Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1>CS(C)=O.O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([OH:1])=[CH:5][C:6]=1[O:13][CH3:14])([O-:12])=[O:11]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(O)ccc1[N+](=O)[O-]
Reaction time: 2.5 h

Procedure:
A solution of sodium hydroxide was added to a stirred solution of 4-fluoro-2-methoxynitrobenzene (11.1 g.) in DMSO (60 ml.) at ambient temperature and the mixture was heated at 85 degC. for 2.5 hr. The cooled solution was diluted with water (100 ml.) and extracted with ether (3×100 ml.) The combined ethereal solution was extracted with 2n NaOH (3×75 ml.) and the combined aqueous phase brought to pH 2 by the addition of 2N HCl. The precipitated product was collected and washed with water. The product was dried over phosphorous pentoxide. Yield 7.4 g. m/Z 170.1(M+H). It was used without further purification in the next step (cf Example 1c).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCN(C2CCCC2)CC1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (40%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[C:5]([N:13]=O)[C:4]([CH3:15])=[N:3]1.[K+].[Br-]>[Pd].CCOC(C)=O>[CH3:10][C:9]([CH3:12])([CH3:11])[CH2:8][NH:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:15])[C:5]=1[NH2:13]
Reactant: Cc1nn(C)c(NCC(C)(C)C)c1N=O
Agent: [Pd]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(NCC(C)(C)C)c1N
Temperature: 23 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
(2,5-Dimethyl-4-nitroso-2H-pyrazol-3-yl)-(2,2-dimethyl-propyl)-amine (3.44 g, 16.36 mmol), 400 mg of 10% Pd/C and 60 mL EtOAc were placed under a balloon of H2 and stirred at 23° C. After 4 h, the reaction mixture was filtered through Celite and evaporated to an orange oil. Flash chromatography on silica gel, eluting with CHCl3/MeOH (20/1), gave a yellow solid. Recrystallization from hot hexanes/EtOAc gave 2.86 g (14.57 mmol, an 89% yield) of the tidle compound as an off-white crystalline solid. mp: 65-69° C.; 1H NMR (300 MHz, CDCl3): δ 1.00 (s, 9H), 1.65 (brs, 2H), 2.13 (s, 3H), 2.77 (brs, 2H), 2.89 (brs, 1H), 3.62 (s, 3H); IR (KBr, cm−1): 3347-3204brs, 2952s, 2903w, 1599m, 1528m, 1495m, 1477m, 1378m, 1316m; MS (ES) m/z (relative intensity): 197 (M++H, 100).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10](=[S:12])[NH2:11])=[CH:2]1.Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17]>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[S:12][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:11]=2)=[CH:2]1
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)c1c[nH]c2ncccc12
Solvent: CCO
Product: O=C(O)c1csc(-c2c[nH]c3ncccc23)n1
Reaction time: 16 h
Yield: 99.3 %

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridine-3-carbothioic acid amide (2.53 g, 14.37 mmol), bromopyruvic acid (2.4 g, 14.37 mmol) in ethanol (50 mL) was refluxed for 2 h. The solution was left at room temperature for 16 h and precipitated solid was filtered to give 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazole-4-carboxylic acid (3.5 g, 100%) as a yellow solid MS 246 (M+1).
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[C:15]([OH:22])[C:12]=2[C:13]=1[CH3:14])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].NN.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)CO>[CH2:1]([C:9]1[O:10][C:11]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[C:15]([OH:22])[C:12]=2[C:13]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1ccc2oc(C(=O)c3ccccc3)c(C)c2c1O
Agent: NN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: OCCO
Product: CCCc1ccc2oc(Cc3ccccc3)c(C)c2c1O
Yield: 58 %

Procedure:
A mixture of 2-benzoyl-4-hydroxy-3-methyl-5-propylbenzofuran (1.2 g; 4mmoles), potassium hydroxide pellets (1.5 g; 28mmoles), ethylene glycol (25 ml) and 99% hydrazine (0.7 ml) was heated at 135°-155° C. for 3 hours. The mixture was cooled, acidified with 20% citric acid solution, extracted with ether, dried (Na2SO4), filtered, concentrated, and chromatographed to obtain 650 mg of the title compound as an oil which was crystallized from hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](Br)=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:10]([O:12]CCCC)=[CH2:11].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:10](=[O:12])[CH3:11])=[CH:5][N:4]=1
Reactant: COc1ncccc1Br
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(C)=O)cn1
Temperature: 110 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
2-Methoxybromopyridine (25 g) and n-butyl vinyl ether (66.6 g) were dissolved in DMF (250 ml). To the solution were added 1,3-bis(diphenylphosphino)propane (3.62 g) and Pd(OAc)2 (896 mg) and aq. K2CO3 under nitrogen atmosphere. The reaction mixture was stirred for 2 hours at 100-120° C. The mixture was cooled to 25° C. To the solution was added 1N aq. HCl (625 ml). The solution was stirred for 1 hour at 25-30° C. The solution was portioned to EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with water and brine, and dried over MgSO4. Evaporation of solvent in vacuo gave oily residue. The residue was purified by chromatography on silica gel (EtOAc:n-Hexane=1:5, v/v) to give 2-methoxy-5-acetylpyridine as a solid (12.14 g).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[NH:20][C:19]=2[CH3:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].F[C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>CN(C=O)C>[C:38]([N:20]1[C:21]2[C:26](=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:18]([CH2:17][CH2:16][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]2[CH2:9][CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:19]1[CH3:29])(=[O:39])[C:37]1[CH:41]=[CH:42][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CCCC3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CCCC1CCCCC1)c(C)n2C(=O)c1ccccc1

Procedure:
Reaction of 3-{2-[2-(3-cyclohexylpropyl)piperidino]ethyl}-5-methoxy-2-methylindole with a mineral oil dispersion of sodium hydride in DMF and reaction of the resulting sodium salt with 4-fluorobenzoyl chloride affords 1-benzoyl-3-{2-[2-(3-cyclohexylpropyl)piperidino]ethyl}-5-methoxy-2-methylindole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([C:6]([OH:8])=[O:7])[NH:14][CH2:13][CH2:12][N:11]([CH3:15])[CH3:10]
Reactant: CN(C)CCN
Reactant: COC(=O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](NCCN(C)C)C(=O)O
Yield: 33.2 %

Procedure:
28.6 g (0.22 mol) of maleic acid-monomethyl ester, 40 ml of triethylamine and 17.6 g (0.20 mol) of 2-dimethylaminoethylamine are reacted in a manner analogous to that described in Example 1. Further processing according to Example 1 yields 14.5 g (33.2% of theory) of a crystalline aspartic acid derivative, which melts at 164° to 166°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:10]=3[O:11][CH:12]=2)=[CH:4][CH:3]=1.[N+:21]([O-:26])([N+]([O-])=O)=[O:22]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:10]=3[O:11][C:12]=2[N+:21]([O-:26])=[O:22])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: Brc1ccc(-c2coc3c2ccc2ccccc23)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1oc2c(ccc3ccccc32)c1-c1ccc(Br)cc1

Procedure:
A solution of 2 g. of the product of step B in 50 ml. of dichloromethane is treated with 2.0 g. of dinitrogen tetraoxide, and the mixture is stirred at about 20° C. for about 18 hours. The mixture is evaporated, and the residue obtained is recrystallized from aqueous ethanol to provide yellow crystals of 3-(4'-bromophenyl)-2-nitronaphtho-[1,2-b]furan, m.p. 230°-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C:13]2([C:28]#[N:29])[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[CH:27]=[CH:26][NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[OH-].[NH4+]>C(O)C.[Ni]>[NH2:29][CH2:28][C:13]1([C:11]([NH:10][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH3:9])=[O:12])[CH2:14][CH2:15][N:16]([C:19]2[C:20]3[CH:27]=[CH:26][NH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:17][CH2:18]1
Reactant: C[C@@H](NC(=O)C1(C#N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H](NC(=O)C1(CN)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Reaction time: 36 h
Yield: 58.6 %

Procedure:
Raney® nickel (293 mg, 1.71 mmol) was added to a solution of (R)—N-(1-(4-chlorophenyl)ethyl)-4-cyano-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (Intermediate 45) (466 mg, 1.14 mmol), in ethanol (30 mL). Ammonium hydroxide (10 mL) was added. This mixture was first purged with nitrogen, then placed under a balloon of hydrogen and stirred for 36 hours. The reaction mixture was filtered through celite and the solvent evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% 7N ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford (R)-4-(aminomethyl)-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (276 mg, 58.6%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:7][C:6]3[CH:16]=[CH:17][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)=[CH:9][CH:10]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1ccc(CNCc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)cc1
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
To a mixture of 4-(4-(trifluoromethyl)phenoxy)benzaldehyde (1.4 g, 5.2 mmol) in anhydrous dichloroethane (10 mL), at room temperature under nitrogen, was added (4-fluorophenyl)methanamine (0.6 mL, 52 mmol). The mixture was stirred for 3 minutes before acetic acid (0.42 mL, 7.3 mmol) was added dropwise via syringe. After an additional 30 minutes, sodium triacetoxyborohydride (1.6 g, 7.3 mmol) was added to the reaction mixture. After 20 h, the reaction was quenched with 1 N aqueous NaOH (30 mL) then extracted with chloroform. The organic extracts were combined, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (ISCO system, eluting with 0-5% MeOH in CHCl3) to afford the desired compound (0.51 g, 24%) as a colorless oil. MS (ESI): 376.1 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[C:11]2[NH:12][C:13](=[O:15])[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[F:5][C:6]1[C:11]2[NH:12][C:13](=[O:15])[O:14][C:10]=2[CH:9]=[C:8]([N+:1]([O-:4])=[O:2])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2c(F)cccc2o1
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2c(F)cc([N+](=O)[O-])cc2o1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Nitric acid (70%, 2.50 ml, 0.0389 mol) is added dropwise at −10° C. to a solution of 4-fluoro-1,3-benzoxazol-2(3H)-one (Step 4, 5.95 g, 0.0389 mol) in concentrated sulfuric acid (60 ml). The reaction is stirred at −10° C. for 30 minutes and then poured into ice water. The resulting precipitate is collected by filtration and dried under reduced pressure to give desired product contaminated with approximately 10–15% of the undesired 5-nitro isomer (7.2 g, 93%); mp 177–9° C.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C.[C-]#N.[K+].COC1C=CC(O)=CC=1>>[C:1]([O:6][CH2:7][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: C=C(C)C(=O)OC
Agent: COc1ccc(O)cc1
Agent: [C-]#N
Agent: [K+]
Product: C=C(C)C(=O)OCCCCCCCCCCCCCCCCCC
Temperature: 75 °C
Reaction time: 3.5 h

Procedure:
300 g of methyl methacrylate (3 mole), 135 g of stearyl alcohol (0.5 mole), 4.35 g of KCN (1%) and 0.108 g of hydroquinone methyl ether (250 ppm) are added to a 1 liter round-bottomed flask. The mixture is heated to about 75° C. by conducting air through it and the methyl methacrylate/methanol-azeotrope is removed at a temperature of 65° C. at the head of the column by way of a 1 m vigreux column. The trans-esterification is completed after 3.5 hours. After cooling down of the flask, the sump is filtered to remove the potassium cyanide, and the filter residue is washed with a little methyl methacrylate. The filtrate is concentrated at 40° C. under a water jet vacuum. A white, crystalline residue of stearyl methacrylate of 162 g = 96% will result.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:21]>C1C2C(=CC=CC=2)CCC1.CCOCC.[Pd]>[ClH:21].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NCCc3ccccc32)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: c1ccc2c(c1)CCCC2
Product: COc1ccc(-c2nccc3ccccc23)cc1OC
Reaction time: 3 h
Yield: 23 %

Procedure:
A sample of 1-(3,4-Dimethoxyphenyl) 3,4-dihydroisoquinoline (A2) from 3.0 g of the hydrochloride (9.9 mmol) was boiled with 10% Pd/C (240 mg) in tetralin (30 ml). After 3 h the reaction was complete by tlc and the cooled mixture was diluted with ether and the catalyst was filtered. The filtrate was treated with HCl gas and the precipitated hydrochloride was collected by filtration. Recrystallization from CH2 /Cl2 /i-PrOH afforded 700 mg (23%) of pure 1-(3,4-dimethoxyphenyl) isoquinoline hydrochloride, mp 208°-228° dec.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[C:13](O)(=[O:18])[CH2:14][C:15](O)=[O:16]>>[OH:18][C:13]1[C:6]2[C:7](=[C:8]3[CH:9]=[CH:10][CH:11]=[C:2]([CH3:1])[C:3]3=[CH:4][CH:5]=2)[O:12][C:15](=[O:16])[CH:14]=1
Reactant: Cc1cccc2c(O)cccc12
Reactant: O=C(O)CC(=O)O
Product: Cc1cccc2c1ccc1c(O)cc(=O)oc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
The mixture of 5-methyl-1-naphthol (6) (1.0 g, 6.33 mmol), malonic acid (658 mg, 6.33 mmol), and PPA (10 g) was heated at 75° C. for 3 h. After the reaction, ice-water was added to the black residue. The solid was filtered, dissolved in 10% Na2CO3 solution, and stirred overnight. The basic solution was filtered, and the filtrate was acidified with 2 N HCl solution until the pH was about 4. The precipitate was then filtered and purified by silica gel chromatography to yield 7 (620 mg, 43%) as a yellow solid. mp 223-225° C.; 1H NMR (DMSO-d6) δ 2.69 (s, 3H), 5.70 (s, 1H), 7.57-7.61 (m, 2H), 7.86 (d, J=9.0 Hz, 1H), 7.92 (d, J=9.0 Hz, 1H), 8.23 (d, J=7.5 Hz, 1H), 12.8 (br s, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=O)C.[NH2:15][C@@H:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)=[O:18]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:5]([OH:4])=[C:6]([CH:10]=1)[C:7]([NH:15][C@H:16]([C:17](=[O:18])[NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=1)[CH2:34][CH:35]([CH3:36])[CH3:37])=[O:9]
Reactant: CC(C)C[C@H](N)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Product: CC(C)C[C@H](NC(=O)c1cc(Cl)ccc1O)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 24.8 %

Procedure:
Using 2-acetoxy-5-chlorobenzoic acid and (S)-2-amino-4-methyl-N-[3,5-bis-(trifluoromethyl)phenyl]pentanamide as the raw materials, the same operation as the Example 302(2)-(3) gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][N:26]([CH3:38])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)=[O:28]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:34]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:27]([N:26]([CH3:38])[CH3:25])=[O:28])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN(C)C(=O)c1ccccc1B(O)O
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccccc1-c1ccc2c(c1)C1(CC(c3ccccc3)O2)N=C(N)N(C)C1=O
Temperature: 120 °C
Yield: 6.8 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 2-(dimethylcarbamoyl)phenylboronic acid (20 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 2-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzamide (1.60 mg, 6%). 1H-NMR (MeOD): 2.45 (m, 3H), 2.56 (m, 1H), 2.64 (m, 1H), 2.86 (m, 3H), 3.36 (s, 3H), 5.81 (m, 1H), 7.14 (m, 1H), 7.21 (m, 1H), 7.33 (m, 1H), 7.44 (m, 9H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[H][H]>[Ni].CO.C(OCC)(=O)C.N>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[N:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCN(c2ccc(C#N)cn2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN1CCN(c2ccc(CN)cn2)CC1
Yield: 103.8 %

Procedure:
A mixture of 2 g (8 mmol) 6-(4-ethyl-piperazin-1-yl)-nicotinonitrile, 1.3 g Raney Nickel (B113Z, Degussa) in 25 ml methanol, 15 ml ethyl acetate and 5 ml ammonia aq. (ca. 25%) was treated with 1 bar hydrogen at 30-35° C. for 4 h. The mixture was filtered and the residue washed three times with 20 ml ethyl acetate each and the combined organic phases evaporated to dryness to yield 1.83 g (97%) of the title compound as white crystals. (m/e): 261.1 (MH+; 100%).
Reaction SMILES: [CH2:1]([N:8]([CH3:29])[CH2:9][CH2:10][CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[C:25]([CH:27]=O)[CH:24]=[CH:23][N:22]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[CH2:1]([N:8]([CH3:29])[CH2:9][CH2:10][CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[C:25]([CH2:27][NH:33][CH:30]2[CH2:32][CH2:31]2)[CH:24]=[CH:23][N:22]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: CN(CCCN(Cc1cc(C=O)ccn1)C(=O)OC(C)(C)C)Cc1ccccc1
Product: CN(CCCN(Cc1cc(CNC2CC2)ccn1)C(=O)OC(C)(C)C)Cc1ccccc1

Procedure:
By General Procedure A from tert-butyl N-{3-[benzyl(methyl)amino]propyl}-N-[(4-formylpyridin-2-yl)methyl]carbamate and cyclopropanamine. Purification by column chromatography using DCM:MeOH:NH4OH (8:2:1) gave the title compound. 1H NMR (300 MHz, CDCl3), (rotamers) δ ppm: 8.4 (d, 1H), 7.4-7.2 (m, 7H), 4.5 (s, 2H), 3.9 (s, 2H), 3.7-3.2 (m, 4H), 2.6-1.7 (m, 8H), 1.4 (d, 9H), 0.6-01.3 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH3:9])[CH:5]=[N:6][CH:7]=1.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:9])[S:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:22])[F:23])=[CH:17][CH:16]=2)(=[O:20])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: CNc1cncc(Br)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CN(c1cncc(Br)c1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h

Procedure:
To a microwave vial equipped with a stir bar and charged with 5-bromo-N-methylpyridin-3-amine (0.250 g, 1.3 mmol) in isopropanol (3 ml), was added 4-(trifluoromethyl)benzene-1-sulfonyl chloride (0.820 g, 3.3 mmol) and pyridine (0.32 ml, 4.0 mmol) into the mixture. The vial was capped and placed into a CEM Microwave for 20 minutes at 80° C., while 50 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed mostly desired product. The mixture was diluted with DCM and saturated sodium bicarbonate solution, then extracted the organic layer with DCM (3×25 ml). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by ISCO silica-gel chromatography in a gradient of 0-5% isopropanol/DCM. The fractions with desired product were combined and concentrated in vacuo. This gave N-(5-bromopyridin-3-yl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide (0.300 g, 57% yield) as an off-white crystalline solid. MS (ESI pos. ion) m/z: 396 (MH+). Calc'd exact mass for C13H10BrF3N2O2S: 395. 1H NMR (400 MHz, DMSO-d6): 3.24 (s, 3H), 7.79 (s, 2H), 8.01 (s, 3H), 8.46 (s, 1H), 8.66 (s, 1H).