Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]1)([O:15][CH3:16])=[O:14].[Cl:26][C:27]1[C:28]([CH:33]([NH2:50])[C:34]2[CH:43]=[C:42]3[C:37]([CH:38]=[CH:39][C:40]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[N:41]3)=[CH:36][CH:35]=2)=[N:29][CH:30]=[CH:31][N:32]=1>C1COCC1>[CH3:16][O:15][C:13]([C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23](=[O:25])[NH:50][CH:33]([C:28]2[C:27]([Cl:26])=[N:32][CH:31]=[CH:30][N:29]=2)[C:34]2[CH:43]=[C:42]3[C:37]([CH:38]=[CH:39][C:40]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[N:41]3)=[CH:36][CH:35]=2)[CH2:21][CH2:22]1)=[O:14]
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)CC1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A THF solution (15 mL) of CDI (1.2 g, 7.3 mmol) and trans-4-carbomethoxycyclohexane-1-carboxylic acid (1.2 g, 6.6 mmol) was stirred at 60° C. for 16 h. The reaction mixture was charged with C-(3-chloropyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (compound of Formula IV where Q1=2-phenylquinolin-7-yl) (2.3 g, 6.6 mmol) and stirred at 60° C. for 20 h. The reaction mixture was concentrated in vacuo, taken up in EtOAc, and washed with water (2×) and brine (1×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (20% EtOAc/Hexanes to 100% EtOAc) the desired product as an orange foam; 1H NMR (CDCl3, 400MHz) δ 1.48-1.55 (m, 4H), 1.95-2.06 (m, 4H), 2.17-2.24 (m, 1H), 2.26-2.33 (m, 1H), 3.66 (s, 3H), 6.77 (d, 1H, J=7.6 Hz), 7.36-7.41 (m, 1H), 7.45-7.55 (m, 3H), 7.72-7.77 (m, 1H), 7.81-7.89 (m, 2H), 8.11 (d, 2H, J=7.2 Hz), 8.20-8.25 (m, 1H), 8.39 (d, 1H, J=2.4 Hz), 8.60 (d, 1H, J=2.8 Hz); MS (ES+): m/z 515.0 [MH+]; HPLC: tR=3.1 min (Micromass Platform II, nonpolar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:18]C)=[C:16]([I:17])[C:11]=2[O:10][N:9]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([I:17])[C:11]=2[O:10][N:9]=1
Reactant: COc1ccc2c(-c3ccccc3F)noc2c1I
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2c(-c3ccccc3F)noc2c1I

Procedure:
3-(2-fluorophenyl)-7-iodo-6-methoxy-1,2-benzisoxazole (8.2 g) is refluxed 18 hours in 130 ml of CH2Cl2 containing 6.6 ml of BBr3. The reaction mixture is poured into H2O and extracted into ether. Drying and evaporation gives a crystalline product that is triturated well with hexane to yield 3-(2-fluorophenyl)-6-hydroxy-7-iodo-1,2-benzisoxazole, mp 212°-214° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>[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.O1CCCC1>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:3]=[CH:4][C:5]=2[O:12][C:9]2([CH2:11][CH2:10]2)[CH2:8]1
Reactant: CC1(C)CC2(CC2)Oc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CC2(CC2)Oc2ccc(C#C[Si](C)(C)C)cc21

Procedure:
Following general procedure D and using 6-bromo-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 36, 0.44 g, 1.65 mmol), triethyl amine (4 mL), anhydrous tetrahydrofuran (5 mL), copper(I)iodide (0.95 g, 0.5 mmol), trimethylsilyl acetylene (1.62 g, 16.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.4 g, 0.56 mmol), the title compound was obtained as a brown oil (0.4 g, 86%).
Reaction SMILES: [C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=O.[ClH:13].Cl.[NH2:15][CH2:16][C:17]1[O:21][C:20]([C:22]([O:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:35](=[NH:37])[NH2:36])[CH:31]=3)[CH:26]=2)=[O:23])=[CH:19][CH:18]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:13].[C:9]([O:8][C:1]([CH2:2][CH2:3][C:4]([NH:15][CH2:16][C:17]1[O:21][C:20]([C:22]([O:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:35](=[NH:36])[NH2:37])[CH:31]=3)[CH:26]=2)=[O:23])=[CH:19][CH:18]=1)=[O:6])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)o3)ccc2c1
Reactant: CC(C)(C)OC(=O)CCC(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCC(=O)NCc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To 11.4 g of mono-t-butyl succinate, 23.5 g of 6-amidino-2-naphthyl 5-aminomethylfuran-2-carboxylate dihydrochloride and 0.66 g of DMAP was added 115 ml of pyridine, and the mixture was stirred with ice-cooling. After 10 minutes, 25.6 g of DCC was added and the mixture was stirred for 3 hours while cooling with ice and for 16 hours at room temperature. The precipitated crystals were filtered off, and the filtrate was added in small portions into 2 l of ether and stirred at room temperature for 3 l hours. After removing the supernatant by decantation, 1 l of acetone was added to the residue and stirred for 1 hour. The precipitate was collected by filtration, then dissolved in 60 ml of methanol and 3 g of active carbon was added to the solution. The mixture was stirred for 30 minutes while cooling with ice, then the insolubles were filtered off and the filtrate was added into 1.5 l of acetone. The mixture was stirred for 5 hours while cooling with ice, and the precipitated crystals were collected by filtration to obtain 21 g of the intended product.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[N:5][N:6]([CH3:13])[C:7]=1[N:8]=[CH:9]OCC)#[N:2].[CH3:22][NH2:23]>C(O)C>[CH3:22][NH:23][C:1]1[N:2]=[CH:9][N:8]=[C:7]2[N:6]([CH3:13])[N:5]=[C:4]([C:14]3[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C:3]=12
Reactant: CN
Reactant: CCOC=Nc1c(C#N)c(-c2ccc([N+](=O)[O-])o2)nn1C
Solvent: CCO
Product: CNc1ncnc2c1c(-c1ccc([N+](=O)[O-])o1)nn2C

Procedure:
A mixture of 10.0 grams of 4-cyano-5-ethoxymethyleneamino-1-methyl-3-(5-nitro-2-furyl)-pyrazole, and 100 milliliters of a 33 % solution of methylamine in ethanol was heated at reflux for 30 minutes and cooled. The crystalline solid precipitated was collected, washed with ether and dried. Recrystallisation from dimethylformamide gave 4-methylamino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, having melting point 280°C.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].Cl.[OH-].[NH4+:24]>>[NH2:24][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: Nc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Yield: 100 %

Procedure:
A solution of 2-(4-chloro-3-nitrobenzoyl)benzoic acid (75 g, 0.25 mol) in ammonium hydroxide 28% (250 mL) was heated to 85° C. for four days. Additions of ammonium hydroxide 28% (80 ml) were made three times daily. The solution was partially concentrated in-vacuo, then cooled in an ice bath. To the solution was added 6N hydrochloric acid until the pH became weakly acidic. The solid which formed was collected by vacuum filtration, washed twice with water (250 mL) and dried to afford 2-(4-amino-3-nitrobenzoyl)benzoic acid (72 g, 100%) as a yellow solid. 1H NMR (400 MHz, d6-DMSO): 8.09 (br s, 3H), 7.99 (d, 1H), 7.75-7.58 (m, 3H), 7.40 (d, 1H), 7.09 (d, 1H); MS (EI) for C14H10N2O4: 309 (MNa+)
Reaction SMILES: C[O-].[Na+].[NH:4]1[CH:11]=[CH:10][C:8](=[S:9])[NH:7][C:5]1=[O:6].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:9][C:8]2[CH:10]=[CH:11][NH:4][C:5](=[O:6])[N:7]=2)=[CH:15][CH:16]=1
Reactant: O=c1[nH]ccc(=S)[nH]1
Reactant: Clc1ccc(CBr)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1nc(SCc2ccc(Cl)cc2)cc[nH]1
Yield: 67.3 %

Procedure:
Sodium methoxide (0.057 g, 1.050 mmol) was added to a mixture of 4-thiouracil (0.128 g, 1.0 mmol) and 1-(bromomethyl)-4-chlorobenzene (0.216 g, 1.05 mmol) in 1 mL MeOH. After stirring the reaction at RT overnight, the reaction mixture was concentrated, partitioned between EtOAc and sat. NH4Cl. The organic phase was dried (MgSO4), concentrated and the residue was subjected to ISCO flash chromatography (silica gel/methylene chloride to 80:20 methylene chloride-MeOH gradient) to afford 4-(4-chlorobenzylthio)pyrimidin-2(1H)-one 2A (0.17 g, 0.673 mmol, 67% yield) as a light yellow solid. 1H NMR (400 MHz, methanol-D) δ 7.58 (1H, d, J=6.78 Hz), 7.43 (2H, d, J=8.53 Hz), 7.30 (2H, d, J=8.53 Hz), 6.39 (1H, d, J=6.78 Hz), 4.44 (2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][C:14](O)=[O:15])[N:12]=2)=[CH:4][CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CC(=O)O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A solution of 2-(4-bromophenyl)-5-methyl-4-oxazoleacetic acid (39.1 g, 0.13 mol) in dry THF (175 mL) was treated dropwise with borane/THF complex (227 mL of a 1.0 M solution in THF, 1.3 mol) over 2 h at about 35° C. After stirring 2 h at room temperature under N2, the reaction was quenched with slow addition of methanol (60 mL) and stirred overnight at room temperature. The reaction was diluted with 1 N NaOH (50 mL) and extracted with CH2Cl2 (2×200 mL). The organic layer was washed with H2O (3×100 mL), dried (MgSO4), and concentrated. The crude product (38.7 g) was recrystallized from toluene (200 mL, wash solid with cold hexanes) to give 26.9 g (72%) of 2-(4-bromophenyl)-5-methyl-4-oxazoleethanol as a white powder. Rf=0.37 in 10% MeOH/CH2Cl2. 1H NMR (500 MHz, CDCl3) 7.84-7.82 (m, 2H), 7.57-7.55 (m, 2H), 3.91 (q, J=5.5 Hz, 2H), 3.14 (t, J=6 Hz, OH), 2.72 (t, J=5.5 Hz, 2H), 2.33 (s, 3H); 13C (125 MHz, CDCl3) 158.7, 144.5, 134.2, 131.9, 127.4, 126.4, 124.3, 61.8, 28.1, 10.1; IR (KBr) 3293, 2948, 1642, 15985, 1480, 1472, 1401, 1053, 1003, 836, 734 cm−1; UV (EtOH) max 290 nm (20860); Anal. Calculated for C12H12BrNO2: C, 51.09; H, 4.29; N, 4.96; Br, 28.32. Found C, 51.31; H, 4.06; N, 4.90; Br, 28.19.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1>CC#N>[CH3:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][N:22]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(c1)C(c1ccccc1)NCC2
Reactant: O=C1CCC(=O)O1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)C(c1ccccc1)N(C(=O)CCC(=O)O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
25.5 g (255 mmol) of succinic anhydride and 20.3 ml (146 mmol) of NEt3 were added in succession to a solution of 16.3 g of the crude product 7-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline from a) in MeCN (300 ml) and the mixture was stirred for 16 h at RT. It was then concentrated to small volume under vacuum. The residue was taken up with DCM (400 ml). It was then washed with a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with DCM (2×400 ml). The collected organic phases were washed with 1N aqueous hydrochloric acid (400 ml) and with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (gradient heptane/EE 1:1 heptane/EE/AcOH 2:2:1) of the residue and subsequent crystallisation of the residue from EE produced 6.79 g (21 mmol, 24% over 2 stages) of 4-(7-methyl-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C@@H:3]1[C:9]([O:11]CC)=[O:10].Cl>>[CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)[C@H]1[C@@H](C=C(Cl)Cl)C1(C)C
Agent: Cl
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 30 °C
Reaction time: 40 h

Procedure:
1.0 g of ethyl (±)-cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylate of formula (II), in which X represents chlorine atom and R represents ethyl group, was added to the medium above and the mixture was allowed to react with shaking at 30° C. for 40 hours. After the reaction was over, the pH of the reaction mixture was adjusted to 2 or lower with concentrated hydrochloric acid and the mixture was subjected to extraction with methyl isobutyl ketone. Next, an internal standard (dimethyl phthalate) was added to the extract and the mixture was analyzed by gas chromatography (column: 3% Thermon 3000, 1.1 m, 140° C.). Then, the yield of 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylic acid [in formula (I), X is Cl and R is H] and the recovery rate of the ethyl 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylate used as the starting material were calculated by comparing their peak areas with that of dimethyl phthalate. It was found that all of the remaining ethyl 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylate which was not converted to 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylic acid was recovered. After that, the extract was mixed with IN sodium hydroxide solution to extract 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylic acid as sodium salt into the aqueous layer. Next, the pH of the aqueous layer was adjusted to 2 or lower with HCl solution to liberate 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylic acid which was then extracted by using methyl isobutyl ketone. After that, the extract was concentrated and evaporated to dryness to obtain substatially pure 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][N:9]=2)[C:5]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:4]=2[O:3]1.C(OCC)(=[O:29])C>>[C:24]([C:21]1[CH:22]=[CH:23][C:4]2[O:3][C:2]([CH3:26])([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:10][N+:9]=3[O-:29])[C:5]=2[CH:20]=1)#[N:25]
Reactant: CCOC(C)=O
Reactant: CC1(C)C=C(c2ccc(-c3ccccc3)cn2)c2cc(C#N)ccc2O1
Product: CC1(C)C=C(c2ccc(-c3ccccc3)c[n+]2[O-])c2cc(C#N)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 6, from 2,2-dimethyl-4-(5-phenyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile there was obtained 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-phenylpyridine N-oxide of melting point 173°-175° C. (from ethyl acetate).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)=[O:30]>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1cccc(Cl)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cccc(Cl)c2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(3-chlorophenyl)-1-hexanone were reacted and treated in the same manner as in Example 172 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-chlorophenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: F[C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:20][O-:21].[Na+].CO>>[CH3:20][O:21][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Fc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Yield: 89 %

Procedure:
A solution of 7-fluoro-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (100 mg, 0.31 mmol) in 1 M sodium methoxide-methanol (30 mL) is stirred under reflux for 42 h. The resulting mixture is concentrated under reduced pressure, diluted with water and neutralized with dilute HCl to give 7-methoxy-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (92 mg, 89%) as a white solid. 1H NMR (DMSO) δ 10.22 (1H, brs), 9.57 (1H, s), 8.63 (1H, s), 8.19 (1H, s), 7.86 (1H, brd, J=7.9 Hz), 7.39 (1H, t, J=7.9 Hz), 7.35 (1H, dd, J=7.9, 1.5 Hz), 6.96 (1H, s), 4.00 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:23]3[NH:27][CH:26]=[N:25][N:24]=3)=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[C:12]=2[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:13]([C:12]1[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[C:10]([C:23]2[NH:27][CH:26]=[N:25][N:24]=2)[S:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:37]([CH:34]2[CH2:36][CH2:35]2)=[O:38])[CH:7]=1)#[N:14]
Reactant: N#Cc1c(-c2ccnc(N)c2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1c(-c2ccnc(NC(=O)C3CC3)c2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a mixture of 2-(2-aminopyridin-4-yl)-4-(2,4-dichlorophenyl)-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (0.100 g, 0.24 mmol) in pyridine (0.39 mL, 4.8 mmol) and methylene chloride (10 mL) was added cyclopropanecarbonyl chloride 0.050 mL, 0.54 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours. Saturated sodium bicarbonate solution (5 mL) was added and the mixture was vigorously stirred for 15 min. The mixture was extracted with DCM, dried, filtered and evaporated and the residue was purified by column chromatography on silica gel (40 g) using DCM to 3% MeOH in DCM over 30 minutes to afford the product (0.041 g, 36%). LCMS: (FA) ES+, 481, 483. 1H NMR (400 MHz, d4-Methanol) 8.49-8.42 (m, 2H), 8.40 (s, 1H), 7.66 (dd, J=5.58, 1.76 Hz, 1H), 7.62 (t, J=1.16, 1.16 Hz, 1H), 7.46-7.44 (m, 2H), 1.99-1.87 (m, 1H), 1.11-1.03 (m, 2H), 1.00-0.94 (m, 2H)
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12]([CH3:21])([CH3:20])[C:13](=[O:19])[NH:14]2>CCCCCC>[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12]([CH3:21])([CH3:20])[C:13](=[O:19])[NH:14]2
Reactant: COc1cccc2c1C(C)(C)C(=O)N2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC1(C)C(=O)Nc2cccc(O)c21
Temperature: 220 °C
Reaction time: 0.75 h
Yield: 68.9 %

Procedure:
Pyridine hydrochloride (51.10 g, 442.2 mmol) and 4-methoxy-3,3-dimethyl-1,3-dihydro-indol-2-one (21.61 g, 113.0 mmol) are combined and stirred in a melt at 220° C. for 45 minutes. Heating is removed and when the mixture cooled to 100° C., water (60 mL) is added, followed by ethyl acetate (150 mL) at 65° C. The layers are separated and the aqueous phase is extracted five times with ethyl acetate (50 mL). The combined organic layers are extracted first with a combination of aqueous hydrochloric acid (1N, 10 mL) and a saturated solution of sodium chloride (10 mL), then with a combination of a saturated solution of sodium bicarbonate (10 mL) and a saturated solution of sodium chloride (10 mL). After drying over magnesium sulfate, the solvent is removed via rotary evaporation. The crude material is dissolved in ethyl acetate (200 mL) and hexane (200 mL) at 60° C. Crystallization is allowed to begin slowly over 1 hour at 50° C. After stirring for 12 hours at 24° C., the slurry is cooled to 0° C. for 1 hour, then vacuum filtered washing twice with cold 1:1, ethyl acetate:hexane (35 mL, 0° C.) to provide 13.8 g (98.6% purity, 68% yield) of 4-hydroxy-3,3-dimethyl-1,3-dihydro-indol-2-one, mp 224-225° C. MS (ES+) m/z 178 (M++1). From the filtrate a second crop (5.0 g, 98.4% purity, 25% yield) is obtained to give a total yield of 93%.
Reaction SMILES: [CH3:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:28][NH:29]C(OC(C)(C)C)=O)[C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)=[O:16])=[CH:10][CH:9]=1)=[O:5].[ClH:41]>C(Cl)Cl>[ClH:41].[ClH:41].[CH3:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:28][NH2:29])[C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)=[O:16])=[CH:12][CH:13]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1C(=O)OCc1ccc(C(CN)C(=O)Nc2ccc3cnccc3c2)cc1
Reaction time: 9 h

Procedure:
To 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2-methylbenzoate (E140) in CH2Cl2 was added HCl (4N in dioxane) and the solution was stirred for 8-10 h. The solvents were evaporated to give pure 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2-methylbenzoate dihydrochloride (E141).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[C:20]1([C:30](Cl)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:30]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: O=C(Cl)c1cccc2ccccc12
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1cccc2ccccc12

Procedure:
The procedure of Example 134 was carried out using 3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg, 0.156 mmole) in place of 1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 1-naphthoyl chloride (29.7 mg, 0.156 mmole) in place of p-trifluoromethylbenzoyl chloride. The product was chromatographed on silica gel (15% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized from Et2O to give the title compound which was dried in vacuo at 65° C.: (m.p. 162°-167° C.).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)[N:3]=1
Reactant: C1=COCCC1
Reactant: N#Cc1ccc2[nH]nc(Br)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Yield: 76.1 %

Procedure:
To a solution of 13.67 g (61.56 mmol) of 3-bromo-1H-indazole-5-carbonitrile and 2.06 g (10.8 mmol, 0.175 equiv.) of p-toluenesulfonic acid monohydrate in 247 mL of anhydrous tetrahydrofuran (THF) was added 11.2 mL (123 mmol, 2.00 equiv.) of 3,4-dihydro-2H-pyran. The mixture was refluxed under a nitrogen atmosphere for 14 h. The reaction was quenched with saturated aqueous sodium bicarbonate (sat. aq. NaHCO3). The mixture was extracted twice with EtOAc. The combined organics were washed with 2×sat. aq. NaHCO3, 1×sat. aq. NaCl, and dried over Na2SO4. Chromatography of the crude material on 200 g of silica gel using 30% EtOAc in hexanes afforded the title compound (14.34 g, 76% yield): ES-MS (m/z) 306 [M+1]+.