Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1.O>C(O)(=O)C>[N:18]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)[CH:21]=[CH:25][CH:24]=[CH:23]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Solvent: CC(=O)O
Solvent: O
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1-n1cccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
Compound 2 (0.060 g, 0.25 mmol) was dissolved in acetic acid (1.0 mL) and the solution was added with 2,5-dimethoxytetrahydrofuran (99 μL, 0.77 mmol), followed by stirring at room temperature for 2 hours. Then, to the reaction mixture, water was added and the precipitated solid was filtered. The solid was recrystallized from ethanol to obtain Compound 162 (14 mg, 20%).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C@@H:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][OH:11])=[O:7])=[C:4](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O1CCCC1>[C:29]([NH:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C@@H:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][OH:11])=[O:7])=[C:4](/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:3]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)N[C@H](CO)Cc2ccccc2)c(/C=C/c2ccccc2)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)N[C@H](CO)Cc2ccccc2)c(/C=C/c2ccccc2)c1
Reaction time: 16 h
Yield: 69.7 %

Procedure:
1 g (2.7 mmol) of (S)-4-amino-2(E-2-phenylethen-1-yl)-N-(3-phenylpropan-1-ol-2-yl)benzamide (intermediate 43f) was suspended in 50 ml of tetrahydrofuran and mixed with 0.25 ml (2.7 mmol) of acetic anhydride at 100° C. The mixture was stirred for 16 h. The reaction was then concentrated under reduced pressure and the residue was recrystallized from ethanol. 0.78 g (71%) of the product was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:20]1([C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 15.9 %

Procedure:
A solution of 16-hydroxyhexadecanoic acid (1.36 g, 5.00 mmol), triphenylmethyl chloride (1.53 g, 5.50 mmol), triethylamine (1.25 ml) and 4-dimethylaminopyridine (10.03 g, 0.25 mmol) is stirred overnight in dry dimethylformamide at ambient temperature under nitrogen. After 16 hours stirring, the brown cloudy solution is poured into ice-water and extracted with dichloromethane (5×50 ml). The organic phases are washed with saturated ammonium chloride solution (2×100 ml), water (2×100 ml) and dried over MgSO4. The solvent is removed under reduced pressure and the product purified by flash chromatography on a silica column with dichloromethane/methanol (20:1) as eluant to yield the title compound as a yellow oil (0.41 g). 13C NMR (75 MHz, CDCl3): δ 24.9, 25.7, 26.3, 29.2, 29.5, 29.6, 29.7, 30.0, 32.8, 34.1, 62.9, 63.7, 86.2, 144.5, 177.2. MS (CI): 515 (M+H)
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1)#[N:3].[CH:30]([CH:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)=O>COCCOC>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:30][CH:32]2[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]2)=[CH:28][CH:29]=1)#[N:3]
Reactant: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC1CCC(=O)CC1
Agent: [Cl-]
Solvent: COCCOC
Product: N#Cc1ccc(C=CC2CCC(=O)CC2)cc1
Temperature: 0 °C
Yield: 110.7 %

Procedure:
63.3 g of p-cyanobenzyl-triphenylphosphonium chloride, 17.2 g of potassium t-butylate and 195 ml of ethylene glycol dimethyl ether were placed while stirring and gassing with nitrogen in a sulphonation flask, whereby the internal temperature rose to 44° C. The brown suspension was cooled to 0° C. and treated within 2 minutes with a solution of 16.7 g of 4-formylcyclohexanone in 100 ml of ethylene glycol dimethyl ether. The cooling bath was then removed and the mixture was stirred at room temperature for a further 3.5 hours. The suspension was subsequently poured into 500 ml of water and extracted three times with 600 ml of methylene chloride each time. The organic phases were washed twice with 500 ml of 10% (wt./vol.) sodium chloride solution each time, dried over sodium sulphate, filtered and concentrated, there being obtained 76.9 g of a brownish paste. Chromatographic separation of this crude product on silica gel with methylene chloride as the eluent gave 33.0 g of 4-[2-(p-cyanophenyl)vinyl]cyclohexanone as a yellow-brownish oil.
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15]N1CCOCC1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C[Mg]Br.O1CCCC1.Cl>C(#N)C>[Br:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Br
Reactant: CN1CCOCC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: C[Mg]Br
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
A mixture solution of 2-bromo-3-(trifluoromethyl)benzoic acid (2.50 g, 9.29 mmol), N, O-dimethylhydroxylamine hydrochloride (1.18 g, 12.1 mmol), N-methylmorpholine (2.1 mL, 18.6 mmol), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (3.78 g, 12.1 mmol) in acetonitrile (45 mL) was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was added with 1 N aqueous hydrochloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (90 mL), added with a solution (0.93 M) of methyl magnesium bromide in tetrahydrofuran (13.0 mL, 12.1 mmol) at −20° C., and stirred at room temperature for 18 hours. The reaction solution was poured over 1 N aqueous hydrochloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless oily substance (1.27 g, yield 44%).
Reaction SMILES: C12BC(CCC1)CCC2.[CH:10]([C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][CH:13]=1)=[CH2:11].[OH-:25].[Na+].OO>O1CCCC1.O>[OH:25][CH2:11][CH2:10][C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 9-borabicyclo[3.3.1]nonane (9-BBN, 5.65 g, 46.3 mmol) in anhydrous tetrahydrofuran was added to a solution of t-butyl 4-vinylbenzoate (8.47 g, 42.1 mmol) prepared in the Preparative Example 102 in anhydrous tetrahydrofuran in a nitrogen stream. The obtained mixture was stirred at room temperature for 3 hours. 15 ml of water and 17 ml of 3N NaOH were added to the reaction mixture successively, followed by the dropwise addition of 30% aqueous hydrogen peroxide at 50° C. or below. The obtained mixture was stirred as such for one hour and poured into water. The mixture thus obtained was extracted with ethyl acetate. The organic phase was washed with an aqueous solution of common salt, dehydrated and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography (developer: n-hexane/ethyl acetate=1:1) to give the objective compound. yield: 8.71 g
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:24]2[CH:25]=[CH:26][C:21]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17]
Reactant: Nc1ncc(Br)cc1OCc1ccccc1Cl
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1ccccc1Cl
Temperature: 87.5 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
5-Bromo-3-(2-chloro-benzyloxy)-pyridin-2-ylamine (4.50 g, 14.3 mmol), 4-carboxybenzeneboronic acid (2.62 g, 15.8 mmol), tetrakis(triphenylphosphine)palladium(0) (0.56 g, 0.5 mmol), potassium carbonate (6.90 g, 50 mmol), dimethylformamide (36 mL), and water (18 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 82 to 93° C. over a period of 4 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed product at Rf 0.3 and a few small impurities. The mixture was cooled to 45° C. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and discarded. The combined filtrate was diluted with 216 mL of water and 4 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and stirred for 30 minutes with 3 g of Celite and 3 g of Norit. The solids were collected by vacuum filtration through a pad of Celite and washed with 10 mL of water. The solids were discarded. The combined filtrate was cooled in an ice bath and acidified to pH 7 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 20 mL of ethanol-water 1:1 and dried under vacuum to give 2.7 g (53% yield) of 4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-benzoic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10](Cl)[N:11]=1)[C:5](OC)=O.CNS(C)(=O)=O.Cl[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[N:28]=1)[C:23]([OH:25])=[O:24]>>[CH3:10][N:11]([CH2:2][CH:3]1[CH2:5][CH:4]1[CH3:9])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[N:28]=1)[C:23]([OH:25])=[O:24]
Reactant: CN(c1cc(C(=O)O)cc(Cl)n1)S(C)(=O)=O
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: CNS(C)(=O)=O
Product: CC1CC1CN(C)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)n1

Procedure:
Prepared from Methyl 2,6-dichloroisonicotinate, methyl(methylsulfonyl)amine and intermediate 3.3.1 following a similar procedure as described for the preparation of intermediate 4.2c.1. 1H NMR (400 MHz, CD3OD) δ 7.02 (s, 1H), 6.96 (s, 1H), 3.55 (A of ABX, dd, J=14.4, 6.0 Hz, 1H), 3.29 (B of ABX, dd, J=14.4, 7.2 Hz, 1H), 3.35 (s, 3H), 3.15 (s, 3H), 3.12 (s, 3H), 1.03 (d, J=6.0 Hz, 3H), 0.82-0.66 (m, 2H), 0.48-0.41 (m, 1H), 0.28-0.22 (m, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OC([NH:18][C@H:19]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:20][C:21](O)=[O:22])=O)(=O)C1C=CC=CC=1.C(OC(N[C@H](CC1C=CC=CC=1)CCO)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCCC1.CO.[OH-].[OH-].[Pd+2].O.C(OCC)(=O)C>[NH2:18][C@H:19]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:20][CH2:21][OH:22]
Reactant: O=C(O)C[C@@H](Cc1ccccc1)NC(=O)OC(=O)c1ccccc1
Agent: [Pd+2]
Agent: O=C(N[C@@H](CCO)Cc1ccccc1)OCc1ccccc1
Agent: O=C[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N[C@@H](CCO)Cc1ccccc1
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a solution (70 mL) of lithium aluminum hydride (1.50 g, 39.5 mmol, 3.0 equivalents) in tetrahydrofuran was added dropwise a solution of (R)-N-(benzoyloxy-carbonyl)-3-amino-4-phenylbutanoic acid (4.84 g, 13.1 mmol), which was obtained by the method described in Tetrahedron, 44, p. 5525, 1988 and Journal of Organic Chemistry (J. Org. Chem.), 64, p. 6411, 1999, in tetrahydrofuran (30 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was cooled on ice, excess lithium aluminum hydride was decomposed with ethyl acetate and water. The deposited solid was removed by filtration using a filtration aid, and the filtrate was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated. After the resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=50:50), the resulting (R)-N-(benzyloxycarbonyl)-3-amino-4-phenyl-1-butanol (1.37 g, 5.09 mmol) was dissolved in methanol (30 mL), and to the solution were added 20% palladium hydroxide/carbon (200 mg) and ammonium formate (1.30 g, 20.6 mmol, 4.1 equivalents), and then the mixture was stirred for 1 hour with heating. After the catalyst was removed by using a filtration aid, the solvent was evaporated. To the residue was added ethyl acetate, and the deposited solid was collected by filtration to obtain the title compound (730 mg, 87%).
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=[O:2].B.[Na]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:13][CH2:14]2)=[O:8])=[CH:26][CH:27]=1
Reactant: O=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: B
Agent: [Na]
Solvent: CO
Product: O=C(c1ccc(CO)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reaction time: 2 h
Yield: 77.6 %

Procedure:
1-[1-(4-Formylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (500 mg) is dissolved in methanol (10 ml) and thereto is added sodium boron hydride (63 mg) under ice cooling and the mixture is stirred for 2 hours. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=2:1) and recrystallized from n-hexane/ethanol to give 1-[1-(4-hydroxymethylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (390 mg) as white powder, m.p.: 138°-39° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]3[C:17]([O:19][C:20](=O)[C:8]=23)=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([N:25]2[C:17](=[O:18])[C:9]3[CH:10]=[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]4=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:8]=3[C:20]2=[O:19])[CH2:24][CH2:23]1
Reactant: O=C1OC(=O)c2c1cc1ccccc1c2-c1ccccc1
Reactant: NC1CC1
Product: O=C1c2cc3ccccc3c(-c3ccccc3)c2C(=O)N1C1CC1

Procedure:
1-Phenyl-2,3-naphthalenedicarboxylic anhydride (3.0 g) and cyclopropylamine (5 ml) were shaken for 5 minutes. The reaction mixture became very warm and excess cyclopropylamine was evaporated in vacuo. The solid remaining was then heated at 220° to 240° for 5 minutes in a nitrogen atmosphere. The solid formed was allowed to cool and was recrystallised from light petroleum (b.p. 40°-60°)/chloroform to give 2-cyclopropyl-1,3-dioxo-4-phenylbenz[f]isoindoline, (2.7 g, m.p. 198°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[N:8][C:7]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:6]2.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:8]=1
Reactant: COc1ccc2c(O)nc(N3CCCC3)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(N3CCCC3)cc2c1
Temperature: 0 °C
Yield: 48.3 %

Procedure:
A solution of 6-methoxy-3-(pyrrolidin-1-yl)isoquinolin-1-ol (300 mg, 1.228 mmol) in POCl3 (8 mL) was refluxed for 4 h. After concentration, the residue was taken into a mixture of 100 mL of DCM and 50 mL of water, cooled to 0° C., neutralized with 3 N NaOH, dried over MgSO4, concentrated and purified via silica gel chromatography (5-20% EtOAc:Hex) to give 1-chloro-6-methoxy-3-(pyrrolidin-1-yl)isoquinoline (156 mg, 48.3% yield) as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.95 (d, J=9.5 Hz, 1H), 6.85 (d, J=9.2 Hz, 1H), 6.80 (s, 1H), 6.43 (br. s., 1H), 3.89 (s, 3H), 3.56-3.49 (m, 4H), 2.08-2.03 (m, 4H); MS m/z 263.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:9]2[C:4](=[N:5][C:6]([N:20](C(OC(C)(C)C)=O)[NH:21][C:22](OC(C)(C)C)=O)=[CH:7][CH:8]=2)[CH:3]=1.[CH3:36]C(O)=O>>[CH3:36][C:22]1[N:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[N:10]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:12])=[O:13])[C:9]=3[CH:8]=[CH:7][C:6]2=[N:20][N:21]=1
Reactant: CC(=O)O
Reactant: Cc1cc2nc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2n1S(=O)(=O)c1ccccc1
Product: Cc1cc2c(ccc3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
di-tert-Butyl 1-[2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (9.4 g, 19 mmol, from Step 3) in AcOH (150 mL) was heated in the range of 115-120° C. for 20 hours. Upon cooling to room temperature, the solvent was removed in vacuo. After this cyclization, purification via HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded 1,7-dimethyl-6-(phenylsulfonyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])C.[Li]CCCC.C(C1[CH:39]=[CH:38][C:26]([C:27]([N:29]([CH3:37])[CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=1)#N.O>C1COCC1>[CH3:37][N:29]([CH:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1)[C:27](=[O:28])[C:26]1[CH:38]=[CH:39][C:15]([C:14]2[NH:3][C:4](=[O:13])[C:5]3[C:6]([CH:12]=2)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=3)=[CH:24][CH:25]=1
Reactant: CN1CCC(N(C)C(=O)c2ccc(C#N)cc2)CC1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)C4CCN(C)CC4)cc3)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a solution of N,N-diethyl-2,3-dimethyl-benzamide (578 mg, 2.82 mmol) in anhydrous THF (3 mL) under N2 at −78° C. was added dropwise n-BuLi (2.5M in n-hexanes, 2.4 mL, 5.92 mmol) to give a deep red solution. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was transferred dropwise, via syringe, to a reaction vessel containing 4-cyano-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (725 mg, 2.82 mmol) in anhydrous THF (5 mL) at −78° C. and under N2. The reaction mixture was stirred at −78° C. for 3.5 h. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (10 mL) and CH2Cl2 (10 mL). The combined organic layers concentrated in vacuo and the resultant solid was triturated with 2:1 isohexane/EtOAc, filtered and dried in vacuo. The crude material was purified by silica gel column chromatography, eluting with CH2Cl2 and increasing the polarity to 15% MeOH/CH2Cl2 to afford N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-(1-methyl-piperidin-4-yl)-benzamide as a white solid (487 mg, 44%).
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[CH:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([O:43][C:44]3[CH:49]=[CH:48][C:47]([N+:50]([O-])=O)=[CH:46][N:45]=3)[CH:39]=2)[O:34]1>>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[CH:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([O:43][C:44]3[N:45]=[CH:46][C:47]([NH2:50])=[CH:48][CH:49]=3)[CH:39]=2)[O:34]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2F)O3)nc1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2F)O3)nc1

Procedure:
6-[2-(2,4-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 starting from 845 mg of 2-[2-(2,4-difluorophenyl)chroman-6-yloxy]-5-nitropyridine (Example 69(d)). 1H NMR (400 MHz, d6-DMSO) δ: 7.58 (m, 1H), 7.51 (d, 1H, J 3.3 Hz), 7.30 (m, 1H), 7.15 (m, 1H), 7.05 (dd, 1H, J 8.3, 3.3 Hz), 6.84-6.73 (m, 3H), 6.70 (d, 1H, J 8.3 Hz), 5.27 (dd, 1H, J 10.3, 2.3 Hz), 5.01 (s, 2H), 2.97 (m, 1H), 2.73 (m, 1H), 2.13 (m, 1H), 2.03 (m, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][N:14]=[C:13]([NH:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)[CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:17][NH:16][C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)[O:15][N:14]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1cc(-c2ccc3cnccc3c2)on1)Cc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNc1cc(-c2ccc3cnccc3c2)on1)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a solution of tert-butyl(S)-1-(5-(isoquinolin-6-yl)isoxazol-3-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.027 g, 0.053 mmol) in 5 mL of DCM was added TFA (0.50 mL, 6.5 mmol). The mixture was stirred for 30 minutes and diluted with 20 mL of EtOAc. The mixture was washed twice with 10 mL of 10% aqueous Na2CO3 and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 10% MeOH/DCM) afforded N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(isoquinolin-6-yl)isoxazol-3-amine (0.013 g, 60% yield) as a clear oil. MS m/z: 413 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 9.26 (s, 1H), 8.48 (d, J=5.8 Hz, 1H), 8.34 (s, 1H), 8.19 (d, J=8.6 Hz, 1H), 8.01 (dd, J=1.3 Hz, 8.6 Hz, 1H), 7.90 (d, J=5.9 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 6.52 (s, 1H), 3.45-3.25 (m, 2H), 3.34 (s, 2H), 3.18 (dd, J=7.4 Hz, 13.5 Hz, 1H), 3.00 (dd, J=5.5 Hz, 13.5 Hz, 1H), 2.75 (dd, J=7.9 Hz, 13.5 Hz, 1H), 2.22 (dt, 1.8 Hz, 6.7 Hz, 1H).