Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O)(=O)C.C([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[F:27])[C:20](=[O:30])[C:19]([C:31]([O:33]CC)=[O:32])=[CH:18]2)[C:14]([F:36])=[CH:13][C:12]=1[F:37])(C)(C)C>O>[NH2:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[F:27])[C:20](=[O:30])[C:19]([C:31]([OH:33])=[O:32])=[CH:18]2)[C:14]([F:36])=[CH:13][C:12]=1[F:37]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Reaction time: 7 h
Yield: 95 %

Procedure:
To a mixed solution of 0.5 ml of 4N hydrochloric acid and 0.5 ml of acetic acid was added 235 mg of ethyl 1-[6-(t-butylamino)-3,5-difluoropyridine-2-yl]-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 7 hours. After adding 1 ml of distilled water, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 182 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[CH3:35][NH2:36]>CN(C)C=O.O1CCCC1>[CH3:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[O:24][CH:25]=[C:26]([C:28]([NH:36][CH3:35])=[O:29])[N:27]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)co2)c(=O)[nH]c1=S
Reactant: CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1coc(Cn2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=S)[nH]c2=O)n1

Procedure:
N,N'-Carbonyldiimidazole (0.073 g) and the product of example 37(0.2 g) in N,N-dimethylformamide (3 ml) was stirred at room temperature. After 0.5 h Methylamine (0.6 ml of a 2M solution in tetrahydrofuran) was added. After a further 0.5 h the solution was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 20% ethyl acetate in iso-hexane. Yield 0. lg.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:7][C:8]=1[CH2:9][OH:10])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(=O)([O-])O.[Na+].ClCCl>[CH:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[O:7][C:8]=1[CH:9]=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1C=O

Procedure:
[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (0.46 g, 1.612 mmol), Dess-Martin periodinane (1.36 g, 3.22 mmol) and dichloromethane (25 mL) are stirred 1 hr at room temperature. The mixture is diluted with aqueous saturated sodium hydrogen carbonate (100 mL) and dichloromethane (100 mL). The layers are separated, the aqueous layer is washed with dichloromethane (100 mL). The organic ishes are combined, washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The product is purified over silica eluting with 3:1 hexanes:ethyl acetate to afford 4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde as a white solid, 0.41 g, 90%. %. MS (M++1) 284.
Reaction SMILES: O=C1NCCN1C1SC(C([O-])=O)=CN=1.[O:15]=[C:16]1[NH:20][CH2:19][CH2:18][N:17]1[C:21]1[S:22][C:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=1.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1>>[F:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][N:20]2[CH2:19][CH2:18][N:17]([C:21]3[S:22][C:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)[C:16]2=[O:15])=[CH:38][CH:39]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C(F)(F)F
Agent: O=C([O-])c1cnc(N2CCNC2=O)s1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C(F)(F)F
Yield: 94 %

Procedure:
Following the procedure as described in Example 24, making variations as required to replace 2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thiazole-5-carboxylate to react with 1-(bromomethyl)-4-fluorobenzene, the title compound was obtained as a colorless solid in 94% yield: 1H NMR (300 MHz, CDCl3) δ 7.28-7.25 (m, 2H), 7.06-7.01 (m, 2H), 4.46 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 4.13-4.07 (m, 2H), 3.50-3.44 (m, 2H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 418.1 (M+1).
Reaction SMILES: [Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3](Cl)=[O:4].N1C=CC=CC=1.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH2:24][NH:23][CH2:22][CH2:21]2>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH2:24][N:23]([C:3](=[O:4])[CH:2]([Br:1])[CH:6]([CH3:8])[CH3:7])[CH2:22][CH2:21]2
Reactant: CC(C)C(Br)C(=O)Cl
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC)CN(C(=O)C(Br)C(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Racemic body α-bromoisovaleryl chloride (327 mg, 1.64 mmol) on the market and 4-(N,N-dimethylamino)pyridine (about 10 mg) were added to a pyridine (8 ml) suspension of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (472 mg, 2.05 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with chloroform (50 ml), washed with 1 N hydrochloric acid (50 ml) and a 1 N aqueous sodium hydroxide solution (50 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and used, without isolating and purifying the obtained gummy substance, in the reactions in Examples 27 and 28.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C@@H:10]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:11]([O:13]CC)=[O:12])=[CH:4][C:3]=1[Cl:37].CO.C1COCC1.[OH-].[Li+]>O>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C@@H:10]([NH:16][C:17]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:23][CH2:24]2)=[O:18])[C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[Cl:37]
Reactant: CCOC(=O)[C@@H](Cc1cc(C)c(N)c(Cl)c1)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1N
Temperature: 40 °C
Reaction time: 20 h

Procedure:
The mixture of 4.1 g (7.8 mmol) ethyl (R)-3-(4-amino-3-chloro-5-methyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionate, 60 ml of methanol and 60 ml THF was combined with a solution of 1.5 g (36.8 mmol) lithium hydroxide in 30 ml of water and stirred for 20 hours at 40° C. The reaction mixture was evaporated down under reduced pressure, the residue was taken up in 50 ml of water and acidified by the addition of 2-molar hydrochloric acid solution. The resulting precipitate was suction filtered and dried at 35° C. in the circulating air dryer.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][C@@H:14]([OH:28])[CH2:15]3)[N:10]=2)=[CH:7][CH:6]=[C:5]([O:29][CH3:30])[N:4]=1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](O)(=[O:39])=[O:38])=[CH:33][CH:32]=1>CC(O)C>[S:37]([O:28][C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([C:17]3[C:22]([C:9]([C:8]4[C:3]([O:2][CH3:1])=[N:4][C:5]([O:29][CH3:30])=[CH:6][CH:7]=4)=[N:10]2)=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=3)[CH2:15]1)([C:34]1[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](O)C[C@H]21
Solvent: CC(C)O
Product: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](OS(=O)(=O)c3ccc(C)cc3)C[C@H]21
Temperature: 60 °C
Yield: 97.1 %

Procedure:
(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-eth oxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol (1.5 g; 3.6 mmol) is dissolved in 9 ml of 2-propanol. The solution is heated up to 60° C. 723 mg (3.8 mmol) of p-toluenesulfonic acid are added. The solution is cooled down to room temperature and stirred over night. From a part of the solution seed crystals are produced and added to the remaining solution. The crystals are filtered off and dried to obtain 1.98 g (94%) of the title compound (m.p.: 218° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>[Cu](I)I.CCOC(C)=O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Reactant: Brc1ncccn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2ncccn2)c1
Temperature: 115 °C
Yield: 105.7 %

Procedure:
A mixture of (S)-[1-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1 g, 4.2 mmol), 2-bromo-pyrimidine (0.58 g, 5.1 mmol), potassium carbonate (powder, 1.4 g, 10.1 mmol), copper iodide (325 mesh powder, 0.6 g, 3.2 mmol) and pyridine (5 mL) was heated at 115° C. for 12 h. CH2Cl2 (100 mL) was added, the reaction mixture was filtered through celite and rinsed with CH2Cl2 (2×50 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 1:1/Hexane:EtOAc to give the title product (1.4 g, quantitative yield).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=CC=2)=[CH:4][C:3]=1OC1C=CC(S(O)(=O)=O)=C(N)C=1.N1C(Cl)=NC(Cl)=NC=1Cl>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Oc2cc(Sc3ccc(S(=O)(=O)O)cc3)c3c(c2N)C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Clc1nc(Cl)nc(Cl)n1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Example 5 was repeated, except that the compounds shown in 1st and 2nd columns of the following table were used in place of the 1-amino-2-(3'-amino-4'-sulfophenoxy)-4-(4-sulfophenylthio)anthraquinone and cyanuric chloride, respectively, thereby obtaining a corresponding anthraquinone compound. The color shade obtained by dyeing cotton with the compound is as shown in a 3rd column of the table. Each compound can exhibit superior dye performances as described hereinabove.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.[NH2:22][CH2:23][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25][O:26][CH3:27].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:31]([O:30][C:29]([NH:28][C@@H:24]([CH2:25][O:26][CH3:27])[CH2:23][NH:22][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1)=[O:35])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(C)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC[C@@H](CNc1cc(C#N)c(C(=O)OC)c(Nc2cccc(C)c2)n1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a screw-top vial was added methyl 6-chloro-4-cyano-2-(m-tolylamino)nicotinate (0.28 g, 0.928 mmol), (R)-tert-Butyl 1-amino-3-methoxypropan-2-ylcarbamate (0.227 g, 1.114 mmol), and DIPEA (0.211 mL, 1.206 mmol) in DMF (3 mL). The resulting yellow solution was stirred at RT for 12 h, diluted with EtOAc (30 mL) and washed with water (2×20 mL) and brine (20 mL). The organic phase was dried with Na2SO4 and concentrated to give the title compound as thick yellow oil, which was used without further purification (470 mg). [M+H] calc'd for C24H31N5O5, 470. found, 470.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:33]=1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:34][C:33]4[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:32]=4[O:31][CH3:30])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cc(OC)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 70.1 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 2,5-dimethoxybenzaldehyde (631 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (8042 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (290 mg) as yellow oil.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[NH:12])[NH2:11])=[CH:6][CH:5]=1.[Cl:15][C:16]([SH:19])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:15][C:16]1[S:19][N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([F:13])([F:14])[F:2])=[CH:9][CH:8]=2)[N:12]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1ccc(-c2nsc(Cl)n2)cc1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
To a solution of 4-(trifluoromethyl)benzenecarboximidamide hydrochloride (2.60 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 770 mg (29.2%) of the desired product as an oil.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][CH2:23][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([CH2:17][C:18]([OH:20])=O)[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:30]([NH2:32])[CH3:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[CH2:30]([NH:32][C:18](=[O:20])[CH2:17][C:14]1[CH:13]=[C:12]2[C:11]3=[C:16]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9][N:10]3[CH2:23][CH2:22][CH:21]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=1)[CH3:31]
Reactant: CCN
Reactant: O=C(O)Cc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCNC(=O)Cc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
To a solution of 2-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)acetic acid (16), (85 mg, 0.229 mmol) in dichloromethane (10 mL) were added Ethyl amine (0.015 mL, 0.229 mmol), EDCI (103 mg, 0.538 mmol), followed by HOBt (72 mg, 0.538 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The reaction was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 5% MeOH:CH2Cl2 to give N-ethyl-2-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)acetamide (371), (27 mg, 29%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[O:36][CH:37]([CH3:39])[CH3:38]>ClCCl>[CH:37]([O:36][C:35](=[O:40])[NH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:9]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C:22]4=[O:27])=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[C:13]=2[O:14][CH3:15])[CH2:4][CH2:5]1)([CH3:39])[CH3:38]
Reactant: CC(C)OC(=O)Cl
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)CC2)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(=O)OC(C)C)CC2)c1OC

Procedure:
To a stirring solution of 4-[2-(1-Aminomethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 182) (150 mg, 0.272 mmol) in dichloromethane (10 mL), were added triethylamine (0.082 g, 0.811 mmol) and isopropyl carbonochloridate (66 mg, 0.544 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 183 to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[CH3:23][C:24](C)([O-])[CH3:25].[K+].C(Br)C=C.O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH2:25][CH:24]=[CH2:23])[CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C=CCBr
Product: C=CCn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In one portion, 0.7 g (2.2 mmole) of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.3 g (2.6 mmole) of potassium t-butoxide in 30 ml of dry dimethylformamide which was cooled to 0° C. After stirring for 15 minutes, 1.0 ml (11 mmole) of allyl bromide was added and the mixture was allowed to warm to room temperature. Water was added and the mixture was extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a yellow oil. Purification by column chromatography (silica gel, 20 g; eluent 5% ether in methylene chloride) gave a yellow oil. Crystallization from a mixture of ether and petroleum ether gave a tan solid (mp 100°-102° C.). Recrystallization from a mixture of ether and petroleum ether gave colorless prisms, mp 104°-106° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[C:11]([OH:15])(=[O:14])[CH:12]=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][O:10][CH:12]2[C:11]([OH:15])=[O:14]
Reactant: OCCc1ccccc1Br
Reactant: O=CC(=O)O
Product: O=C(O)C1OCCc2c(Br)cccc21

Procedure:
A solution of 2-(2-bromophenyl)ethanol (40 g, 0.2 mol) and glyoxylic acid (16 g, 0.22 mol) in 100 mL of trifluoacetic acid was refluxed overnight. The solvent was concentrated. Water and ammonium hydroxide was added to the residue to adjust the pH of the solution over 7. The solution was extracted with diethyl ether, and the aqueous layer was adjusted to about 3 with 1M HCl, and then the solution was extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was without purification to give 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylic acid. 1H-NMR (400 MHz, CDCl3) δ 7.52 (d, J=7.6 Hz, 1H), 7.12 (t, J=7.8 Hz, 2H), 5.33 (s, 1H), 4.27˜4.33 (m, 1H), 3.99˜4.06 (m, 1H), 2.87˜2.89 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.I[C:26]1[CH:39]=[N:38][C:29]2[NH:30][C:31]3[CH:36]=[N:35][C:34]([Br:37])=[CH:33][C:32]=3[C:28]=2[CH:27]=1>C(=O)([O-])[O-].[Na+].[Na+].CC1CCCO1.C(Cl)Cl>[Br:37][C:34]1[N:35]=[CH:36][C:31]2[NH:30][C:29]3[N:38]=[CH:39][C:26]([C:14]4[CH:13]=[CH:12][C:4]([CH2:5][N:6]5[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]5)=[C:3]([O:2][CH3:1])[CH:15]=4)=[CH:27][C:28]=3[C:32]=2[CH:33]=1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1CN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC1CCCO1
Product: COc1cc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)ccc1CN1CCCCC1
Temperature: 85 °C
Yield: 60.8 %

Procedure:
A degassed mixture of 1-[2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine (885 mg, 2.7 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (500 mg, 1.3 mmol), 1,1′-[bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (163 mg, 0.2 mmol) in 2N aqueous sodium carbonate solution (10 mL) and 2-methyltetrahydrofuran (20 mL) was heated at 85° C. for 18 h. The cooled reaction mixture was diluted with DCM (100 mL) and washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue (357 mg, 61%) that was used in the next step without purification. 1H NMR (CDCl3, 300 MHz): 8.83 (d, J=2.0 Hz, 1H), 8.70 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.14 (s, 1H), 3.96 (s, 3H), 3.65 (s, 2H), 2.56-2.48 (m, 4H), 1.67-1.59 (m, 4H), 1.52-1.41 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=O)=[CH:12][C:11]=3[CH:20]=2)[CH:2]=1.[CH3:21][N:22]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([NH:34][C:33]4[CH:35]=[CH:36][C:30]([CH2:29][N:22]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH3:21])=[CH:31][CH:32]=4)=[O:19])=[CH:12][C:11]=3[CH:20]=2)[CH:2]=1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3cccnc3)ccc2OCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4cccnc4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 23.5 %

Procedure:
To a solution of 7-(3-pyridyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4-(N-methyl-N-(tetra-hydropyran-4-yl)aminomethyl)aniline (0.12 g) and triethylamine (0.16 ml) in dimethylformamide (50 ml) was added diethyl cyano-phosphate (0.1 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give 7-(3-pyridyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)-methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 146) (0.06 g) as colorless crystals.