Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12](OCC)=[O:13])=[CH:7]2.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([CH2:12][OH:13])=[CH:7]2
Reactant: CCOC(=O)c1cc2cccc(F)c2n1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1c(CO)cc2cccc(F)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
Ethyl 7-fluoro-1-methyl-1H-indole-2-carboxylate (4.5 g) was dissolved in dry THF (50 ml), and cooled to -78° under nitrogen. Diisobutylaluminium hydride (DIBAL) (1M solution in hexane; 22.3 ml) was added and the mixture was stirred at -78° for 3 h, then allowed to warm to room temperature over 1 h. A further portion of DIBAL :(3 ml) was added to the recooled mixture at -78°, and stirring was continued for a further 16 h. Saturated ammonium chloride solution (10 ml) was added and the mixture was stirred for 30 min. Magnesium sulphate (dried, 10 g) was added, and the resultant mixture was filtered and evaporated in vacuo to leave an oil which was purified by FCC eluting with ether:hexane (1:1) to give the title compound (1.55 g) as a solid, m.p. 89°-91°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([NH2:12])=[NH:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[Cl:22][C:23]([SH:26])(Cl)Cl>ClCCl>[Cl:22][C:23]1[S:26][N:12]=[C:10]([CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:11]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)C(OC1CCCCO1)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1cccc(C(OC2CCCCO2)c2nsc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To an ice-cooled solution of 2-(3-chlorophenyl)-2-(tetrahydropyran-2-yloxy)acetamidine hydrochloride (12.0 g, 39.51 mmol) in dichloromethane (20 mL) and sodium hydroxide (9.49 g, 0.237 mol, dissolved in 60 mL water) was added a solution of perchloromethyl mercaptan (9.18 g, 49.46 mmol) in dichloromethane (50 mL) over a period of 35 min. The reaction mixture was stirred at ice-cold temperature for a further 1 h and the organic layer was collected, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a mixture of hexane and ethyl acetate (94/6) afforded the title compound as a light yellow oil (8.4 g, 61.5%). 1H-NMR (CDCl3) δ7.56 (d, J=6.9 Hz, 1H, Ar--H), 7.39-7.44 (m, 1H, Ar--H), 7.28-7.32 (m, 2H, Ar--H),6.08 and 6.03 (s, 0.5H each, α-H), 4.84 and 4.72 (t, J=3.1Hz, 0.5H each, OCHO), 3.49-3.92 (m, 2H, OCH2), 1.55-1.94 (m, 6H, 3CH2).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([S:10][CH3:11])[CH:3]=1.CO.Cl.O>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([S:10][CH3:11])[CH:3]=1
Reactant: CSc1cc(F)ccc1C#N
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(F)ccc1CN
Temperature: 60 °C
Yield: 7.6 %

Procedure:
4-Fluoro-2-(methylthio)benzonitrile (prepared as in Anthony, N. J. et al. PCT Appl. WO 02/30931, 2002) (1.67 g, 0.1 mol) was dissolved in 20 mL THF (under N2) and treated with 10 mL 2M BH3—(CH3)2S. This was heated at 60° C. for 2 hrs. Heating was discontinued and 5 mL MeOH was cautiously added, followed by the cautious addition of 4 mL 6N HCl. Then 20 mL more H2O added and EtOAc and the layers were separated. The aqueous layer was made basic with 1N NaOH and extracted with CH2Cl2. The extracts were dried (MgSO4), filtered, concentrated and dried in vacuum to give the title compound (1.3 g, 76%)as a solid. 1H NMR (500 MHz, CDCl3) δ: 7.20-7.31 (1 H, m) 6.90 (1H, dd, J=2.4 Hz) 6.75-6.86 (1H, m) 3.86 (2H, s) 2.47 (3H, s). LC/MS (M+H): 172.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([CH:24]=[O:25])[CH:21]=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:26]([NH2:28])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[CH:29]1([Mg]Br)[CH2:31][CH2:30]1>C1COCC1>[CH:29]1([CH:24]([OH:25])[C:22]2[CH:21]=[N:20][N:19]([CH2:18][C:14]3[CH:13]=[C:12]4[C:17]([C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[CH:9][C:10]([C:26]([NH2:28])=[O:27])=[N:11]4)=[CH:16][CH:15]=3)[CH:23]=2)[CH2:31][CH2:30]1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(Cn3cc(C=O)cn3)cc2n1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(Cn3cc(C(O)C4CC4)cn3)cc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a 0° C. solution of 4-(4-fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carboxamide (3-9, 36.0 mg, 0.0960 mmol, 1.0 equiv.) in anhydrous THF, under nitrogen was added dropwise 0.5 M cyclopropylmagnesium bromide in THF (0.769 mL, 0.385 mmol, 4.0 equiv.). The resulting mixture was stirred at 0° C. for 1 hour, quenched with sat. aqueous NH4Cl, extracted with ethyl acetate (3×5.0 mL), dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 7-({4-[cyclopropyl(hydroxy)methyl]-1H-pyrazol-1-yl}methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-10, 25.0 mg, 62.4%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.228 (s, 1H); 8.084 (br s, 1H); 7.995 (s, 1H); 7.929 (d, J=8.81 Hz, 1H); 7.625 (s, 1 μl); 7.515 (s, 1H); 7.442-7.506 (m, 3H); 7.206-7.249 (m, 2H); 5.777 (br s, 1 μl); 5.526 (s, 2H); 4.044 (d, J=8.48 Hz, 1H); 1.185-1.258 (m, 1H); 0.599-0.638 (m, 2H); 0.331-0.454 (m, 2H). LRMS m/z (M+H)+ 417.2 found, 417.2 required.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])#[CH:2].I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[O:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:2]=1
Reactant: Oc1ccccc1I
Reactant: C#Cc1ccccc1OC
Product: COc1ccccc1-c1cc2ccccc2o1

Procedure:
The general procedure was used to convert 2-ethynyl-anisole and 2-iodophenol to the title product. Purification by flash chromatography (10% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a white solid (348 mg, 77% yield). 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=7.73, 1H), 7.58 (d, J=6.41, 1H), 7.48 (d, J=8.10, 1H), 7.34 (s, 1H), 7.26-7.18 (m, 3H), 7.03 (t, 1H), 6.89 (d, J=8.29, 1H), 3.86 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 156.42, 153.83, 152.15, 129.77, 129.20, 126.95, 124.08, 122.62, 121.01, 120.69, 119.25, 110.93, 110.78, 106.31, 55.87. Anal. Calcd. for C15H12O2: C, 80.34; H, 5.39. Found C, 80.60; H, 5.65. m.p.: 76° C.
Reaction SMILES: [K+].[Br-].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([N+:13]([O-])=O)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]>CO.[Pd]>[NH2:13][C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: Cc1ccc([N+](=O)[O-])c(C(N)=O)c1
Agent: [Pd]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(N)c(C(N)=O)c1
Yield: 96.3 %

Procedure:
A mixture of 5-methyl-2-nitrobenzoic acid (12) (36.2 g, 0.2 mol) and SOCl2 (50 mL) was heated under reflux for 20 min, during which a homogeneous solution was obtained. After removal of the excess SOCl2 with the aid of a water aspirator, the residue was dissolved in dry THF (40 mL) and the solution added dropwise with stirring to an ice-cold solution of NaOH (8 g, 0.2 mol) in 28% NH4OH (300 mL). The precipitate was collected, washed with water, and recrystallized from EtOH-H2O to obtain 5-methyl-2-nitrobenzamide (13) (31.5 g, 87%) as a white solid; mp 176°-177° C. [lit. (Findeklee, Ber. 38:3558, 1905) mp 176°-177° C.]; IR (KBr) V 1655 Cm-1 (amide C=O). A solution of 13 (31.5 g, 0.175 mol) in MeOH (250 mL) was shaken With 5% Pd-C (0.5 g) under 3 atm. of H2 for 24 h in a Parr apparatus. A solid formed after the initial heat of reaction subsided. The mixture was heated to boiling to redissolve the product, and was filtered while hot. The filtrate was evaporated under reduced pressure and the residue dried at 90° C. for 1 h (caution: some sublimation may occur) to obtain 2-amino-5-methylbenzamide (14) as a white solid (25.3 g, 96%); mp 173°-175° C. [lit. (Findeklee) mp 179° C.]; 1H-NMR (CDCl3) δ6.60 (d, 1H, J=8 Hz, C3 -H). To an ice-cold suspension of 14 (25.3 g, 0.168 mol) in 3.6N HCl (260 mL) was added dropwise over 25 min a solution of NaNO2 (12.75 g) in H2O (100 mL) while keeping the internal temperature below 5° C. After another 20 min of stirring at this temperature, 10N NaOH (100 mL) was added, causing all the solid to dissolve. The solution was acidified to pH 2 with 12N HCl and chilled. The solid was filtered and recrystallized from EtOH to obtain off-white needles (26.2 g, 97%); mp 217°-218° C. (dec, gas evolution) [lit. (Ferrand et al., Eur. J. Med. Chem. 2:337, 1987) mp 219°-220° C.]; IR (KBr) v 1680 (lactam C=O); 1H--NMR (d6 --DMSO+D2O) δ3.30 (s, 3H, 6--Me), 8.00 (m, 3H, aryl); UV (95% EtOH) λmax 208, 225, 282 nm.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)CCCCC1.[S:26]1[CH:30]=[CH:29][N:28]=C1C=O.[BH4-].[Na+]>CO>[S:26]1[CH:30]=[CH:29][N:28]=[C:1]1[CH2:7][NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1nccs1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(NCC2CCCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCc1cccc(NCc2nccs2)c1
Reaction time: 18 h

Procedure:
Å-3 Molecular sieves were added to a solution of aniline 17 (0.4 g, 1.6 mmol) and thiazole-2-carbaldehyde (0.18 g, 1.6 mmol) in MeOH. The reaction mixture was stirred for 18 h and then NaBH4 (0.121 g, 3.2 mmol) was added and the reaction mixture was stirred for overnight. The reaction mixture was filtered through Celite, concentrated under reduced pressure Purification by column chromatography (100-200 silica mesh, 20% EtOAc in hexane) gave tert-butyl 3-(3-(thiazol-2-ylmethylamino)phenyl)propylcarbamate as a brown oil. Yield (0.17 g, 31%); 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J=3.2 Hz, 1H), 7.56 (d, J=3.2 Hz, 1H), 6.96 (t, J=7.6 Hz, 1H), 6.80 (bs, 1H), 6.45-6.38 (m, 4H), 4.55 (d, J=6.0 Hz, 2H), 2.91 (q, J=6.4 Hz, 2H), 2.39 (t, J=7.2 Hz, 2H), 1.59 (quintet, J=7.2 Hz, 2H), 1.37 (s, 9H).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=1.CN(C)[CH:24]=[O:25]>C1COCC1>[C:18]([C:16]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([CH:24]=[O:25])[CH:17]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C=O)cc2c1OCC2(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 28.1 %

Procedure:
t-Butyllithium (11.9 mL, 20.3 mmol, 1.7M in pentane) is added dropwise to a solution of 5-bromo-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan (3.60 g, 12.7 mmol) in 50 mL of anhydrous THF at -78° C.; the resulting reaction mixture is stirred at -78° C. for 15 min and N,N-dimethylformamide (1.0 mL, 13.0 mmol) is introduced. The reaction mixture is kept at -78° C. for 0.5 h, quenched with water, warmed to room temperature, and extracted with ether. The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10%→20% ether-hexane) gives 0.83 g (28%) of 7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-formylbenzo[b]furan as a yellowish oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=1[CH2:15][O:16][CH:17]([CH2:20][CH2:21][OH:22])[CH2:18]O>O>[F:12][C:13]1[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=1[CH2:15][O:16][CH:17]1[CH2:20][CH2:21][O:22][CH2:18]1
Reactant: OCCC(CO)OCc1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Fc1ccccc1COC1CCOC1
Temperature: 200 °C

Procedure:
0.1 g of p-toluenesulphonic acid was added to 4.26 g (0.02 mol) of 2-(2-fluorobenzyloxy)-butane-1,4-diol and the mixture was slowly heated to 200° C. under a waterpump vacuum. A mixture of water of reaction and 3-(2-fluorobenzyloxy)-tetrahydrofurane was obtained in the distillate. After fractional distillation, 3.8 g (97.5% of theory) of 3-(2-fluorobenzyloxy)-tetrahydrofurane of boiling point 140° C./14 mm Hg were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:13][CH2:14]2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(Cl)cc2)CC1
Yield: 134 %

Procedure:
A mixture of p-bromochlorobenzene (3.13 g, 16.3 mmol), tert-butyl (piperidin-4-yl)-N-methylcarbamate (3.5 g, 10.8 mmol), palladium acetate (73 mg, 0.33 mmol), (S)-(−)-BINAP (305 mg, 0.49 mmol) and sodium tert-butoxide (2.2 g, 22.9 mmol) in toluene (30 ml) was refluxed under a nitrogen atmosphere for 3 hours. Ethyl acetate and water were added to the reaction mixture, the mixture was stirred for a while. The insoluble substances were removed by filtration through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) to afford tert-butyl N-[1-(4-chlorophenyl)piperidin-4-yl]-N-methylcarbamate (4.7 g, yield 89%) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][C:3]=1[I:12].[OH-].[Li+].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[NH2:42]>C(OCC)(=O)C.ClCCl.O.CO>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:42][C:41]2[CH:43]=[CH:44][C:45]([O:46][CH3:47])=[C:39]([O:38][CH3:37])[CH:40]=2)=[O:8])=[CH:4][C:3]=1[I:12]
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: COc1ccc(N)cc1OC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccc(N)c(I)c2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 500 mL round bottom flask was charged with methyl 4-amino-3-iodobenzoate (10.0 g, 36.1 mmol), methanol (270 mL), water (30 mL), and lithium hydroxide (1.82 g, 43.3 mmol). The vessel was flushed with nitrogen, fit with a reflux condenser, and the mixture heated to a gentle reflux for 20 h. The resulting mixture was then cooled to room temperature, acidify with 2N hydrochloric acid, then concentrated in vacuo. A 500 mL round bottom flask was charged with the resulting solid (9.5 g, 36.7 mmol) and dichloromethane (180 mL) was added. Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (10.0 g, 39.5 mmol) and triethylamine (11.1 mL, 79.2 mmol) were added. 3,4-Dimethoxyaniline (11.1 g, 72.1 mmol) was then added and the resulting mixture was stirred at room temperature for 24 h. The resulting mixture was then diluted with ethyl acetate and washed with 1N NaOH. The organic layer was dried with MgSO4, filter, then concentrate in vacuo to yield 4-amino-N-(3,4-dimethoxyphenyl)-3-iodobenzamide. 1H NMR (300 MHz, CDCl3) δ 8.23 (s, 1 H), 7.73 (d, J=8.5 Hz, 1H), 7.42 (s, 1H), 7.30 (d, J=8.6 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 3.74 (s, 3H), and 3.72 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH2:32][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CI)cc1
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Sodium iodide (99 mg, 0.660 mmol) and 4-(chloromethyl)benzonitrile (100 mg, 0.660 mmol) were dissolved in Acetone (Volume: 2.199 mL) and allowed to stir at room temperature for 4 hours. The resulting solid was filtered and the filtrate concentrated to obtain 4-(iodomethyl)benzonitrile (130 mg, 0.535 mmol, 81% yield) as an orange oil. It was taken directly to the next step without characterization and purification. N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (100 mg, 0.266 mmol) was dissolved in 1.0 mL of DMF and added to a suspension of sodium hydride (12.78 mg, 0.320 mmol) in 2.0 of DMF. The reaction was stirred at 80° C. for 10 minutes before adding 4-(iodomethyl)benzonitrile (129 mg, 0.533 mmol) dissolved in 2.0 mL of DMF. The reaction was allowed to stir overnight. After 18 hours, the reaction was cooled to room temperature before diluting with water and ethyl acetate. The organic phase was washed with water followed by saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was purified via column chromatography using 50% ethyl acetate/hexanes to 100% ethyl acetate. The purification provided product as a white solid. (Yield: 50 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.78-7.67, 7.66-7.57, 7.49, 7.43-7.01, 6.80-6.68, 5.65-5.51, 4.62, 4.54-3.83, 3.16-2.83, 2.75, 2.35-2.26, 1.80-1.24
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:11][C:10]=2[F:20])[S:6][C:5]=1[NH:21][C:22]1[N:27]=[C:26]([CH3:28])[C:25]([CH2:29][O:30][CH:31]2[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]2)=[CH:24][CH:23]=1)=[O:3].Cl.[OH-].[Na+]>C(#N)C>[NH:33]1[CH2:32][CH:31]([O:30][CH2:29][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:5]3[S:6][C:7]([C:9]4[C:10]([F:20])=[CH:11][C:12]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:13][C:14]=4[F:15])=[CH:8][C:4]=3[C:2]([NH2:1])=[O:3])=[N:27][C:26]=2[CH3:28])[CH2:34]1
Reactant: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1COC1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1COC1CNC1
Temperature: 50 °C

Procedure:
tert-Butyl 3-{[6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)-2-methylpyridin-3-yl]methoxy}azetidine-1-carboxylate (146 mg, 0.248 mmol) was suspended in acetonitrile (4 mL). Aqueous hydrochloric acid (3.7 mL of 1N, 3.7 mmol) was added, and the reaction was allowed to react at room temperature overnight. It was then heated to 50° C. for 5 hours. The mixture was cooled to room temperature, neutralized with 1 N aqueous sodium hydroxide and extracted with ethyl acetate (3×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1CC1C=CC=CC=1)[CH3:2].[ClH:20]>CO>[ClH:20].[CH2:18]([N:3]([CH2:1][CH3:2])[C:4](=[O:17])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)[CH3:19]
Reactant: CCN(CC)C(=O)[C@@H]1CCCN1Cc1ccccc1
Agent: Cl
Solvent: CO
Product: CCN(CC)C(=O)[C@@H]1CCCN1
Yield: 130.3 %

Procedure:
N,N-Diethyl-1-(phenylmethyl)-L-prolinamide (1.603 g, 6.156 mmol) was dissolved in a mixture of MeOH (50 mL) and 1N HCl (14 mL, 14 mmol), degassed and placed under argon. 10% Pd/C (480 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for 2 h. The contents were then degassed, and the Pd/C was removed by filtration through a fiberglass filter, washing with MeOH. The filtrate was concentrated in vacuo to provide pure N,N-diethyl-L-prolinamide hydrochloride (1.658 g, >99%). LCMS: (M+H)+: 171.1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCO)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 1.16 mL (10 mmol) of benzoylchloride in 10 mL dichloromethane is added to 0.93 mL (10 mmol) of 4-amino-butan-1-ol and 4.2 mL (30 mmol) of triethylamine dissolved in 50 mL of dichloromethane. The mixture is stirred overnight. 50 mL of saturated sodium carbonate solution is added. The organic phase is separated, dried with sodium sulfate and the solvent evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=O)[CH:13]=[N:14][CH:15]=1>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([C:16]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:13]=[N:14][CH:15]=1
Reactant: Nc1ccccc1S
Reactant: O=Cc1cncc(Br)c1
Solvent: CCO
Product: Brc1cncc(-c2nc3ccccc3s2)c1
Temperature: 100 °C
Yield: 48.5 %

Procedure:
To a mixture of 2-aminothiophenol (500 mg, 3.99 mmol) and 5-bromo-3-pyridinecarboxaldehyde (743 mg, 3.99 mmol) was added ethanol (10 mL). The mixture was then heated to reflux (100° C.) overnight under ambient air. After cooling, the mixture was dried under vacuum then redissolved in methylene chloride (100 ml). Solution was washed with water (100 ml) and brine (50 ml), and dried over sodium sulfate. The crude material was run through a plug of silica (16% ethyl acetate in hexanes), and precipitated from methanol to give 564 mg of the material 10 in 49% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])[CH:3]=1>C(O)(=O)C.CO.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Sc1ccccc1Br
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(Br)cc1Sc1ccccc1Br
Temperature: 40 °C
Yield: 99 %

Procedure:
To a mixture of 4-bromo-2-(2-bromophenylsulfanyl)-nitrobenzene, 1e (15.56 g; 40 mmol) in acetic acid (200 mL) and methanol (400 mL) was added zinc (15.7 g; 240 mmol) over a 30 min period. The mixture was heated to 40° C. for 1 h overnight, filtered, evaporated, and dried under vacuum overnight. The residue was suspended in 1N NaOH solution and extracted with methylene chloride. The organic phase was dried over MgSO4, filtered, and evaporated. The residue was purified via flash column chromatography (eluent gradient: 0 to 10% EtOAc in heptane) to yield 14.2 g (99%) of title compound 4-bromo-2-(2-bromophenylsulfanyl)-aniline, 2e.