Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[OH:18].[CH2:19](I)[CH3:20]>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[O:18][CH2:19][CH3:20]
Reactant: COC(C)(OC)c1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: CCI
Product: CCOc1c(Br)cc(C(C)(OC)OC)cc1C(C)(C)C

Procedure:
2-Bromo-6-tert-butyl-4-(1,1-dimethoxyethyl)phenol (20 g; for synthesis see CA02515715) was alkylated with ethyl iodide analogously to the conditions of O4.070. 19.67 g of the title compound were obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[K+].CN(C)[CH:20]=[O:21]>O>[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:20]=[O:21])=[CH:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: Cc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(C=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A 12-l. three-necked flask, equipped with a mechanical stirrer, a thermometer and a dropping funnel provided with a Drierite drying tube was charged with 610 ml (7.9 moles) of N,N-dimethylformamide. The flask was immersed in an ice bath and 217 g (1.42 moles) of phosphorus oxychloride was added at 5°-10° with stirring over 1 hour. The dropping funnel was rinsed with 20 ml of dimethylformamide and the light pink orange oil was stirred for further 10 minutes in the ice bath. Then a solution of 156 g (1.19 moles) of 6-methylindole in 156 ml of dimethylformamide was added at 5°-10° C. over a period of 1 hour. The ice bath was removed and the red orange solution was stirred for an additional hour, while the flask content warmed up to room temperature. At the end of the reaction period, 1.17 kg of crushed ice was added. The temperature fell to -10° and after a short time a light yellow slurry was formed. The reaction mixture was stirred for 1 hour, as the temperature came to 15°. Then a solution of 840 g (13.0 moles) of potassium hydroxide pellets (87% assay) in 2 l of water was added over 30 minutes, during which time the pot temperature rose to 50°. After the addition was complete, the dropping funnel was replaced by a reflux condenser and the orange solution was heated rapidly with stirring on a steam bath to 93° and kept at this temperature for 30 minutes. The mixture was allowed to stand at room temperature overnight. The precipitate was collected by suction filtration, washed with water and dried at 60° (constant weight) to give 186.5 g (98%) of product as orange crystals, m.p. 183°-186°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([S:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7]2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CO>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][SH:7]2[C:4]3([CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[S:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]2=3)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: c1ccc2c(c1)CSC1(CCNCC1)S2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(CC[SH]2c3ccccc3CSC23CCNCC3)cc1

Procedure:
To 111 mgs (0.47 mmol) of dithioketal from Step A in 1 mL of methanol was added 157 mgs of sodium bicarbonate and 118 mg (0.54 mmol) of 2-(4-nitrophenyl)ethyl bromide. The reaction was refluxed for 6 hrs and then concentrated at reduced pressure. The residue was chromotographed (silica gel, 2.5% CH3OH/CH2Cl2) to give after concentration and crystallization from ethyl acetate/Hexanes, 120 mgs of product as the free base.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)P(N(C)C)(N(C)C)=O.C(Cl)Cl.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>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5]2[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:3]=[C:2]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9](=[O:11])[CH2:8]1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccn3)c2C1
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: ClCCl
Product: CC1(C)CC(=O)c2c(Cc3ccccc3)cn(-c3ccccn3)c2C1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-bromo-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one (10 mg, 0.31 mmol), benzyltributylstannane (253 mg, 0.68 mmol) and dichlorobis(triphenylphosphine)palladium (50 mg, 0.08 mmol) in hexamethylphosphoramide (1 mL) was heated at 70° C. for 48 h. The mixture was cooled to room temperature, diluted with DCM (2 mL), and the solution chromatographed on silica gel, eluting with isohexane: EtOAc (4:1). The title compound (45 mg, 43%) was isolated as a colourless solid. mp 111-113° C. Found: C, 79.7; H, 6.7; N, 8.3%. Calc. C22H22N2O: C, 79.97; H, 6.71; N, 8.48%. 1H NMR (360 MHz, CDCl3) δ 1.11 (6H,s), 2.39 (2H,s), 2.93 (2H,s), 4.17 (2H,s), 6.61 (1H,s), 7.16-7.34 (7H,m), 7.77 (1H, d of t, J=7.7 and 1.9 Hz), 8.50-8.53 (1H,m). MS (ES+) 331 (M+1).
Reaction SMILES: [OH-].[K+].[CH2:3]([C:5]([S:26]([CH3:29])(=[O:28])=[O:27])([CH2:11][CH2:12][N:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:14]1=[O:25])[C:6]([O:8]CC)=[O:7])[CH3:4].O1CCCC1CO.O.Cl>O>[CH2:3]([C:5]([S:26]([CH3:29])(=[O:28])=[O:27])([CH2:11][CH2:12][N:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:14]1=[O:25])[C:6]([OH:8])=[O:7])[CH3:4]
Reactant: CCOC(=O)C(CC)(CCn1ccc(-c2ccccc2)cc1=O)S(C)(=O)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCC1CCCO1
Product: CCC(CCn1ccc(-c2ccccc2)cc1=O)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Potassium hydroxide (37 mg, 0.66 mmol, 6.0 equiv) was added to a solution of ethyl 2-ethyl-2-(methylsulfonyl)-4-(2-oxo-4-phenylpyridin-1(2H)-yl)butanoate (43 mg, 0.11 mmol, 1.0 equiv) in 2:2:1 tetrahydrofuran-methanol-water (2.5 mL) at 0° C. The reaction was allowed to warm to room temperature and stir overnight. The reaction was concentrated under reduced pressure to provide a wet residue that was diluted with water (5 mL) and acidified (to pH=2) with 1.0 hydrochloric acid. The resulting white precipitate was filtered, washed with water, and dried under reduced pressure to provide the title compound (34 mg, 85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.09 (t, J=7.52 Hz, 3H) 1.42 (s, 3H) 1.93-2.07 (m, 1H) 2.23-2.37 (m, 2H) 2.55 (d, J=5.66 Hz, 1H) 3.25 (s, 3H) 4.10-4.24 (m, 2H) 4.47-4.59 (m, 2H) 6.63-6.67 (m, 1H) 6.90 (d, J=1.95 Hz, 1H) 7.44-7.50 (m, 4H) 7.54-7.62 (m, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22](O)=[O:23])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:57])([F:56])[CH2:54][NH2:55]>ClCCl.CN(C=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22]([NH:55][CH2:54][C:53]([F:57])([F:56])[F:52])=[O:23])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a mixture of racemic-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (I-2a) (0.15 g, 0.41 mmol) in dichloromethane (3 mL) and DMF (1 mL) was added HATU (0.23 g, 0.62 mmol). The mixture was stirred for 15 mins followed by addition of 2,2,2-trifluoroethylamine (0.08 g, 0.82 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a white ppt which was filtered and dried under high vacuum to give the title compound as a white powder (0.109, 55%). 1H NMR (400 MHz, CDCl3) δ7.34-7.25 (m, 3H), 7.12 (t, J=7.5 Hz, 2H), 7.01 (t, J=7.7 Hz, 3H), 6.91 (t, J=8.4 Hz, 3H), 6.54 (d, J=8.4 Hz, 2H), 5.81 (s, 1H), 4.29 (s, 2H), 4.01-3.88 (m, 3H), 2.48-2.43 (m, 1H), 1.62-1.49 (m, 2H), 1.27-1.20 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:24])[N:17]([CH2:21][CH2:22]Cl)[CH2:18][CH2:19]Cl)([CH3:14])([CH3:13])[CH3:12]>CS(C)=O.CCOC(C)=O>[C:11]([O:15][C:16]([N:17]1[CH2:21][CH2:22][C:8]([C:9]#[N:10])([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)=[O:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccc(I)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 4-iodophenylacetonitrile (6.88 g, 28.3 mmol, 1 eq.) and bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (7.2 g, 30 mmol, 1.05 eq.) in DMSO (100 mL) under argon (Ar) was added NaNH2 (2.46 g, 60 mmol, 2 eq.) in portions over 15 min. The reaction was stirred at room temperature for 0.5 h, then poured onto ice (200 g), diluted with EtOAc (250 mL) and stirred for 1 h. The organic layer was separated and the aqueous layer was washed repeatedly with EtOAc until colorless. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to afford an orange oil which was purified by flash column chromatography by eluting with 7-12% EtOAc/hexanes to yield 4-cyano-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a pale orange oil/solid (8.28 g, 18.96 mmol, 67%). 1H NMR (300 MHz, CDCl3): δ 7.82 (dd, 2H), 7.26 (dd, 2H), 4.38 (br. s, 2H), 4.28 (br. t, 2H), 2.15 (m, 2H), 2.0 (td, 2H), 1.59 (s, 9H). (Ref.: D. Gnecco et al, Org. Prep. Proceed. Int., (1996) 28 (4), 478-480.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[Cl:19])[CH:3]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[Cl:19])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Cl)cc1Oc1ccc([N+](=O)[O-])cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc([N+](=O)[O-])cc1Cl

Procedure:
A mixture of the product from step (i) (0.3 g), ethyl bromoacetate (0.22 ml) and sodium acetate (0.164 g) in dry ethanol (5 ml) was heated under reflux 7 h. Ethyl bromoacetate (0.5 ml) and sodium acetate (0.34 g) were added and heated for a further 16 h. The solvent was evaporated under reduced pressure and the residue purified by chromatography on silica eluting with 5-7% ethylacetate/isohexane, yield 0.212 g.
Reaction SMILES: [H-].[Na+:2].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=O.Cl[CH2:13][C:14](=[O:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17]>C1COCC1>[CH2:10]([O:9][C:3]([C:4]1[CH2:13][C:14]([O-:20])=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:5]=1[CH3:7])=[O:8])[CH3:11].[Na+:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)C(C(=O)OC)=C([O-])C1
Temperature: 18 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
In a 12 L round bottom flask, NaH (60% dispersion in mineral oil, 159 g, 3985 mmol) was added in portions to stirred anhydrous THF (4004 mL) to give a gray suspension. The mixture was cooled to about 5° C. in an ice/salt bath before ethyl acetoacetate (506 mL, 3985 mmol, Alfa Aesar) in anhydrous THF (200 mL) was added dropwise via an addition funnel over about 1 h during which time the temperature gradually increased to about 18° C. After the addition was complete, the reaction was stirred at ambient temperature for about 1 h and then a solution of methyl 4-chloroacetoacetate (230 mL, 1993 mmol, Oakwood) in anhydrous THF (200 mL) was added dropwise via an addition funnel over about 1 h. The resulting mixture was stirred at ambient temperature for about 2 h and then heated at about 50° C. for about 16 h. The reaction mixture was concd in vacuo. The orange solid was cooled to about 5° C. and an ice/water mixture (2 L) was added. The suspension was mixed by rotating on the rotovap without vacuum for about 30 min. The solid was collected by filtration and washed with ice-cold water (750 mL). Once most of the solvent (about 90%) had been removed, the wet solid was triturated with MeCN (750 mL), stirred for about 30 min and then the solid was collected by filtration while washing with Et2O (2×500 mL). The solid was dried in air for about 16 h and then in vacuo at about 55° C. to give sodium 4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate (485 g, 98%): 1H NMR (DMSO-d6) δ 3.95 (q, J=7.1 Hz, 2H), 3.48 (s, 3H), 2.69 (q, J=2.0 Hz, 2H), 2.47 (t, J=2.1 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11]Br>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1F
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 1-(2-fluorophenyl)ethanone (15.1 g) in acetic acid (150 mL) was added bromine (5.8 mL). The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 22.9 g, yield 97%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:7][N:6]=1)[CH3:4].C(N(CC)CC)C.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[C:25]([NH:1][CH2:2][CH:3]([C:5]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:7][N:6]=1)[CH3:4])(=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC(=O)Cl
Reactant: CC(CN)c1nsc(NC(=O)OC(C)(C)C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NCC(C)c1nsc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl [3-(2-amino-1-methylethyl)-1,2,4-thiadiazol-5-yl]carbamate (0.27 mmol) was dissolved in DCM (5 mL) and triethylamine (1.4 eq) was added followed by n-butyric acid chloride (1.1 eq). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. Purification, using preparative LCMS (30–70% MeCN over 10 min followed by 100% MeCN for 5 min), afforded tert-butyl [3-(2-butyrylamino-1-methyl-ethyl)-[1,2,4]thiadiazol-5-yl]-carbamate. Deprotection was carried out in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 1.5 h at room temperature. The solvent was removed under reduced pressure affording the crude product which was converted to the sulfonamide using method C without any further purifications.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH2:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:11])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH2:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:11])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C)(CCc1cccs1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(CCc1cccs1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
2-Methyl-2-(2-thienyl)ethylmalonic acid diethylester (52.7 g, 0.19 mol) obtained in Example 1) (a) was dissolved in a mixture of ethanol (240 ml) and water (80 ml), potassium hydroxide (11.4 g, 0.20 mol) was added thereto in an ice bath, and the solution was stirred for 2 hours. And then potassium hydroxide (5.7 g, 0.1 mol) was added thereto three times, one portion every 1 hour, and the reaction solution was stirred for 6 hours in total. Water (300 ml) and ice-cold 10% hydrochloric acid (500 ml) were added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=2:1-0:1) to afford the title compound (28.6 g, 60% yield) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8]O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:41])C(=O)C1>C(Cl)Cl>[CH2:1]([O:3][CH2:4][O:5][C:6]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][Br:41])[CH3:2]
Reactant: CCOCOc1c(C)cccc1CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOCOc1c(C)cccc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
To a stirred solution of 2-(ethoxymethoxy)-3-methylbenzyl alcohol (Ib) (2.67 g, 13.6 mmol) and triphenylphosphine (5.35 g, 20.4 mmol) in CH2Cl2 (70 mL) was added NBS (3.63 g, 20.4 mmol) at RT. The reaction was stirred at RT for 2 h, and quenched with water (15 mL). The product was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (hexane/ethyl acetate=10:1, v/v) yielded the compound IIb as a colorless oil (1.56 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])[CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 69.9 %

Procedure:
(2R)-2-(4-Chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (300 mg, 1 mmol), K2CO3 (170 mg, 1.2 mmol), and 4-methoxybenzyl chloride (170 mg, 1.1 mmol) in DMF (25 mL) was heated to 60° C. for 18 h. The reaction was then diluted with EtOAc (150 mL) and washed with H2O, brine, dried over MgSO4 and concentrated to give a crude white wax. Further purification by flash chromatography (SiO2, 25% EtOAc/hexanes) afforded the titled compound (297 mg) as a white solid in 70% yield. [α]D=+44.2 (c 1.00, MeOH); MS (ESI), (M−H)−422.9; 1H NMR (CDCl3) δ7.63 (d, 2H, J=7.0), 7.42 (d, 2H, J=7.0), 7.25 (d, 2H , J=8.0), 6.79 (d, 2H, J=8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.36 (dd,2H, J=50, 15), 4.26 (t, 1H, J=7.2), 3.78 (s, 3H), 1.83 (m, 1H), 1.18-1.34 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0); IR (KBr) 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm−1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11](O)=[O:12])[N:2]=1.B.C1COCC1.CO>C1COCC1>[OH:12][CH2:11][C:3]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2ccccc2cn1
Temperature: 75 °C
Reaction time: 17 h
Yield: 12.3 %

Procedure:
To a stirred solution of isoquinoline-3-carboxylic acid (0.3179 g, 1.84 mmol) in dry THF (10 mL) at room temperature was added BH3—THF (1.0 M, 7.5 mL, 7.5 mmol). The mixture was stirred for 17 hrs, dry CH3OH (10 mL) was added, and the reaction was heated to 75° C. with stirring for a further 24 hrs. The mixture was concentrated and the residue was treated with dry CH3OH (3×10 mL), removing the solvent by evaporation each time. The crude product was purified by column chromatography (12 g silica gel, 19:1 CH2Cl2:CH3OH) to give 0.0359 g of 3-(hydroxymethyl)isoquinoline as a white film. The solid was dissolved in dry CH2Cl2 (5 mL) and treated with MnO2 (˜85%, 0.2978 g, 2.91 mmol) with stirring for 19 hrs then filtered through celite. Concentration of the filtrate afforded 0.0252 g (9%) of isoquinoline-3-carboxaldehyde as yellow oil. 1H NMR (CDCl3) d 7.73-7.82 (m, 2H), 7.97-8.07 (m, 2H), 8.37 (s, 1H), 9.36 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:10][CH:9]=[CH:8]2)=[N+]=[N-].CN(C)C=O>C(O)C.[Pd]>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([NH:15][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[N:10][CH:9]=[CH:8]2
Reactant: [N-]=[N+]=NCc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: NCc1ccc2c(NC(=O)c3ccccc3)nccc2c1

Procedure:
A solution of 6.4 g of N-[6-(azidomethyl)-1-isoquinolinyl]benzamide in 300 mL of ethanol and 60 mL of N,N-dimethylformamide containing 3.8 g of 5% palladium/calcium carbonate was hydrogenated for 20 hours. Filtration and concentration i. vac. yielded the title compound as an oil. MS (m/e)=277.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]#[N:29].[CH3:30][C:31]([CH3:33])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([C:20]3[CH2:21][CH2:22][N:23]([CH:31]([CH3:33])[CH3:30])[CH2:24][CH:25]=3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]#[N:29]
Reactant: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1C1=CCNCC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1C1=CCN(C(C)C)CC1
Temperature: 55 °C
Reaction time: 6 h
Yield: 54.5 %

Procedure:
To a solution of 4-(2-fluoro-4-methylphenylamino)-7-methoxy-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline-3-carbonitrile (Method 88, 200 mg, 0.51 mmol) in dichloroethane (5 mL), acetone (0.566 mL, 7.70 mmol), and acetic acid (0.147 mL, 2.57 mmol) was added sodium triacetoxyborohydride (544 mg, 2.57 mmol) and the reaction stirred at 55° C. for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue purified with silica chromatography (MeOH/EtOAc (1:1)) to give 120 mg (50%) product. m/z 432.