Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]([O:16][C:17](=[O:30])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[CH2:19][CH2:20][OH:21])([CH3:15])[CH3:14].FC1C=C(C=CC=1)CNCCO.C(N(CC)CC)C>ClCCl>[C:13]([O:16][C:17]([N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[CH2:19][CH2:20][O:21][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])=[O:30])([CH3:12])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1cccc(F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCCNCc1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCN(Cc2cccc(F)c2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add p-toluenesulfonyl-chloride (0.71 g, 3.71 mmol), portionwise, to a mixture of (3-fluoro-benzyl)-(2-hydroxy-ethyl)-carbamic acid dimethyl-ethyl ester (1 g, 3.71 mmol, prepared from 2-(3-fluoro-benzylamino)-ethanol by methods as are known in the art), triethylamine (0.751 g, 7.4 mmol) and dichloromethane (6 mL). Stir the resulting suspension vigorously overnight at room temperature. Add water (10 mL), separate the organic layer, and extract the aqueous layer with dichloromethane (5 mL), twice. Combine the organic layers and wash with citric acid (5 mL, 20% in water), dry with sodium sulfate and evaporate the solvent to give the final, desired compound. The final compound may be purified by chromatography.
Reaction SMILES: CO.Cl[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[N:8][CH:9]=1.[CH3:13][S-:14].[Na+]>O>[CH3:13][S:14][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[N:8][CH:9]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSc1ccc([N+](=O)[O-])nc1
Reaction time: 13 h
Yield: 45.3 %

Procedure:
A methanol (40 mml) solution of 5-chloro-2-nitropyridine (2.0 g. 12.6 mmol) was added dropwise to a methanol (20 ml) solution of sodium thiomethoxide (1.02 g, 13.9 mmol) while being cooled with ice, and after the mixture was stirred for 13 hours while raising its temperature to the room temperature, water added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was recrystalized with ethyl acetate-hexane to obtain 972 mg (yield 45%) of 5-methylthio-2-nitropyridine.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]#[N:18])[C:11]=3[CH2:10][CH2:9]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]2[C:26](=O)[O:27][CH2:28][C:24]=2[CH:23]=1.N1CC[O:35]CC1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[O:35]=[C:28]1[C:24]2[CH:23]=[C:22]([CH2:21][CH2:20][N:4]3[CH2:3][CH2:2][N:1]([CH2:7][CH:8]4[C:16]5[CH:15]=[CH:14][CH:13]=[C:12]([C:17]#[N:18])[C:11]=5[CH2:10][CH2:9]4)[CH2:6][CH2:5]3)[CH:31]=[CH:30][C:25]=2[CH2:26][O:27]1
Reactant: N#Cc1cccc2c1CCC2CN1CCNCC1
Reactant: C1COCCN1
Reactant: O=C1OCc2cc(CCBr)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1CCC2CN1CCN(CCc2ccc3c(c2)C(=O)OC3)CC1
Temperature: 60 °C

Procedure:
To a flask containing 1-(piperazin-1-ylmethyl)-2,3-dihydro-1H-indene-4-carbonitrile (0.04 g, 0.17 mmol) was added 5-(2-bromoethyl)-2-benzofuran-1-(3H)-one (0.02 g, 0.06 mmol), tetrabutyl ammonium iodide (0.02 g, 0.06 mmol) and morpholine (0.08 mL, 0.99 mmol); the resulting mixture was dissolved in DMF (3 mL) and stirred at 60° C. Analysis of the reaction mixture indicated that reaction had gone to completion. The solution was concentrated in vacuo and shot into Mass-directed HPLC for separation to give the desired 1-({4-[2-(3-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)indane-4-carbonitrile. LC-MS (IE, m/z): 402 [M+1]+. (0.27 μM)
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[CH:5]=1)(O)=[O:2].S(Cl)([Cl:25])=O>>[ClH:25].[Cl:25][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2ccc3ncccc3c2)c2ccccc12
Product: Cl
Product: O=C(Cl)c1cn(-c2ccc3ncccc3c2)c2ccccc12

Procedure:
20 cm3 of thionyl chloride are added at 22° C. under an argon atmosphere to 0.69 g (2.1 mmol) of 3-carboxy-1-(quinol-6-yl)-1H-indole. After stirring at reflux for 4 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is successively triturated twice with 10 cm3 of dimethoxyethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1 g of 3-chlorocarbonyl-1-(quinol-6-yl)-1H-indole hydrochloride in the form of an orange-coloured solid which is used directly in the following step.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[N:8]1([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[C:22]4[C:23]5[CH2:24][NH:25][CH2:26][CH2:27][C:28]=5[S:29][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(Cl)(=O)C>C(Cl)Cl>[N:8]1([CH:14]2[CH2:15][CH2:16][CH:17]([O:20][C:21]3[C:22]4[C:23]5[CH2:24][N:25]([C:3](=[O:5])[CH3:2])[CH2:26][CH2:27][C:28]=5[S:29][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:18][CH2:19]2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: c1nc(OC2CCC(N3CCOCC3)CC2)c2c3c(sc2n1)CCNC3
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)N1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c2C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
To a solution of 3-[[4-(morpholin-4-yl)cyclohexyl]oxy]-8-thia-4,6,12-triazatricyclo[7.4.0.0[2,7]]trideca-1(9),2 (7),3,5-tetraene trifluoroacetate (100 mg, crude) in DCM (20 mL) was added TEA (108 mg, 1.07 mmol). The solution was stirred for 10 min at 0° C. under nitrogen. Then acetyl chloride (41.9 mg, 0.53 mmol) was added to the reaction solution at this temperature and the resulting solution was stirred for 1.5 h at room temperature. The reaction was then quenched by the addition of ethanol and concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (Waters): Column: Xbridge Prep C18, 5 μm, 19*50 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (10% CH3CN up to 35% in 11 min, up to 95% in 1.5 min, down to 10% in 1.5 min); detector: UV 254/220 nm. After concentration in vacuo and lyophilization overnight, the corresponding 1-(3-[[4-(morpholin-4-yl)cyclohexyl]oxy]-8-thia-4,6,12-triazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl)ethan-1-one (22.1 mg) was obtained as a white solid. MS (ES): m/z 417 (M+H)+ and 429 (M+Na)+. 1H NMR (300 MHz, CD3OD): δ 8.54 (1H, s), 5.33-5.23 (1H, m), 4.91 (2H, s), 3.97, 3.90 (2H, t, t), 3.76-3.69 (4H, m), 3.05, 2.95 (2H, t, t), 2.67-2.58 (4H, t), 2.34-2.25 (3H, m), 2.25, 2.23 (3H, s, s), 2.10 (2H, d), 1.74-1.45 (4H, m).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22](S(C)(=O)=O)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[NH2:39][C@@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]1>O1CCOCC1.CN1CCCC1=O.C(Cl)Cl>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22]([NH:39][C@@H:40]5[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]5)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(N[C@@H]5CCCN(C(=O)OC(C)(C)C)C5)s4)ccc32)cc1
Temperature: 120 °C
Yield: 50 %

Procedure:
A yellow solution of 2-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (177.5 mg, 0.284 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (Small Molecules, Inc., Hoboken, N.J.; 0.251 mL, 1.296 mmol) in dioxane (2.0 mL) was heated in an open microwave vial at 90° C. for 2 d. The resulting solid residue was taken up in N-methyl-2-pyrrolidinone (0.4 mL) and heated under argon at 120° C. for 2.5 days. The mixture was then diluted with DCM (10 mL), concentrated onto silica gel, and chromatographically purified (silica gel, 0-100% EtOAc/Hex) to provide (R)-tert-butyl 3-(5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-ylamino)piperidine-1-carboxylate (98.0 mg, 0.142 mmol, 50%) as a yellow oil: MS (ESI, pos. ion) m/z: 689.2 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.80 (1H, s), 8.07 (1H, s), 8.06 (1H, d, J=8.2 Hz), 7.93 (1H, d, J=8.7 Hz), 7.82 (2H, d, J=8.4 Hz), 7.62 (1H, t, J=7.8 Hz), 7.28 (2H, d, J=8.0 Hz), 7.24 (2H, s), 6.63 (1H, d, J=8.2 Hz), 5.55 (1H, dt, J=12.0, 5.9 Hz), 4.40 (1H, d, J=6.1 Hz), 3.61-3.74 (2H, m), 3.47-3.57 (2H, m), 3.36-3.45 (2H, m), 3.30 (2H, m), 2.35 (3H, s), 1.47 (9H, s), 1.44 (6H, br. s.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[C:26](=[O:39])[N:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:28]=[CH:29][C:30]=1I)=[O:24].[CH2:40]([NH2:42])[CH3:41]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[C:26](=[O:39])[N:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:28]=[CH:29][C:30]=1[NH:42][CH2:40][CH3:41])=[O:24]
Reactant: CCN
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4c(I)ccn(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Product: CCNc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(-c3cnn(C)c3)c2)cc1F
Yield: 34 %

Procedure:
A mixture of Example A5 (100 mg, 0.155 mmol) in a methanolic solution of ethylamine (10 mL) was heated at 80° C. for 3 h. The mixture was concentrated to dryness and purified by HPLC to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-4-(ethylamino)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (30 mg, 34%). 1H-NMR (400 MHz, DMSO-d6): δ 13.29 (s, 1H), 10.51 (t, J=5.2 Hz, 1H), 8.52 (m, 1H), 8.47 (d, J=6.0 Hz, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.59 (dd, J=7.6, 11.2 Hz, 1H), 7.50 (d, J=5.2 Hz, 2H), 7.39 (m, 3H), 6.92 (d, J=4.4 Hz, 1H), 6.30 (d, J=8.0 Hz, 1H), 3.88 (s, 3H), 3.48 (m, 2H; obscured by water), 1.26 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 561.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:17][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Yield: 61.5 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxy-phenylamine (0.040 g, 0.13 mmol) was treated with 4-chlorophenyl isocyanate (0.023 g, 0.15 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 67 (0.034 g, 0.08 mmol, 56%) as a white solid. LCMS m/z (%)=449 (M+H79Br35Cl, 72), 451 (M+H81Br35Cl, 100), 453 (M+H81Br37Cl, 26). 1H NMR (400 MHz, acetone-d6) δ: 8.22 (s, 1H), 8.14 (s, 1H), 7.66 (dd, J=2.7, 9.0 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.49 (s, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.12 (d, J=9.0 Hz, 1H), 3.98-4.18 (m, 2H), 3.71 (s, 3H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:8]([C:9]2[C:14]3[CH:15]=[C:16]([C:19]([O:21]CC)=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:25])([CH3:24])[CH:10]=2)[CH2:7][CH2:6][S:5]1)#[N:2].[I-].[Li+]>N1C(C)=CC=CC=1C.C(OCC)(=O)C.Cl>[C:1]([N:3]=[C:4]1[N:8]([C:9]2[C:14]3[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:25])([CH3:24])[CH:10]=2)[CH2:7][CH2:6][S:5]1)#[N:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(N1CCSC1=NC#N)=CC(C)(C)O2
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: CC1(C)C=C(N2CCSC2=NC#N)c2cc(C(=O)O)ccc2O1
Yield: 59.4 %

Procedure:
A mixture of ethyl 4-(2-cyanoiminothiazolidin-3-yl)-2,2-dimethyl-2H-1-benzopyran-6-carboxylate (1.15 g) and lithium iodide (3.44 g) in 2,6-lutidine (11.5 ml) was refluxed overnight. The resulting mixture was dissolved in a mixture of ethyl acetate and 10% hydrochloric acid, and the organic layer was separated and washed with brine. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with 30:1 to 4:1 chloroform-methanol) followed by recrystallization from ethanol to give 4-(2-cyanoiminothiazolidin-3-yl)-2,2-dimethyl-2H-1-benzopyran-6-carboxylic acid (0.63 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][OH:32])[C:6]=2[CH:33]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][O:32][S:35]([CH3:34])(=[O:37])=[O:36])[C:6]=2[CH:33]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(CCO)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)OCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-chloro-5-(2-hydroxyethyl)-1-[6-(2-chlorobenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (3.7 g) in pyridine (50 ml) is added with stirring methanesulfonyl chloride (0.71 ml) under ice-cooling, and the mixture is stirred at room temperature for 3 hours. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The extract is washed with successively with diluted hydrochloric acid and water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-methanesulfonyloxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.8 g) as colorless amorphous.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2[nH]cc(CCNC(=O)c3ccc(-c4ccccc4)cc3)c2c1
Yield: 72.8 %

Procedure:
N-(2-(5-Methyl-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtained following Method C starting from 2-(5-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.080 g, 0.372 mmol), biphenyl-4-carbonyl chloride (0.0864 g; 0.391 mmol), and triethylamine (0.131 mL; 0.930 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel eluting with 1 to 10% ethyl acetate in dichloromethane furnished 0.096 g (73%) of N-(2-(5-Methyl-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH2:9][O:10][CH3:11])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:9][O:10][CH3:11])[CH2:4]1)#[N:2]
Reactant: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60 %

Procedure:
In a 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide (44 mg, 0.071 mmol) and TFA (1.8 ml, 23.4 mmol) were combined with dichloromethane (6 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (4 mL) and ethylenediamine (0.30 ml, 4.4 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 21 mg (59%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide as a white solid. MS: [M+H]+=492; 1H NMR (300 MHz, DMSO-d6) δ: 12.72 (br. s, 1H), 9.16 (s, 1H), 8.74 (d, J=8.7 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.50 (d, J=4.9 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 4.86-5.04 (m, 1H), 4.46-4.73 (m, 2H), 4.17-4.19 (m, 1H), 4.16-4.28 (m, 4H), 4.04-4.16 (m, 1H), 3.77-3.93 (m, 1H), 3.72 (dd, J=9.5, 4.9 Hz, 1H), 3.59-3.68 (m, 1H), 3.27 (app d, J=4.9 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(N(CC)CC)C.Br[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[S:28]1(=[O:38])=[O:37].[Cl-].[Na+].Cl>CN(C)C=O.C1(C)C=CC=CC=1>[O:37]=[S:28]1(=[O:38])[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31](=[O:32])[N:27]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: COc1cccc2c1CC(CN)CC2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC(CNCCCCN1C(=O)c3ccccc3S1(=O)=O)CC2

Procedure:
0.95 g of 2-aminomethyl-8-methoxytetralin (5 mmol), 0.70 ml of triethylamine (5mmol) and 1.59 g of 2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (5 mmol) are stirred at 40° C for 24 h in 19 ml of dimethylformamide. The reaction solution is then stirred into a mixture of 190 ml of 5% strength sodium chloride solution, 60 ml of toluene and 5 ml of 1N hydrochloric acid. After the organic phase has been separated off, the aqueous phase containing the final product precipitated as the resinous hydrochloride is stirred with 60 ml of toluene and 7 ml of triethylamine (50 mmol). The organic phase is separated off again, washed until neutral with water and dried over sodium sulphate. The solvent is distilled off in vacuo. The residue is chromatographed on silica gel 60 (Merck). Toluene/methanol 85:15 is in this case used as the eluent. The main fractions contain the two final products as yellow, viscous oils.
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:48])([F:47])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[C:43]([CH2:45][NH2:46])[CH:42]=[CH:41][N:40]=2)=[CH:35][CH:34]=1>C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:3]([CH2:1][CH3:2])[C:4](=[CH2:8])[C:5]([NH:46][CH2:45][C:43]2[CH:42]=[CH:41][N:40]=[C:39]([C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]([F:48])([F:30])[F:47])=[CH:38][CH:37]=3)[CH:44]=2)=[O:7])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.9 %

Procedure:
A solution of acid 4B (0.25 g, 1 mmol) in THF (20 mL) was added with DEPC (0.17 mL, 1.3 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.27 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (30 mL) and washed with water (50 mL) and brine. The separated organic phase, after drying over Na2SO4, was evaporated under reduced pressure and the residue purified by flash chromatography (7:3 EtOAc:Petroleum ether) to afford a pale orange solid (0.12 g) after crystallization from a mixture of diethyl ether/petroleum ether.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:9]1([C:8](=[O:15])[C:20]#[C:19][CH2:18][CH2:22][CH2:14]/[CH:13]=[CH:12]/[C:7]2[CH:6]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Product: O=C(C#CCCC/C=C/c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
(Cacchi, S. et al. Org. Lett. 2008, 10, 2629) To a flame-dried two-neck 10 mL round-bottomed flask equipped with an argon inlet adapter, a septum, and a stir bar was added PdCl2(PPh3)2 (0.012 g, 0.017 mmol), THF (3 mL), triethylamine (0.14 mL, 1.03 mmol), and benzoyl chloride (0.12 mL, 1.03 mmol). The solution was stirred for 10 min at rt, and copper(I) iodide (0.007 g, 0.034 mmol) was added all at once through the sidearm turning the reaction from cloudy yellow to clear orange. The reaction was stirred for 10 min, and enyne S1 (0.146 g, 0.86 mmol) in THF (0.5 mL) was added all at once via syringe. The reaction was stirred for 3 h until complete by TLC, in which time the reaction became cloudy and yellow. Water was added to the reaction, and the aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were washed with 1 M hydrochloric acid, sat'd aq ammonium chloride, and brine, dried over magnesium sulfate, gravity filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (25 g silica cartridge, 0-10% ethyl acetate/hexanes) to yield product 5e as a yellow oil (0.168 g, 71%).