Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:17][C:18]=3[O:23][CH:24]([CH3:26])[CH3:25])[N:13]=2)=[CH:7][C:6]=1[CH3:31].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:52]>CN(C=O)C>[Br:52][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:17][C:18]=3[O:23][CH:24]([CH3:26])[CH3:25])[N:13]=2)=[CH:7][C:6]=1[CH3:31]
Reactant: Cc1cc(-c2nc3cc(OC(C)C)cc(OC(C)C)c3c(=O)[nH]2)cc(C)c1OCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cc(OC(C)C)cc(OC(C)C)c3c(=O)[nH]2)cc(C)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one (0.73 g, 1.70 mmol) in DMF (10 mL) were added PPh3 (0.49 g, 1.87 mmol) and CBr4 (0.62 g, 1.87 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, solvent was removed under reduced pressure. The residue was triturated with ether and ethyl acetate. The solid was dried and purified by the Simpliflash system (2% methanol in CH2Cl2 as eluent) to give 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one as a white solid. Yield: 0.39 g (47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22](O)=[O:23])=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=O.CNC.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:25][N:27]([CH3:28])[C:22]([C:17]1[NH:18][C:19]2[C:15]([CH:16]=1)=[CH:14][C:13]([NH:12][S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:10])=[O:11])=[CH:21][CH:20]=2)=[O:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Agent: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
110 mg 5-(3,5-dichloro-phenylsulphonylamino)-1H-indole-2-carboxylic acid are dissolved in 4 ml of tetrahydrofuran, combined with 51 mg carbonyldiimidazole and stirred for 3 hours at ambient temperature and for 1 hour at 40° C. After cooling to ambient temperature 600 μl of a 2 M solution of dimethylamine in tetrahydrofuran are added and the mixture is stirred overnight at ambient temperature. The solvent is eliminated in vacuo, the residue is divided between ethyl acetate and 0.5 N hydrochloric acid and the organic phase is washed with water and saturated sodium chloride solution. After drying with magnesium sulphate the solvent is eliminated in vacuo and the residue is chromatographed on silica gel (ethyl acetate).
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:39])[C:8]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[CH:38]=[CH:37][C:22]([C:23]([NH:25][C@H:26]([C:33]([O:35]C)=[O:34])[CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[O:24])=[CH:21][CH:20]=2)=[C:9]([NH:11]C(=O)C)[N:10]=1)(=O)C.C=O.[C:42]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C.CN(C)C=O>[NH2:4][C:5]1[NH:6][C:7](=[O:39])[C:8]([CH2:15][CH2:16][CH2:17][N:18]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:25][C@H:26]([C:33]([OH:35])=[O:34])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])=[CH:37][CH:38]=2)[CH3:42])=[C:9]([NH2:11])[N:10]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(NCCCc2c(NC(C)=O)nc(NC(C)=O)[nH]c2=O)cc1)C(=O)OC
Agent: C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(CCCc1c(N)nc(N)[nH]c1=O)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Yield: 130.7 %

Procedure:
To a stirred solution of 1.99 g (3.6 mmol) of dimethyl N-[4-[3-(2,4-bis(acetamido)-1,6-dihydro-6-oxo-5-pyrimidinyl)propylamino]benzoyl]-L-glutamate in 50 ml of acetonitrile and 5 ml of dimethylformamide was added 2 ml of 37% aqueous formaldehyde followed by 0.50 g (8.0 mmol) of sodium cyanoborohydride and 2 ml of acetic acid. After 18 hours the mixture was filtered to remove the solids and the filtrate was spin evaporated in vacuo. The residue was diluted with 100 ml of ice water, and then extracted with four 25 ml portions of methylene dichloride. The combined extracts were filtered through glass wool and spin evaporated in vacuo to give 2.1 g of the title compound as an oil which was a single spot on TLC. The oil was dissolved in 50 ml of ethanol and 50 ml of 1N sodium hydroxide and stirred at 70° C. for 20 hours. The reaction was cooled and spin evaporated in vacuo to a syrup. The syrup was dissolved in 50 ml of water, cooled on ice, and acidified to pH 3-4 with concentrated hydrochloric acid. The white solids were collected, washed with water, and finally with ether; yield, 1.10 g (67%), mp 190°-200° C. (one spot on TLC). Recrystallization from ethanol gave the analytical sample; yield, 0.54 g (33%, mp (166°-1678° changes to hard foam) 198°-204°; TLC (pyridine:BuOH:H2O/1:1:1); NMR (DMSO-d6) δ 8.16 (d, 1H, ArCONH), 7.71 (d, 2H, Ar), 6.66 (d, 2H, Ar), 5.94 (s, 2H, NH2), 5.76 (s, 2H, NH2) 4.36 (m, 1H, CHCO2H), 3.34 (m, 2H, CH2N(CH3)Ar), 2.93 (s, 3H, NCH3).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[OH:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[O:22][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Product: Fc1ccc(COc2cc3ccc(Br)cc3cc2C23CC4CC(CC(C4)C2)C3)cc1
Yield: 85.9 %

Procedure:
Following the procedure of Example 1(a), but reacting 1.1 g (3 mmol) of 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene with 420 μl (3.3 mmol) of 4-fluorobenzyl bromide, 1.2 g (86%) of the expected compound were obtained in the form of a colorless oil.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:23]1[CH2:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:24]1=[O:40]>C(Cl)Cl>[CH2:38]([O:37][C:35]([CH2:34][N:25]1[C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH2:28][CH2:29][CH:23]([NH:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:24]1=[O:40])=[O:36])[CH3:39]
Reactant: CCOC(=O)C(N)CCc1ccccc1
Reactant: CCOC(=O)CN1C(=O)C(Br)CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCC)CCc2ccccc21

Procedure:
Ethyl 2-amino-4-phenylbutyrate is treated in the presence of potassium carbonate in methylene chloride with 3-bromo-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one to give 1-ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H[1]benzazepin-2-one of example 10.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[C:22]2[S:27](Cl)(=[O:29])=[O:28])(=[O:15])[CH3:14].C(N(CC)CC)C.Cl>O1CCCC1>[C:1]1([CH2:11][NH:12][S:27]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:23]=2[CH:24]=[CH:25][CH:26]=[C:17]3[NH:16][C:13](=[O:15])[CH3:14])(=[O:29])=[O:28])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: NCc1cccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2c(S(=O)(=O)NCc3cccc4ccccc34)cccc12
Yield: 80.3 %

Procedure:
1-Naphthylmethylamine (174 mg, 1.1 mmol) was dissolved in tetrahydrofuran (10 ml), and 5-(acetylamino)-1-naphthalenesulfonyl chloride (284 mg, 1 mmol) was added under ice cooling and stirring. Then, triethylamine (0.17 mL, 1.2 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous sodium hydrogen carbonate, water, and saturated brine, and after the layer was dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized by a mixed solvent of ethyl acetate/diisopropyl ether to give the title compound as a light brown crystal (325 mg, 80.4%).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.CO.[NH3:36]>>[NH2:36][CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:30])([F:31])[F:29])=[CH:23][CH:22]=1
Reactant: N
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Solvent: CO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN)cc1)C(F)(F)F
Temperature: 140 °C

Procedure:
A mixture of ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (0.9 g, 1.70 mmol, Intermediate B) in 2 M NH3 in MeOH (10 mL, 20.0 mmol) was heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 30 min. The mixture was concentrated and purified on silica gel [2% MeOH in CH2Cl2 to 2% (2 N NH3-MeOH) in CH2Cl2) to give 2-(4-((2S)-2-(aminomethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a white foam (500 mg).
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([OH:14])=[O:13])=[C:5]([F:15])[CH:4]=1)#[N:2].S(Cl)(Cl)=O.[CH3:20]O>>[C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([O:14][CH3:20])=[O:13])=[C:5]([F:15])[CH:4]=1)#[N:2]
Reactant: COc1cc(CC(=O)O)c(F)cc1C#N
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(OC)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (4-cyano-2-fluoro-5-methoxyphenyl)acetic acid (5.0 g, 24 mmol) in methanol (50 mL) at 0° C. was added thionyl chloride (2.3 mL, 31 mmol) drop-wise. The mixture warmed slowly to rt and stirred 12 h, then was concentrated in vacuo and dried under high vacuum to provide methyl (4-Cyano-2-fluoro-5-methoxyphenyl)acetate. 1H NMR (500 MHz, CD3OD) δ 7.35 (d, J=5.3 Hz, 1H), 7.19 (d, J=5.4 Hz, 1H), 3.96 (s, 3H), 3.82 (s, 3H), 3.81 (s, 2H).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH2:4]([N:22]1[C:26](=[O:27])[NH:25][NH:24][C:23]1=[O:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH3:29][C:30](C)=[O:31]>>[OH:31][CH2:30][CH2:29][N:25]1[C:26](=[O:27])[N:22]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:23](=[O:28])[N:24]1[CH2:2][CH2:1][OH:3]
Reactant: CCCCCCCCCCCCCCCCCCn1c(=O)[nH][nH]c1=O
Reactant: CC(C)=O
Reactant: C1CO1
Product: CCCCCCCCCCCCCCCCCCn1c(=O)n(CCO)n(CCO)c1=O

Procedure:
132 g of ethylene oxide are introduced into a melt of 530 g of 4-stearyl-1,2,4-triazolidine-3,5-dione (starting material 3) over a period of 6 hours at 120° C. in such a way that no ethylene oxide escapes. The reaction mixture is cooled and subsequently dissolved in 2.5 liters of acetone. A deposit precipitates on cooling and is isolated by filtration under suction and washed with acetone, giving 575 g of 1,2-bis-(2-hydroxyethyl)-4-stearyl-1,2,4-triazolidine-3,5-dione in the form of colourless crystals melting at 68° to 79° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][C:16](=[O:28])[CH2:17][C:18]2[CH:23]=[C:22]([Br:24])[C:21]([O:25][CH3:26])=[C:20]([Br:27])[CH:19]=2)[CH:10]=[CH:11][CH:12]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:24][C:22]1[CH:23]=[C:18]([CH2:17][C:16]([NH:15][CH2:14][CH2:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=2)=[O:28])[CH:19]=[C:20]([Br:27])[C:21]=1[O:25][CH3:26]
Reactant: COc1c(Br)cc(CC(=O)NCCc2cccc(N)c2)cc1Br
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1c(Br)cc(CC(=O)NCCc2cccc(NS(C)(=O)=O)c2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (0.0313 g, 0.000273 mol) was added to DMAP (0.0334 g, 0.000273 mol) in methylene chloride (6 mL). To the resulting white complex N-[2-(3-amino-phenyl)-ethyl]-2-(3,5-dibromo-4-methoxy-phenyl)-acetamide (0.1 g, 0.000226 mol) in methylene chloride (6mL) was added dropwise. The reaction mixture was stirred for 18 h at room temperature, washed with 1 N HCl and 1 N NaOH. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel, 1:1 ethyl acetate-hexane mixture). Yield 0.058 g, 49%. MS m/e 518.7 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:14])[CH2:11][C:12]#[N:13])=[CH:5][C:4]=1[O:15][CH2:16][CH2:17][O:18][CH3:19].[CH3:20][N:21]([CH:23](OC)OC)[CH3:22].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])CN>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:23][N:21]1[CH:20]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:5]=2)[C:10](=[O:14])[C:11]([C:12]#[N:13])=[CH:22]1
Reactant: COC(OC)N(C)C
Reactant: COCCOc1cc(CC(=O)CC#N)ccc1OC
Reactant: COc1ccc(CN)cc1OC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COCCOc1cc(-c2cn(Cc3ccc(OC)c(OC)c3)cc(C#N)c2=O)ccc1OC
Temperature: 100 °C
Yield: 54.7 %

Procedure:
To a stirred solution of 4-[4-methoxy-3-(2-methoxyethoxy)phenyl]-3-oxo-butyronitrile (9.91 g, 34.5 mmol) in 20 mL of anhydrous DMF was added DMF-DMA (20.2 mL, 152 mmol). The resulting mixture was heated at 100° C. for 15 h and was concentrated in vacuo. The crude material was mixed with 3,4-dimethoxybenzylamine (0.687 mL, 41.4 mmol) in 20 mL of anhydrous toluene and the mixture was heated at reflux for 2 h. The reaction mixture was cooled, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with gradient 50-100% EtOAc/hexane to yield 8.5 g (55% yield) of 1-(3,4-dimethoxybenzyl)-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]-4-oxo-1,4-dihydro-pyridine-3-carbonitrile as a yellow/orange foam.
Reaction SMILES: [BrH:1].O[CH2:3][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[CH:5]=1>>[Br:1][CH2:3][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[CH:5]=1
Reactant: Br
Reactant: O=c1cc(CO)cc[nH]1
Product: O=c1cc(CBr)cc[nH]1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Hydrobromic acid (2 mL) was added to a solution of 4-(hydroxymethyl)pyridin-2(1H)-one (200 mg, 1.6 mmol) was at 0° C. The mixture was stirred at 110° C. for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/MeOH) to afford the 4-(bromomethyl)pyridin-2(1H)-one. MS ESI calc'd. for C6H7BrNO [M+H]+ 188 and 190. found 188 and 190. 1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 7.36 (d, J=6.8 Hz, 1H), 6.39 (s, 1H), 6.17 (d, J=6.8 Hz, 1H), 4.45 (s, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[N:9]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18](Br)=[N:19][CH:20]=2)[CH:13]=[CH:12][N:11]=[CH:10]1>>[N:9]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:19][CH:20]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: OB(O)c1cccs1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1csc(-c2ccc(Cn3ccnc3)cn2)c1

Procedure:
Synthesized using 2-thiophenylboronic acid (118 g, 0.92 mmol) and 1a (110 mg, 0.46 mmol) according to Method C. Yellow solid. Yield: 101 mg, 0.42 mmol, 91%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.13 (s, 2H), 6.90 (s, 1H), 7.11 (t, J=4.4 Hz, 2H), 7.41-7.43 (m, 2H), 7.57-7.59 (m, 2H), 7.63 (d, J=8.2 Hz, 1H), 8.45 (d, J=1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 118.9, 119.0, 125.1, 128.13, 128.14, 129.8, 130.3, 135.7, 137.3, 144.0, 148.4, 152.9; MS (ESI): m/z=242.10 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.[CH2:16]=[O:17].[CH3:18][O-:19].[Na+]>CO>[OH:17][CH2:16][CH:1]([CH2:18][OH:19])[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1
Reactant: C=O
Reactant: C[O-]
Reactant: COc1cc2c(cc1OC)C(C)=NCC2
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1OC)C(C(CO)CO)=NCC2
Yield: 79 %

Procedure:
To 1 mole (205.3 g) of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline 100 ml of a 30% aqueous formaldehyde solution and then freshly prepared sodium methylate (1 g of sodium+50 ml of methanol) are added. The mixture is then slightly refluxed in 500 ml of methanol for 2 hours. The reaction mixture is evaporated under reduced pressure and the obtained crystalline product is recrystallized from a mixture of acetone and ether. The aimed compound is obtained with the same melting point as the product of Example 1.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH2:1]([C:8]1[S:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1sc(Cc2ccccc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Yield: 19.7 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-benzyl4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone (3.32 g, 8.20 mmol) and 1M boron tribromide/CH2Cl2 (1.6 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with a 2, 5 & 10% EtOAc/hexane step gradient gave 0.63 g (18%) of the title compound. 1H NMR (DMSO-d6) δ consistent.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH3:16])[CH:8]=[CH:7][C:6]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:5]=2[O:4]1.[Br:17]Br.O>C(Cl)(Cl)Cl>[Br:17][C:7]1[C:6]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]([CH2:2][F:1])([CH3:16])[CH:8]=1
Reactant: CC1(CF)C=Cc2cc([N+](=O)[O-])ccc2O1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1(CF)C=C(Br)c2cc([N+](=O)[O-])ccc2O1

Procedure:
To 8.24 g of 2-fluoromethyl-2-methyl-6-nitro-2H-1-benzopyran dissolved in 100 ml of chloroform was added dropwise 2.7 ml of bromine with stirring under cooling with water, and the mixture was stirred for 20 hours at room temperature. After the solvent was removed, 100 ml of dioxane and 2N NaOH solution were added to the residue and stirred at room temperature for 16 hours. When ice-water was added to the reaction mixture, crystals were separated out. The crystals were collected by filtration, washed with water and dissolved in methylene chloride. It was washed with water and dried. The solvent was evaporated off to obtain 11.01 g of 4-bromo-2-fluoromethyl-2-methyl-6-nitro-2H-1-benzopyran with a melting point of 116°-117° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:26]([CH:29]=1)[C:27]#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:27]([C:26]1[CH:29]=[C:22]([CH:23]=[CH:24][C:25]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:21][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1)#[N:28]
Reactant: N#Cc1cc(CCl)ccc1C1CCCCC1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCCC4)c(C#N)c3)cc21
Temperature: 25 °C
Reaction time: 41 h
Yield: 64.5 %

Procedure:
To a solution of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (166.0 mg, 0.641 mmol) and 5-(chloromethyl)-2-cyclohexylbenzonitrile (147.0 mg, 0.629 mmol) in N,N-dimethylformamide (15 mL) was added cesium carbonate (246.0 mg, 0.755 mmol). The mixture was stirred at room temperature for 41 h. The mixture was diluted with ethyl acetate, filtered through Celite®, concentrated under reduced pressure and purified by silica gel column chromatography to provide the title compound as a yellow foam (185.3 mg). LCMS m/z=457.5 [M+H]+; NMR (400 MHz, CDCl3) δ ppm 1.18-1.28 (m, 1H), 1.30 (t, J=7.20 Hz, 3H), 1.41-1.52 (m, 4H), 1.79 (dd, J=12.82, 1.33 Hz, 1H), 1.85-1.93 (m, 4H), 2.06-2.15 (m, 1H), 2.50 (dd, J=16.80, 11.24 Hz, 1H), 2.68-2.86 (m, 4H), 2.94-3.04 (m, 1H), 3.49-3.61 (m, 1H), 4.16-4.25 (m, 2H), 5.06 (s, 2H), 6.82 (dd, J=8.78, 2.46 Hz, 1H), 6.97 (d, J=2.53 Hz, 1H), 7.21 (d, J=8.72 Hz, 1H), 7.37 (d, J=8.21 Hz, 1H), 7.62 (dd, J=8.15, 1.71 Hz, 1H), 7.71 (d, J=1.52 Hz, 1H), 8.47 (bs, 1H).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16].NCC1[CH:26]=[CH:25][C:24]([C:27]2[CH2:31][C:30]([C:36]3[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([Cl:43])[CH:37]=3)([C:32]([F:35])([F:34])[F:33])[O:29][N:28]=2)=[CH:23][CH:22]=1>O1CCCC1.C(OCC)(=O)C>[Cl:43][C:38]1[CH:37]=[C:36]([C:30]2([C:32]([F:34])([F:33])[F:35])[O:29][N:28]=[C:27]([C:24]3[CH:23]=[CH:22][C:11]([CH2:12][NH:8][C:1]([NH:16][CH2:15][C:14]([F:18])([F:17])[F:13])=[O:2])=[CH:26][CH:25]=3)[CH2:31]2)[CH:41]=[C:40]([Cl:42])[CH:39]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Reactant: NCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.4 %

Procedure:
In a solution of 0.32 g of 1,1′-carbonylbis-1H-imidazole in 7.0 mL of tetrahydrofuran, 0.20 g of 2,2,2-trifluoroethylamine was added, and stirred at room temperature for 1.5 hour. Then, in the reaction mixture, a solution of 0.39 g of 3-[4-(aminomethyl)phenyl]-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole synthesized in Step 6 of Synthetic Example 1 in 5.0 mL of tetrahydrofuran was added, and continued to stir at room temperature further for 2.5 hours. After the completion of the reaction, the reaction mixture was diluted with 20 mL of ethyl acetate, washed with water (15 mL×2), and dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure. The residue was purified with medium pressure preparative liquid chromatography (medium pressure collection apparatus: YFLC-Wprep manufactured by Yamazen Corporation) that was eluted with ethyl acetate-hexane (gradient of 1:8 to 1:1) to obtain 0.43 g of the aimed products as colorless resinous substance.