 mg of pyridine under an inert atmosphere and cooled to −25° C. with stirring. 129 mg of thionyl chloride are then slowly added dropwise such that the temperature always remains below −20° C. Following the complete addition of the thionyl chloride, the mixture is stirred for a further 20 minutes. A further 27 mg of 3-hydroxy-2-methylpyrazole are added, and 42 mg of thionyl chloride are slowly added dropwise such that the temperature always remains below −25° C. 4 μl of cold water are then added and the mixture is warmed to 0° C. After separating the organic phase from the aqueous phase, the aqueous phase is extracted twice with 5 ml of ethyl acetate in each case. The combined organic phases are dried, giving 370 mg of [3-(ethylsulfinyl)-2-methyl-4-(methylsulfonyl)phenyl](5-hydroxy-1-methyl-1H-pyrazol-4-yl)methanone (91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][C:14]=2[C:22]2[C:23]([O:28][CH3:29])=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:40][S:41](Cl)(=[O:43])=[O:42].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:19][S:41]([CH3:40])(=[O:43])=[O:42])=[O:18])=[CH:15][C:14]=2[C:22]2[C:23]([O:28][CH3:29])=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1cnc(OC(C)C)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncccc1-c1cc(C(=O)NS(C)(=O)=O)ccc1Oc1cnc(OC(C)C)c(Cl)c1
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To a solution of 4-[(5-chloro-6-isopropoxypyridin-3-yl)oxy]-3-(2-methoxypyridin-3-yl)benzamide (Preparation 27, 436 mg, 1.05 mmol) in anhydrous THF (10.0 mL) was added lithium bis(trimethylsilyl) amide (1.0 M in THF, 2.63 mL, 2.63 mmol). The solution was stirred for 30 minutes before the addition of methanesulfonyl chloride (210 uL, 2.63 mmol). The reaction mixture was stirred for 1 hour and then a saturated aqueous solution of ammonium chloride (25 mL) was added to the reaction mixture. The reaction mixture was partitioned between water (30 mL) and EtOAc (25 mL). The aqueous phase was separated and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a solid. The material was purified by silica gel column chromatography, eluting with 60:40:1 heptane/EtOAc/acetic acid. Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a solid (230 mg):
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH3:13])=[C:9]([CH2:11]Cl)[CH:10]=1)=[O:5])[CH3:2].[C-:14]#[N:15].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH3:13])=[C:9]([CH2:11][C:14]#[N:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CCl)c(C)s1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(CC#N)c(C)s1
Temperature: 70 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
A solution of the 4-chloromethyl-5-methyl-thiophene-2-carboxylic acid ethyl ester mixture from part 2 (25.6 g) in DMF (350 mL) is treated with potassium cyanide (20 g, 0.312 mol) and heated to 70° C. with stirring for 2 h. After cooling to room temperature, the solution is diluted with water and extracted with chloroform (2×). The combined organic layers are washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (10% ethyl acetate in heptane) to give 4-cyanomethyl-5-methyl-thiophene-2-carboxylic acid ethyl ester (4.7 g, 18.8%; 2 steps) as a white solid. mp 55-57° C.; 1H NMR (CDCl3, 300 MHz) δ 7.63 (s, 1 H), 4.28 (q, J=6.0 Hz, 2 H), 3.60 (s, 2 H), 2.48 (s, 3 H), 1.38 (t, J=6.0 Hz, 3 H).
Reaction SMILES: [C:1](/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)#[N:2]>C(O)C.[Pd]>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)#[N:2]
Reactant: N#C/C=C/c1cccc2cc[nH]c12
Agent: [Pd]
Solvent: CCO
Product: N#CCCc1cccc2cc[nH]c12

Procedure:
A solution of 7-[2-(E)-cyanoethenyl]indole (0.28 g) in ethanol (75 ml) was hydrogenated at 50 psi over 10% palladium on charcoal (0.1 g) for 4 hours. The catalyst was filtered off and the filtrate was evaporated to give the product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:12][N:13]([CH3:17])[CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30].[Br-].[K+].[OH-].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:20]1[CH:19]=[C:18]([CH:11]2[C:10]3[C:15](=[CH:16][C:7]([C:35]4[CH:36]=[CH:37][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:33][CH:34]=4)=[CH:8][CH:9]=3)[CH2:14][N:13]([CH3:17])[CH2:12]2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CN1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN1Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 80 °C
Yield: 23.7 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (300 mg, 0.68 mmol) from Step G of Example 11, 4-(methylsulfonyl)phenylboronic acid (176 mg, 0.88 mmol), potassium bromide (243 mg, 2.04 mmol) and potassium hydroxide (114 mg, 2.04 mmol) in toluene (7 mL) was degassed with argon and then tetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) was added. The mixture was degassed again and then heated to 80° C. for 3 hours. The mixture was cooled to room temperature, diluted with dichloromethane/methanol (9:1), and filtered through a plug of silica. The filtrate was concentrated and the residue partially purified by column chromatography (hexanes to ethyl acetate) to give 4-(3,4-dichlorophenyl)-2-methyl-7-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (72 mg, 24%) as an off-white solid: ESI MS m/z 446 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:3][CH2:4][C:5]#N.[H-].C([Al+]CC(C)C)C(C)C.C([O:29]CC)C.Cl>C(Cl)Cl>[CH3:1][C:2]([CH3:16])([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:3][CH2:4][CH:5]=[O:29]
Reactant: CC(C)(CCC#N)CO[Si](C)(C)C(C)(C)C
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(CCC=O)CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a cooled (-78° C.) solution of 4.5 g (18.6 mmol) of 4,4-dimethyl-5-t-butyldimethylsilyloxyvaleronitrile in 36 mL of dry CH2Cl2 was added dropwise, over 30 min., 20.4 mL (20.4 mmol;1.1 eq) of a 1.0M solution of diisobutyl-aluminum hydride in CH2Cl2. After stirring for 2 h at -78° C., the cooling bath was removed and the solution allowed to warm to 0° C. To the crude (0° C.) reaction mixture was added 50-60 mL of ethyl ether, followed by the cautious addition of 10% HCl, until the mixture became strongly acidic (pH=1-2). Separation of the layers and three extractions of the aqueous phase with 100 mL ether, drying over MgSO4 and concentrating the combined organic layers gave 3.6 g (79%) of the title compound as a faint yellow oil, sufficiently pure to be used in the next step. TLC: (Silica) Rf 0.28 (CH2Cl2 /pentane 3:7), detection with Purpald.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[O:15]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOC(C)=O.ClC1C2C(=NC=CC=2)N=CC=1>C(OCCO)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: Clc1ccnc2ncccc12
Solvent: CCOCCO
Solvent: CCOC(C)=O
Product: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
In a 100 mL round-bottomed flask fitted with a condenser, 4-chloro-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.250 g, 1.20 mmol) and 3-phenoxyaniline (0.245 g, 1.32 mmol) were taken up in 20 mL 2-ethoxyethanol and heated at reflux for 1 hour, until TLC analysis (20% EtOAc in hexanes) showed complete disappearance of the 4-chloronaphthyridine. After cooling to room temperature, the reaction mixture was partitioned between 40 mL each EtOAc and 5% Na2CO3. The aqueous layer was extracted twice more with EtOAc, and the combined organic layers washed three times with brine, dried over anhydrous MgSO4, filtered, and evaporated to give 6-fluoro-4-(3-phenoxyphenylamino)-1,7-naphthyridine-3-carbonitrile as a brown oil of sufficient purity to be used directly in the next step: 1H NMR (400 MHz, DMSO-D6) δ 6.94-7.18 (m, 6 H) 7.33-7.51 (m, 3 H) 8.15 (s, 1 H) 8.68 (s, 1 H) 9.05 (s, 1 H) 10.12 (s, 1 H).