Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5](O)=[O:6].C(N1C=CN=C1)([N:22]1C=CN=C1)=O.C([O-])(=O)C.[NH4+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH2:22])=[O:6]
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 59.1 %

Procedure:
To a solution of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (145.0 mg, 0.33 mmol) in N,N-dimethylformamide (1.50 ml), 1,1′-carbonylbis(1H-imidazole) (60 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 7 hours to obtain a homogeneous solution. Ammonium acetate (65 mg, 0.83 mmol) was added, and stirred for 2 h. Water (10 ml) was added, and the precipitated solid was filtered, washed with hot methanol to obtain 2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide as an yellow solid (85 mg, 58%) LC/MS: [9.59 min; 436, 438]
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=O.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15]>C1(C)C=C(C)C=C(C)C=1>[OH:1][CH2:6][CH2:5][O:4][CH2:3][C:2]1[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]=1
Reactant: Nc1ccccc1N
Reactant: O=C1COCCO1
Solvent: Cc1cc(C)cc(C)c1
Product: OCCOCc1nc2ccccc2[nH]1

Procedure:
Using a Dean-Stark separator, 1.4-dioxan-2-one (204 g, 20 mmol) and 1.2-diaminobenzene (2.16 g, 20 mmol) were heated under reflux in mesitylene (150 ml) for 10 h. The crystals formed on cooling were then filtered off with suction (2.94 g. 77% of theory). Rf (dichloromethane:methanol 10:1)=0.45, MS (EI)=192 (M+, 20%), 148 (20%), 147 (40%), 132 (100%), 1H-NMR (DMSO-d6): 3.6 (4H, s); 4.65 (1H, s); 4.7 (2H, s); 7.1-7.2 (2H, m); 7.45 (1H, d); 7.55 (1H, d); 12.4 (1H, br s).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:18][C:17]([OH:28])=[N:16]2)=[CH:11][CH:10]=1.N1C=CC=CC=1.O>ClCCl.C(OCC)(=O)C>[CH3:1][N:2]([CH3:6])[C:3](=[O:4])[O:28][C:17]1[N:18]=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=2)[N:16]=1
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Reactant: CN(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2nc(OC(=O)N(C)C)nn2-c2ccc(OC)cc2)cc1
Temperature: 45 °C
Reaction time: 17 h
Yield: 35.5 %

Procedure:
Dimethylcarbamic chloride was added to a mixture of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (200 mg, 0.673 mmol) and pyridine (0.114 ml, 1.41 mmol) in dichloromethane (5 ml). Then the solution was stirred at 45° C. for 17 hours. Water and ethyl acetate were poured into the mixture and the organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (hexane-ethyl acetate 1:2). The desired product was washed with isopropyl ether to give 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-yl dimethylcarbamate. (88 mg, 35.5% yield)
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:5])#[N:2].CO[CH:16]=[CH:17][C:18](=O)[CH3:19].N12CCN(CC1)CC2.CO/C=C/C(=O)C.Cl>COCCOCCO>[F:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])=[CH:12][CH:11]=1
Reactant: COC=CC(C)=O
Reactant: N#CCC(=O)Nc1ccc(F)cc1
Agent: C1CN2CCN1CC2
Agent: CO/C=C/C(C)=O
Agent: Cl
Solvent: COCCOCCO
Product: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Temperature: 120 °C
Yield: 31.2 %

Procedure:
A solution of 2-cyano-N-(4-fluorophenyl)acetamide (15 g, 84.2 mmol), 4-methoxybut-3-en-2-one (12.6 g, 125.9 mmol) and 1,4-diazabicyclo[2.2.2]octane (9.4 g, 84.2 mmol) in 2-(2-methoxyethoxy)ethanol (150 mL) was stirred with heating at 120° C. for 5 hr. (3E)-4-Methoxybut-3-en-2-one (4.2 g, 41.9 mmol) and 1,4-diazabicyclo[2,2,2]octane (4.7 g, 41.9 mmol) were further added to the reaction mixture, and the mixture was stirred with heating at 120° C. for 1 hr. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (6 g, 31%) as a pale-brown solid.
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[N:4]=1>C(OCC)C>[NH2:1][C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[N:4]=1
Reactant: Fc1cc(F)nc(F)n1
Reactant: N
Solvent: CCOCC
Product: Nc1nc(F)cc(F)n1
Temperature: 25 °C

Procedure:
69.7 g (4.1 mol) of liquid ammonia were added at -30° to -20° C. to a stirred mixture of 250 g (1.865 mol) of 2,4,6-trifluoropyrimidine and 3.3 1 of diethyl ether within 1 hour. To work up, the reaction mixture was warmed to 25° C. and the precipitate was filtered off. Washing with ether, stirring in water, renewed filtration and drying resulted in 203 g (83% of theory) of the desired product (melting point 214°-216° C.). It was possible by concentrating the ether filtrate to about 1/3 of its volume to isolate a further 20 g (8% of theory) of this compound, of melting point 193°-196° C., from a 1:1 mixture with the isomeric 4-amino compound. Comparative experiment (according to SU-A 547,447--1975)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]2.[OH:26]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]2)=[O:26]
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCSc3cc(Br)ccc3Br)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)c3cc(Br)ccc3Br)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(2,5-dibromophenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][CH:12]([C:23]([OH:25])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][CH:12]([C:23]([OH:25])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)O)c1ccccc1Cl
Yield: 84 %

Procedure:
The same procedure is used as in Example 1, o-chlorobenzoyl chloride and DL-tryptophane being used. Yield 84%. Melting point 56° to 70° C.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Cl:5][C:6]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:7]=1[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[NH:11][CH:10]=1>CN(C)C=O>[Cl:5][C:6]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:7]=1[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[N:11]([CH3:3])[CH:10]=1
Reactant: CI
Reactant: COC(=O)c1ccc2[nH]cc(Cc3ccc(Cl)cc3Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(Cl)cc1Cl)cn2C
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.7 %

Procedure:
60% sodium hydride (0.07 g) and then methyl iodide (0.18 g) are added in that order to an N,N-dimethylformamide solution of 3-(2,4-dichlorobenzyl)-5-methoxycarbonylindole (0.34 g), and stirred at room temperature for 19 hours. After concentrated under reduced pressure, this is extracted with water and ethyl acetate. The resulting extract is washed with water, dried, concentrated, and purified through silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 7/1) to obtain 3-(2,4-dichlorobenzyl)-5-methoxycarbonyl-1-methylindole (55) (0.30 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]([N:15]=[C:16]=S)([CH3:14])[CH3:13].N=C=N.CC1C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[CH:12]([NH:15][C:16]1[NH:10][C:4]2[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[C:3]=2[N:11]=1)([CH3:14])[CH3:13]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1N
Reactant: CC(C)N=C=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N=C=N
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(Cl)c(Cl)c(Cl)cc2[nH]1
Yield: 70.3 %

Procedure:
3,4,5-Trichloro-1,2-phenylenediamine (3.12 g, 14.8 mmol), isopropyl isothiocyanate (1.62 g, 16.0 mmol), 1-cyclohexyl-3-2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (8.4 g, 19.9 mmol), and pyridine (50 mL) were used according to general procedure II. The product was recrystallized from 1,4-dioxane to give 2.9 g (72%) of a tan solid. MS (CI): m/z 276 (M+1). Anal. Calcd. for C10H10Cl3N3-(0.10 C4H8O2): C, 43.47; H, 3.79; N, 14.62. Found. C, 43.70; H, 3.89; N, 14.43.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([NH:31][CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.Cl>[NH2:34][CH2:33][CH2:32][NH:31][C@@H:10]1[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][C@H:11]1[N:13]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[S:14]([C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)(=[O:15])=[O:16]
Reactant: CC(C)CCN([C@@H]1CN(Cc2ccccc2)C[C@H]1NCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CCN([C@@H]1CN(Cc2ccccc2)C[C@H]1NCCN)S(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of tert-butyl (2-{[(3R,4R)-1-benzyl-4-{(3-methylbutyl)[(4-nitrophenyl)sulfonyl]amino}pyrrolidin-3-yl]amino}ethyl)carbamate in 2N HCl dioxane was stirred overnight at room temperature before the solvent was evaporated to dryness. The resulting tris HCl salt was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CC(N(C)C)=O>[F:10][C:9]1[C:2]([F:1])=[C:3]([CH:4]=[O:5])[CH:6]=[CH:7][C:8]=1[O:11][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C=O)c(F)c2F)nc1
Temperature: 180 °C
Yield: 65.2 %

Procedure:
Combine 2,3-difluoro-4-hydroxy-benzaldehyde (see Canadian patent 1190093) (1.93 g, 12.2 mmol), 6-chloronicotinonitrile (1.69 g, 12.2 mmol), K2CO3 (2.53 g, 18.3 mmol) and DMA (30 ml) in a sealed, pressure vessel. Heat the suspension at 180° C. for five minutes in a microwave (600 Watts), cool to near ambient temperature and pour into aqueous NH4Cl. Extract aqueous with EtOAc (2×), wash with water (2×) and brine, dry (MgSO4) and concentrate. Purify on silica gel (20% EtOAc/Hexane) to give 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinonitrile (2.07 g) as a white solid. 1H NMR (CDCl3): 10.33 (s, 1H), 8.42 (s, 1H), 8.02 (d, 1H), 7.73 (t, 1H), 7.20 (d, 1H), 7.15 (t, 1H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[ClH:5].[CH3:6][N:7]([CH3:12])[CH2:8][CH2:9][CH2:10][Cl:11]>C(O)C>[ClH:11].[ClH:5].[CH3:6][N:7]([CH3:12])[CH2:8][CH2:9][CH2:10][S:3][C:2](=[NH:4])[NH2:1]
Reactant: CN(C)CCCCl
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: CN(C)CCCSC(=N)N

Procedure:
Equimolar quantities of thiourea and 3-(dimethylamino)-1-chloropropane hydrochloride and a little ethanol are heated together at 140° for 3 hours, and the cooled mixture is recrystallised from methanol/isopropanol to give the title product.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(=O)([O-])[O-].[Na+].[Na+].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCOCC1.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>[C:23]1([C:2]2[NH:3][C:4]3[C:9]([C:10]=2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Cc1c(Br)[nH]c2ccccc12
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: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
To a solution of 2.0 g (7.1 mmol) of ethyl (2-bromoindol-3-yl)acetate in 40 ml of dioxane was added under argon 1.2 g (0.11 mmol) of Pd(PPh3)4 and 13.3 ml of 2.0 M sodium carbonate. After stirring at room temperature for ca. 15 min, 1.3 g (11 mmol) of benzeneboronic acid was added, and the mixture was heated at 80° C. under argon overnight. The mixture was cooled to room temperature and solids were removed by filtration. The filtrate was concentrated and chromatographed on silica gel with toluene as an eluent to yield 1.6 g (81%) of the 2-phenyl indole as a yellow crystalline solid.
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([CH2:26][OH:27])[CH:22]=[CH:23][CH:24]=3)[C:19]([N:28]([S:38]([C:41]3[S:42][C:43]([Cl:46])=[CH:44][CH:45]=3)(=[O:40])=[O:39])[S:29]([C:32]3[S:33][C:34]([Cl:37])=[CH:35][CH:36]=3)(=[O:31])=[O:30])=[N:18]2)[CH:11]=1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:5][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([CH2:26][OH:27])[CH:22]=[CH:23][CH:24]=3)[C:19]([N:28]([S:38]([C:41]3[S:42][C:43]([Cl:46])=[CH:44][CH:45]=3)(=[O:40])=[O:39])[S:29]([C:32]3[S:33][C:34]([Cl:37])=[CH:35][CH:36]=3)(=[O:31])=[O:30])=[N:18]2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)N(Cc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(CO)cccc32)c1)C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(CO)cccc32)c1
Reaction time: 1 h
Yield: 66 %

Procedure:
1,1-Dimethylethyl[(3-{[3-{bis[(5-chloro-2-thienyl)sulfonyl]amino}-4-(hydroxymethyl)-1H-indazol-1-yl]methyl}phenyl)methyl]carbamate (for a preparation see Intermediate 71) (93 mg, 0.125 mmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.125 mL) was added to the solution and stirred for 1 h under nitrogen. The reaction mixture was concentrated under a stream of nitrogen and the residue was dissolved in methanol and loaded onto a methanol pre-conditioned sulphonic acid (SCX-2) cartridge (10 g). The cartridge was washed well with methanol, followed by 2M ammonia in methanol. Evaporation of the solvent from the ammoniacal fractions gave the title compound (53 mg, 66%) as a white solid. LCMS (System A) RT=0.89 min, ES+ve m/z 643/645 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=1.O.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccnc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(NCc2ccnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 87.9 %

Procedure:
4-Quinolinecarboxaldehyde (10.0 g, 63.8 mmol) and methyl 4-aminobenzoate (9.64 g, 63.8 mmol) were refluxed under nitrogen in 100 mL of toluene with azeotropic removal of water. After 7 days, the reaction mixture was allowed to cool to room temperature. The imine precipitated as a yellow solid and was collected by filtration. The material was dried under reduced pressure overnight affording 15.5 g (53.4 mmol) of crude product. This was stirred in 270 mL of ethanol and treated with sodium borohydride (2.22 g, 58.7 mmol). The reaction mixture was refluxed for 45 minutes then poured hot over 800 mL of crushed ice. After 45 minutes of stirring, the white solid was filtered and allowed to air dry in the funnel overnight giving 15.6 g of 4-[(4-quinolinylmethyl)amino]benzoic acid as a 5:1 mixture of methyl:ethyl esters. All of the material was refluxed for 18 hours in 180 mL of 1N KOH and then poured hot into a mixture of 180 mL of 1N HCl and 800 mL of water. After 3 hours of stirring, the white solid was filtered and washed successively with methanol and ether affording 13.5 g (48.5 mmol, 76% overall yield) of 4-[(4-quinolinylmethyl)amino]benzoic acid which was air dried in the funnel overnight.
Reaction SMILES: [CH2:1]([C:4]1([CH2:20][CH2:21][NH:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][C:5]21OCCO2)[CH:2]=[CH2:3].Cl>C(O)C>[CH2:1]([C:4]12[C:13]3[CH:12]=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:8]=3[CH2:7][CH:6]=[C:5]1[N:22]([CH2:23][CH:24]1[CH2:26][CH2:25]1)[CH2:21][CH2:20]2)[CH:2]=[CH2:3]
Reactant: C=CCC1(CCNCC2CC2)c2cc(OC)ccc2CCC12OCCO2
Agent: Cl
Solvent: CCO
Product: C=CCC12CCN(CC3CC3)C1=CCc1ccc(OC)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Preparation From 1-allyl-1-[2-(N-cyclopropylmethylamino)ethyl]-2,2-ethylenedioxy-7-methoxy-1,2,3,4-tetrahydronaphthalene (XIXa). To a solution of 30.4 g (85 mmole) XIXa in ethanol (125 ml) was added a solution of 4% hydrochloric acid (125 ml). The reaction mixture was stirred at room temperature overnight (16 hrs) and then concentrated under vacuum to about half volume, alkalified with 10% sodium hydroxide and extracted with ether (2×100 ml). Combined extracts were washed with water (2×80 ml) and dried (MgSO4). Removal of the solvent under vacuum gave 23.0 g (92%) IIe identical with the material prepared in Example 39(a) above.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=O)[CH2:9][CH2:8]2)#[N:2].[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].[BH4-].[Na+]>>[CH2:14]([N:17]([CH2:18][CH2:19][CH3:20])[CH:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)[CH2:15][CH3:16]
Reactant: CCCNCCC
Reactant: N#Cc1cccc2c1CC(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Product: CCCN(CCC)C1CCc2cccc(C#N)c2C1

Procedure:
8-Cyano-2-tetralone (500 mg, 2.9 mMol) was reacted with dipropylamine (0.8 mL, 5.8 mMol) and sodium borohydride (370 mg) as described in Example 1 to give the title compound as a colorless, viscous oil (260 mg, 35%). The hydrochloride salt was formed and crystallization (ethanol/diethyl ether) gave colorless crystals (m.p.=175°-176° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>>[C:18]1([CH3:22])[CH:19]=[CH:20][CH:21]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:17]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Cc1cccc(I)c1
Product: COC(=O)CCc1ccc(C#Cc2cccc(C)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (90 mg, 0.48 mmol) and iodo-3-methylbenzene (0.07 mL, 0.55 mmol) according to the general procedure IB to give 42 mg (36%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:30→1:10). Rf: 0.29 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.46-7.43 (m, 2H), 7.35-7.31 (m, 2H), 7.22-7.12 (m, 4H), 3.67 (s, 3H), 2.99-2.93 (t, 2H, J=7.8 Hz), 2.66-2.61 (t, 2H, J=7.8 Hz), 2.35 (s, 3H); 13CNMR (CDCl3) δ 173.1, 140.8, 138.0, 132.1, 131.7, 129.1, 128.6, 128.3, 128.2, 123.1, 121.3, 89.3, 88.9, 51.6, 35.4, 30.8, 21.2; ESI-MS m/z 301.1 (MNa+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8](OC)[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5])[CH3:2].[CH2:20]([Si](C)(C)C)[CH:21]=[CH2:22].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8]([CH2:22][CH:21]=[CH2:20])[N:7]1[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC(OC)N1C(=O)OC(C)(C)C
Reactant: C=CC[Si](C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCC1CC[C@@H](C(=O)OCC)N1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of 9.25 g of α-methoxycarbamate 168 (33.8 mmol) in 100 ml of anhydrous CH2Cl2 was cooled to −78° C., added initially with 13.50 ml of allyltrimethylsilane (84.6 mmol, 2.5 eq.), followed by dropwise addition of 8.58 ml of BF3.OEt2 (67.7 mmol, 2 eq.) and stirring for one hour. Thereafter, 10 ml of H2O and 30 ml of saturated NaHCO3 solution were added at low temperature, the batch was allowed to come to 0° C., stirred for 30 min and thawed to RT. After separating the phases, the aqueous phase was extracted with 3×50 ml of CH2Cl2, the combined organic phases were washed with 30 ml of saturated NaCl solution and dried over MgSO4. After removing the solvent, the residue was purified using silica gel column chromatography (EE/CH 1:6) to obtain 6.83 g of allyl substitution product 169 (24.1 mmol, 71%) as a colorless oil (mixture of epimers, cis/trans 4:1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1.[C:33]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH2:40])=[O:39])#[CH:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:16]2[CH:31]=[CH:32][C:13]([NH:12][C:4]3[N:3]=[C:2]([C:34]#[C:33][C:35]4[CH:43]=[CH:42][CH:41]=[C:37]([C:38](=[O:39])[NH2:40])[CH:36]=4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=3)=[CH:14][CH:15]=2)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: C#Cc1cccc(C(N)=O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4cccc(C(N)=O)c4)n3)cc2)CC1
Temperature: 120 °C
Yield: 29 %

Procedure:
tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I94) (0.30 g, 0.64 mmol), 3-ethynylbenzamide (I144) (102 mg, 0.70 mmol), copper(I) iodide (12 mg, 10 mol %), triphenylphosphine (17 mg, 10 mol %), bis(triphenylphosphine)palladium(II) chloride (22 mg, 5 mol %), DMF (3 mL) and triethylamine (0.443 mL, 3.18 mmol) were loaded into a microwave tube and degassed with nitrogen for five minutes. The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes then cooled to room temperature. The cooled mixture was added to 5% aqueous potassium carbonate (I50 mL) and the resulting mixture extracted with ethyl acetate (3×150 mL). The combined ethyl acetate phases were washed with water (200 mL), brine (200 mL), dried then evaporated. The residue was chromatographed (Biotage Isolera: 12 g silica cartridge, 20-100% ethyl acetate/petroleum benzine 40-60° C. then 0-10% methanol/ethyl acetate) to give the title compound (I145) (107 mg, 29% yield) as a yellow solid; 1H NMR (400 MHz, d5-DMSO) δ 10.46 (s, 1H), 8.84 (s, 1H), 8.17 (s, 1H), 8.09 (t, J=1.7 Hz, 1H), 8.04 (dt, J=7.9, 1.4 Hz, 1H), 7.77 (dt, J=7.8, 1.3 Hz, 1H), 7.71-7.66 (m, 2H), 7.66-7.52 (m), 7.27 (d, J=8.6 Hz, 2H), 3.44 (s, 2H), 2.33-2.26 (m, 4H), 1.38 (s, 9H). LCMS Method C: rt 5.06 min; m/z 581.1 [M+H]+, 525.1 [M−tBu+2H]+; m/z 579.2 [M−H]−.