Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:39])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:36]([OH:38])=[O:37])[CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1>FC(F)(F)C(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:39])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:36]([OH:38])=[O:37])[CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[NH:12][C:11]([C:13]([F:14])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: Cc1cc(OCC2(C(=O)O)CC2)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(OCC2(C(=O)O)CC2)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.9 %

Procedure:
In trifluoroacetic acid (5.0 mL) and water (0.5 mL) was dissolved 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylic acid (219 mg), and the solution was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, a small amount of tetrahydrofuran was added to the residue, and the mixture was neutralized by 1N aqueous sodium hydroxide solution. Several drops of acetic acid was added to the mixture, the mixture was extracted with ethyl acetate, washed with a saturated brine, and the organic layer was separated and concentrated under reduced pressure. Isopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylic acid (95 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[CH:5]=[N:6]O>C(#N)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]#[N:6]
Reactant: ON=Cc1cc(F)cc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: N#Cc1cc(F)cc(Br)c1
Reaction time: 5 h
Yield: 89.3 %

Procedure:
The above oxime (3.76 g, 17.24 mmol) and copper (II) acetate (370 mg) were dissolved in acetonitrile (100 cm3) under nitrogen and heated under reflux. After 5 h, the mixture was evaporated, the residue taken into EtOAc, washed with sulfuric acid (1N), water, brine, dried (MgSO4) and evaporated to give 3-fluoro-5-bromobenzonitrile (3.08 g, 15.39 mmol, 89%) which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([CH3:28])[CH2:3][N:4]1[C:8]2=[N:9][CH:10]=[N:11][C:12]([NH2:13])=[C:7]2[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][C:15]=2[F:27])=[N:5]1.[C:29]([CH2:31][C:32](O)=[O:33])#[N:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:13][C:12]1[N:11]=[CH:10][N:9]=[C:8]2[N:4]([CH2:3][C@H:2]([NH:1][C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH3:28])[N:5]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:16][C:15]=3[F:27])[C:7]=12
Reactant: C[C@@H](N)Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)CC#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.6 %

Procedure:
To a solution of 1-[(2R)-2-aminopropyl]-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (1826.mg, 4.83 mmol), 2-cyanoacetic acid (821 mg, 9.7 mmol) and TEA (2.0 mL, 14.5 mmol) in DMF (25 mL) was added HATU (2.75 g, 7.24 mmol). The reaction mixture was stirred at room temperature for 20 hr. The mixture was then evaporated to an oil and dissolved in ethyl acetate (100 mL) and washed with 5% citric acid (50 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. The crude material was purified by Isolera (10 g col, 2%-6% MeOH/DCM) to obtain 2.1 g (98%) of N-[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]-2-cyano-acetamide.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH:15]=[O:16])=[O:7])([CH3:4])[CH3:3].IN1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+].[O-]S([O-])(=S)=O.[Na+].[Na+].[CH3:38][OH:39]>>[CH3:38][O:39][C:15](=[O:16])[C:10]1[C:9]([NH:8][C:6]([O:5][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:7])=[CH:14][CH:13]=[N:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C=O
Reactant: CO
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Product: COC(=O)c1cnccc1NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 96 %

Procedure:
Formula 504 where R1, R3 and R4 are H; W. Y and Z are —C═; and X is —N═: To a solution of methanol (100 mL) and N-Boc-4-amino-3-pyridine carboxyaldehyde (8.3 g, 37.3 mmol), were added N-iodosuccinimide (21.0 g, 93.4 mmol) and potassium carbonate (12.9 g, 93.4 mmol) at room temperature. The mixture was stirred for 1 hour and then poured into a saturated Na2S2O3 solution (100 mL). After further dilution with water (100 mL) the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the pure desired methyl ester product, 4-tert-butoxycarbonylamino-nicotinic acid methyl ester (9.0 g, 96%). MS (Cl) m/e: 253.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C(N(CC)CC)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:20]=1
Reactant: Oc1ccccc1Br
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Brc1ccccc1Oc1ccc(-c2ccccc2)cc1
Reaction time: 48 h

Procedure:
A mixture of 2-bromophenol (2.08 g, 12 mmol), 4-biphenylboronic acid (4.75 g, 24 mmol), Cu(OAc)2 (2.20 g, 12 mmol) and triethylamine (6.1 g, 60 mmol) in dioxane (100 mL) was stirred for 48 h. The crude mixture was evaporated onto silica gel and purified by column chromatography eluting with ethyl acetate/heptane 1:9. Yield: 0.73 g (19%). 1H NMR (CDCl3, 500 MHz) 7.65 (m, 1H) 7.55 (m, 4H), 7.43 (m, 2H), 7.25–7.38 (m, 2H), 7.00–7.08 (m, 4H); MS(m/z): 325.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([S:6][CH2:7][C:8]1([CH:16]=[CH:15][CH:14]=[CH:13][CH2:12]1)[C:9](O)=[O:10])=[S:5])[CH3:2].S(Cl)([Cl:21])=O>ClCCl>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([S:6][CH2:7][C:8]1([CH:16]=[CH:15][CH:14]=[CH:13][CH2:12]1)[C:9]([Cl:21])=[O:10])=[S:5])[CH3:2]
Reactant: CCN(CC)C(=S)SCC1(C(=O)O)C=CC=CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=S)SCC1(C(=O)Cl)C=CC=CC1
Yield: 100 %

Procedure:
1-((Diethylcarbamothioylthio)methyl)benzoic acid (0.1 g) was refluxed in a solution of thionyl chloride (1 mL, in excess) and dichloromethane (10 mL) for 2 h. The reaction was then evaporated to dryness and the product obtained as a pale yellow liquid (yield 100%). The product was diluted with dichloromethane to a volume of 1.00 mL (standard solution of 0.353 M) for subsequent reaction with OH terminated Star-PEG MW 116,000 (see below). Conversion of the carboxylic acid to the acid chloride was further verified by the observation that the starting material was a white solid, which was partially insoluble in dichloromethane, whilst the product was a pale, yellow liquid which was completely soluble in dichloromethane. 1H NMR (CD2Cl2, 400 MHz) δ 1.27-1.29 (br.m, 6H, 2×CH3), 3.76 (br.q, J=7.0 Hz, 2H, CH2N), 4.04 (br.q, J=7.0 Hz, 2H, CH2N), 4.66 (s, 2H, CH2S), 7.53 (d, J=8.4 Hz, 2H, aromatic, 8.04 (d, J=8.4 Hz, 2H, aromatic) ppm. 13C (CD2Cl2, 400 MHz) δ 11.8, 12.9, 41.3, 47.5, 50.5, 53.5, 53.7, 54.0, 54.3, 54.5, 130.4, 132.0, 132.5, 146.6, 168.4, 194.3 ppm.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:21])[CH:3]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24]>C(O)CO>[NH2:24][CH2:23][CH2:22][NH:25][C:2]1[C:11]2[C:6](=[C:7]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:21])[CH:3]=1
Reactant: NCCN
Reactant: Cc1cc(C)c(-c2cccc3c(Br)cc(C)nc23)c(C)c1
Solvent: OCCO
Product: Cc1cc(C)c(-c2cccc3c(NCCN)cc(C)nc23)c(C)c1
Reaction time: 4 h

Procedure:
In a sealed tube, heat 4-bromo-2-methyl-8-(2,4,6-trimethyl-phenyl)-quinoline (100 mg, 0.29 mmol) at 140° C. in a mixture of ethylene glycol (1 mL) and ethylene diamine (0.3 mL). After 4 h, cool the reaction mixture and partition between saturated aqueous NaHCO3 and chloroform. Dry the combined organic extracts on Na2SO4 and concentrate under reduced pressure to obtain the title compound as a yellow glass: +APcI MS (M+1)+ 320; 1H NMR (methanol-d4) δ: 7.78 (dd, 1H), 7.39 (t, 1H), 7.34 (dd, 1H), 6.95 (s, 2H), 6.31 (s, 1H), 3.34 (t, 2H), 3.11 (t, 2H), 2.43 (s, 3H), 2.34 (s, 3H), 1.89 (s, 6H).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:24][NH:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21]2)[CH2:16][CH2:15]1)=[O:12].Cl>C(#N)C.O>[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH:20]2[CH2:24][NH:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21]2)[CH2:18][CH2:19]1)=[O:12]
Reactant: COC(=O)[C@@H]1CC(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)CN1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCN(C3CN[C@H](C(=O)O)C3)CC2)c(Cl)c1Cl
Temperature: 70 °C
Yield: 49.9 %

Procedure:
A 2 N solution of lithium hydroxide was heated to 70° C. Methyl 4-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-L-prolinate (Example 52, 0.081 g, 0.20 mM) in acetonitrile (1.1 ml) and water (0.4 ml) was added to the solution and stirred at 70° C. for ten minutes then ambient temperature for twenty minutes. 1 N Hydrogen chloride was added and a minor impurity was extracted using EtOAc. The aqueous layer was lyophilized to give an orange solid that was purified by HPLC eluting CH3CN/H2O (0.1% TFA). Relevant fractions were collected, concentrated and lyophilized to give the desired product as a light orange solid (0.039 g).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([CH:46]=[CH:47][CH:48]=1)[CH2:10][C@@H:11]1[NH:34][C:33](=[O:35])[C@H:32]([CH:36]([CH3:38])[CH3:37])[NH:31][C:30](=[O:39])[C@H:29]([CH3:40])[C@H:28]([O:41][CH3:42])[CH2:27][CH2:26][CH:25]=[CH:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:18](=[O:43])[C@H:17]2[NH:44][N:13]([CH2:14][CH2:15][CH2:16]2)[C:12]1=[O:45])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:6][C:7]1[CH:8]=[C:9]([CH:46]=[CH:47][CH:48]=1)[CH2:10][C@@H:11]1[NH:34][C:33](=[O:35])[C@H:32]([CH:36]([CH3:38])[CH3:37])[NH:31][C:30](=[O:39])[C@H:29]([CH3:40])[C@H:28]([O:41][CH3:42])[CH2:27][CH2:26][CH:25]=[CH:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:18](=[O:43])[C@H:17]2[NH:44][N:13]([CH2:14][CH2:15][CH2:16]2)[C:12]1=[O:45]
Reactant: CO[C@@H]1CCC=CCCCCOC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CO[C@@H]1CC/C=C/CCCCOC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Agent: CO[C@@H]1CC/C=C/CCCCOC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Solvent: C1CCOC1
Product: CO[C@@H]1CCC=CCCCCOC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of (E)-(3S,6S,9R,10R,21S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-benzyl]-6-isopropyl-10-methoxy-9-methyl-19-oxa-1,4,7,25-tetraaza-bicyclo[19.3.1]pentacos-13-ene-2,5,8,20-tetraone in anhydrous tetrahydrofuran (15 mL) was cooled to 0° C. under a nitrogen atmosphere before adding a solution of tetra-N-butylammonium fluoride in tetrahydrofuran (1 M, 0.6 mL, 0.6 mmol). The reaction mixture was allowed to warm to room temperature and was then stirred for 1.5 hours. The reaction mixture was treated with a saturated sodium bicarbonate solution (25 mL) and extracted with ethyl acetate (2×20 mL). The extract was dried over anhydrous sodium sulfate, filtered and evaporated to give a brown gum (73 mg), which was purified by silica gel chromatography using ethyl acetate/iso-hexanes 1:1 then ethyl acetate/iso-hexanes 3:1 to give a colourless gum (22 mg). The gum was further purified by preparative thin layer chromatography using ethyl acetate to yield the title product (9 mg, 12%) as a colourless solid. 1H NMR (300 MHz, CD3CN) δ0.94 (d, J=6.5 Hz, 3H), 0.96 (d, J=6.0 Hz, 3H), 1.22-1.45 (m, 3H), 1.28 (d, J=7.4 Hz, 3H), 1.50-1.70 (m, 5H), 1.76-2.08 (m, 7H), 2.47-2.60 (m, 1H), 2.68-2.92 (m, 2H), 2.82 (d, J=6.3 Hz, 1H), 3.21-3.29 (m, 2H), 3.32-3.65 (m, 1H), 3.45 (s, 3H), 4.00-4.37 (m, 4H), 5.10-5.38 (m, 2H), 5.40-5.52 (m, 1H), 6.59-6.70 (m, 2H), 6.78-6.92 (m, 2H), 7.09 (t, J=7.8 Hz, 1H), 7.16 (d, J=9.1 Hz, 1H), 7.80 (s, 1H). LCMS (m/z) 601.4 [M+H] Tr=4.41 min.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:11]
Reactant: OCc1ccc(O)c(Br)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(CO)nc1Br
Temperature: 25 °C
Yield: 156.8 %

Procedure:
To a solution of 2-bromo-6-(hydroxymethyl)pyridin-3-ol (2.04 g, 10 mmol) and K2CO3 (2.07 g, 15 mmol) in acetone (50 mL) was added iodomethane (1.84 g, 13 mmol) at rt. The reaction mixture was refluxed for 4 h. After that time the reaction was cooled to rt, filtered to remove solids and concentrated under reduced pressure to give (6-bromo-5-methoxypyridin-2-yl)methanol (3.42 g, >99%) as a white solid: 1H NMR (400 MHz, CDCl3): δ 7.25 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 4.70 (s, 2H), 3.93 (s, 3H), 2.78 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[N:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([C:16]3[N:17]=[C:18]([C:19]4[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=4[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]4[CH2:12][NH:11][C:10](=[O:35])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=3)[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N3CCC(N4CCCCC4)CC3)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 63.3 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (17 mg, 0.034 mmol) in DCM (2 mL) was added 1,4′-bipiperidine (16 mg, 0.10 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (13 mg, 63%). LC-MS m/z 604 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 3H), 1.50 (m, 4H), 1.68 (m, 6H), 1.92 (m, 2H), 2.31 (s, 3H), 2.73 (m, 2H), 2.90 (m, 5H), 3.37 (m, 2H), 4.16 (m, 2H), 4.52 (m, 2H), 7.16 (m, 2H), 7.46 (m, 1H), 7.51 (m, 1H), 7.68 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [Mg].Cl[C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[C:8]#[N:9].CN(C)[CH:14]=[O:15]>O1CCCC1.II>[F:11][C:6]1[CH:5]=[CH:4][C:3]([CH:14]=[O:15])=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: CN(C)C=O
Reactant: N#Cc1cc(Cl)ccc1F
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: N#Cc1cc(C=O)ccc1F
Yield: 96 %

Procedure:
Add freshly ground magnesium (1.72 g, 70.7 mmol) to a solution of 5-chloro-2-fluoro-benzonitrile (10.0 g, 64.3 mmol) and N,N-dimethylformamide (5.64 g, 77.1 mmol) in tetrahydrofuran (0.2 M). Add iodine (0.816 g, 3.21 mmol). Heat the solution at reflux for 6 h. Quench the reaction with 1N hydrochloric acid and extract the mixture with ethyl acetate (3×). Dry the combined organic layers with sodium sulfate and concentrate to afford the title compound (9.20 g, 61.7 mmol, 96%): 1H NMR (CDCl3, 400 MHz) δ 7.15 (m, 1H), 7.59 (m, 1H), 7.66 (m, 1H), 10.4 (s, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:7][C:8]2[C:13]([C:14]=1[C:15]([OH:17])=O)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:2]=[N-:3].C1C=C2N=NN(O)C2=CC=1.O.CN1CCOCC1.C(Cl)CCl.[C:46]1([C@@H:52]([NH2:55])[CH2:53][CH3:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O1CCCC1>[N:1]([CH2:4][C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:7][C:8]2[C:13]([C:14]=1[C:15]([NH:55][C@H:52]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:53][CH3:54])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:2]=[N-:3]
Reactant: CC[C@H](N)c1ccccc1
Reactant: [N-]=[N+]=NCc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](NC(=O)c1c(CN=[N+]=[N-])c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
A solution of 3-(azidomethy)-2-phenylquinoline-4-carboxylic acid (2c) (997 mg, 3.28 mmol), HOBT hydrate (760 mg, 4.92 mmol), 4-methylmorpholine (551 μL, 4.92 mmol) in tetrahydrofuran (50 mL) was added EDC (960 mg, 4.92 mmol) at RT under N2. (S)-1-Phenyl propylamine (488.5 mg, 3.62 mmol) was then added and the reaction mixture stirred at RT for 12 h. All solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution, dried over sodium sulfate and then concentrated in vacuo. The residue was purified by chromatography eluting with 15-25% ethyl acetate/hexane to give the title compound (1000 mg, 73%) as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H), 2.01 (m, 2H), 5.17 (q, 1H), 5.19 (s, 2H), 5.72 (b, 1H), 7.21 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.49 (m, 2H). MS APCI, m/z=422 (M+1). LCMS: 2.47 min.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].I[CH2:20][C:21]#[N:22]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:20][C:21]#[N:22])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: N#CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (356 mg) in DMF (5 mL) was added sodium hydride (79 mg of 60% in oil) and iodoacetonitrile (331 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes), followed by washing solid with CH2Cl2 to yield the title compound as a peach-colored solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][C:12]([F:22])=[C:13]([NH:18][CH:19]4[CH2:21][CH2:20]4)[CH:14]=3)[C:9]2=[O:23])=[CH:4][CH:3]=1.C([O:26][C:27](=O)[NH:28][S:29]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)(=[O:31])=[O:30])C>C1(C)C=CC=CC=1>[Cl:37][C:34]1[S:33][C:32]([S:29]([NH:28][C:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][C:12]([F:22])=[C:13]([NH:18][CH:19]5[CH2:21][CH2:20]5)[CH:14]=4)[C:9]3=[O:23])=[CH:4][CH:3]=2)=[O:26])(=[O:31])=[O:30])=[CH:36][CH:35]=1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Reactant: Nc1ccc(-n2ccc3cc(NC4CC4)c(F)cc3c2=O)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(-n2ccc3cc(NC4CC4)c(F)cc3c2=O)cc1)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 110 °C
Yield: 43.7 %

Procedure:
A mixture of 2-(4-Amino-phenyl)-6-cyclopropylamino-7-fluoro-2H-isoquinolin-1-one (Example 11) (23 mg, 0.073 mmol) and (5-Chloro-thiophene-2-sulfonyl)-carbamic acid ethyl ester (Example 12) (28 mg, 0.10 mmol, 1.35 eq) in dry toluene (1.5 mL) was heated at 110° C. for 2 hr. Upon cooling, the reaction was concentrated in vacuo and the crude residue was purified by HPLC (C-18) to give 17 mg (46%) of pure 5-chloro-N-[({4-[6-(cyclopropylamino)-7-fluoro-1-oxoisoquinolin-2(1H)-yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+=533, 535 (Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1.[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:24][CH:21]2[CH2:23][CH2:22]2)[C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1
Reactant: BrCC1CC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H](CC(C)C)N1CC1CC1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Br)cc(N2CCOCC2)c1
Reaction time: 24 h

Procedure:
A solution of 1-bromo-3-chloro-5-fluorobenzene (5.05 g, 24.11 mmol), morpholine (3.15 mL, 36.2 mmol), potassium carbonate (6.66 g, 48.2 mmol), and DMF (45 mL) was stirred at 60° C. for 48 h, then at 110° C. for 24 h. The reaction mixture was concd, and the resulting residue was partitioned between EtOAc and water. The organic phase was dried over magnesium sulfate and concd, affording a crude material that was purified by column chromatography (silica; 0-10% EtOAc in hexanes) to yield 4-(3-bromo-5-chlorophenyl)morpholine as a white amorphous solid. Mass Spectrum (ESI) m/e=276.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([OH:25])=[O:24].C[O-].[Na+:28]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([O-:25])=[O:24].[Na+:28]
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1=C(CC(=O)[O-])c2cc(F)ccc2C1=Cc1ccc(S(C)=O)cc1
Reaction time: 0.33 h

Procedure:
5-fluoro-2-methyl-1-(ρ-methylsulfinylbenzylidene)-3-indenylacetic acid (1.79 g.) in methanol (10 ml.) is added to a solution of sodium methoxide (0.27 g.) in methanol (5 ml.). The reaction mixture is stirred for 20 minutes and evaporated to dryness to yield sodium 5-fluoro-2-methyl-1-(ρ-methylsulfinylbenzylidene)-3-indenylacetate.