Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH:21]1([CH2:26][CH2:27]Br)[CH2:25][CH2:24][CH:23]=[CH:22]1>>[CH:21]1([CH2:26][CH2:27][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:25][CH2:24][CH:23]=[CH:22]1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCCC1C=CCC1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CCC2C=CCC2)c1
Yield: 25.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and 2-(cyclopent-2-en-1-yl)ethyl bromide were reacted by the same method with example 40 to obtain the titled compound (98 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[N:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][NH:20]2)=[C:14]=[O:15].C(N(CC)CC)C>C1COCC1>[NH:20]1[C:21]2[C:17](=[C:16]([NH:13][C:14](=[O:15])[O:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=3)[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: O=C=Nc1cccc2[nH]ccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc2[nH]ccc12)OCc1ccc(C(F)(F)F)cc1
Yield: 53.8 %

Procedure:
[4-(Trifluoromethyl)phenyl]methanol (0.09 g, 0.55 mmol) and the product of Example 80A (0.08 g, 0.5 mmol) in THF (5 mL) were heated at reflux for 16 hours with a catalytic amount of triethylamine. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel eluting with 50% hexane:ethylacetate to provide the title compound as an oil (0.09 g). 1H NMR (300 MHz, DMSO-d6) δ 5.32 (s, 2H), 6.73 (s, 1H), 7.0 (t, 1H), 7.11 (d, 1H), 7.23 (t, 1H), 7.38 (d, 1H), 7.66 (d, 2H), 7.78 (d, 2H), 9.52 (s, 1H), 11.08 (s, 1H). Anal. Calcd. for C17H13N2F3O2; C, 61.08; H, 3.92; N, 8.38. Found: C, 60.97; H, 4.21; N, 8.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7]([CH2:13][NH2:14])=[CH:6]2.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7]([CH2:13][NH:14][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])=[CH:6]2
Reactant: COc1ccc2c(c1)C=C(CN)CO2
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)NCC1=Cc2cc(OC)ccc2OC1
Reaction time: 0.5 h

Procedure:
A solution of 0.49 g (2.57 mmol) of the amine obtained in Step B of Example 40 in 10 ml of dichloromethane is cooled to 0° C.; 1 ml (7.7 mmol) of triethylamine and also 0.41 g (3.85 mmol) of butyryl chloride are then added in succession to the medium. After 30 minutes of stirring under an inert atmosphere, the reaction mixture is acidified with a hydrochloric acid solution (1N); the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. Chromatography on a silica column (eluant: PE/AcOEt: 40/60) yields the title amide in the form of a white solid.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][C:11]1[N:15]([CH2:16][CH2:17][C:18]#[N:19])[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][CH2:8][CH2:9][CH2:10][C:11]1[N:15]([CH2:16][CH2:17][C:18]#[N:19])[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1
Reactant: N#CCCn1c(CCCOC2CCCCO2)nc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: N#CCCn1c(CCCO)nc2ccccc21
Reaction time: 8 h

Procedure:
The crude 3-{2-[3-(tetrahydro-pyran-2-yloxy)-propyl]-benzimidazol-1-yl }-propionitrile was stirred in 250 mL of methanol with sufficient p-toluenesulfonic acid monohydrate to make the solution acidic (pH=1-2). After stirring overnight, the solution was concentrated under reduced pressure, made basic (pH=8) with 1N sodium hydroxide and extracted into 8×50 mL of ethyl acetate. The aqueous layer was saturated with NaCl to aid in extraction of the product. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography using a gradient of ethyl acetate then 10% methanol in ethyl acetate followed by trituration with ether-hexane gave 4.8 g of 3-[2-(3-hydroxy-propyl)-benzimidazol-1-yl]-propionitrile as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9]([CH3:28])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O-:25])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:26]=1[CH3:27])=[O:5].[C:32](OCC)(=O)[CH3:33].CCCCCC>>[CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9]([CH3:28])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:32][CH3:33])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:26]=1[CH3:27])=[O:5]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(/C=C/C(=O)[O-])cc1)CO2
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)CCc1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 84 %

Procedure:
Using (2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)acrylate obtained in Example 178, the title compound was synthesized in the same manner as in Example 180. Yield: 84%. Melting point: 103-105° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([O:21]CC=C)=O)=[N:7][C:6]=2[CH:25]=1.NC[C@@H]1[C@H](C)CCCN1C([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[N:44]1[CH:48]=[N:47][C:46]([C:49]([F:52])([F:51])[F:50])=[N:45]1)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[N:44]3[CH:48]=[N:47][C:46]([C:49]([F:51])([F:52])[F:50])=[N:45]3)=[O:21])=[N:7][C:6]=2[CH:25]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone. ESI-MS (m/z): 533 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([OH:36])[CH:32]=[C:33]([CH3:35])[CH:34]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:36][C:31]2[CH:32]=[C:33]([CH3:35])[CH:34]=[C:29]([O:28][CH3:27])[CH:30]=2)=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: COc1cc(C)cc(O)c1
Product: COc1cc(C)cc(Oc2ncc(Cl)cc2C(=O)N[C@@H](C)c2ccc(C(=O)OC(C)(C)C)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 3-methoxy-5-methylphenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.17 (2H, d, J=2.8 Hz), 7.95 (2H, dd, J=6.6, 1.8 Hz), 7.39 (2H, d, J=8.1 Hz), 6.67 (1H, br.s), 6.55–6.51 (2H, m), 5.40–5.30 (1H, m), 3.80 (3H, s), 2.37 (3H, s), 1.58 (9H, s), 1.57 (3H, d, J=6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][NH:23][C:24](=[O:31])[CH2:25][C:26]([O:28]CC)=[O:27])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][NH:23][C:24](=[O:31])[CH2:25][C:26]([OH:28])=[O:27])[S:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)NCc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc(CNC(=O)CC(=O)O)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 57.1 %

Procedure:
A mixture of 4,5-bis(4methoxyphenyl)-2-ethoxycarbonylacetylaminomethylthiazole (0.43 g) and 4N sodium hydroxide (3 ml), methanol (5 ml) and water (5 ml) was stirred at ambient temperature for 4.5 hours. After allowing to cool to room temperature, the mixture was poured to water, and the aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, and extracted with diethyl ether. The organic layer was washed with water and brine, and dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The resulting residue was triturated with isopropyl ether and diethyl ether, to give 4,5-bis(4-methoxyphenyl)-2-(carboxyacetylaminomethyl)thiazole (0.23 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=3[CH3:18])=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)[nH]n1
Yield: 39.1 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.2 g, 0.728 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.112 g, 0.728 mmol), HOBt (0.128 g, 0.946 mmol), DIPEA (0.165 ml, 0.946 mmol) and EDCI (0.181 g, 0.946 mmol) using the method of Example 34(d) affording 0.117 g of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 2.54 (s, 3H), 2.55 (s, 3H), 4.31 (m, 1H), 4.44 (m, 1H), 4.62 (m, 1H), 6.44 (d, 1H), 7.51 (d, 1H), 7.54 (s, 2H), 11.14 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:5])([F:4])I.[CH2:6]([N:13]([CH3:27])[C:14]([CH2:16][CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH:25]=[O:26])=[O:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>[Zn].CN(C=O)C>[CH2:6]([N:13]([CH3:27])[C:14]([CH2:16][CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH:25]([OH:26])[C:2]([F:5])([F:4])[F:1])=[O:19])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: FC(F)(F)I
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C=O
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)C(F)(F)F
Yield: 24.8 %

Procedure:
Trifluoroiodomethane (2.3 g) was cooled to -78° C. with a trap. DMF (7 ml), (2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (710 mg) and zinc (1.0 g) were added there to. And the mixture was treated with ultrasonic waves for 2 hrs. at room temperature. 1N hydrochloric acid was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (217 mg) having the following physical data:
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O[C:9](=O)[N:10]([C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]=O)=[C:33]([C:39]([F:42])([F:41])[F:40])[CH:32]=2)=[O:29])=[CH:23][CH:22]=1)C)(C)(C)C>>[CH3:1][N:2]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([N:16]3[CH:15]=[N:14][C:13]4[C:17]3=[N:18][CH:19]=[N:20][C:12]=4[NH:10][CH3:9])=[CH:22][CH:23]=2)=[O:29])=[CH:32][C:33]=1[C:39]([F:42])([F:40])[F:41])[CH3:3]
Reactant: CNC
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(C=O)c(C(F)(F)F)c2)cc1
Product: CNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CN(C)C)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from dimethylamine and (9-{4-[3-(4-formyl-3-(trifluoromethyl)phenyl)-ureido]phenyl}-9H-purin-6-yl)-methyl-carbamic acid tert-butyl ester by using the same techniques as in Example 168.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:20]=[N+:21]=[N-:22])(C)C.Cl>C1(C)C=CC=CC=1>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]3[N:22]=[N:21][NH:20][N:2]=3)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a solution of 2-cyano-4'-methylbiphenyl (390 g, 2.02 moles) in toluene (2.3 L) was added trimethyltin azide (525 g, 2.55 moles) at room temperature. The mixture was refluxed for 24 hours, cooled to room temperature, filtered, washed with toluene and sucked dry in a funnel. The precipitate was resuspended in toluene (3.5 L) and THF (250 mL) was added. Anhydrous HCl was bubbled in at a moderate rate at room temperature to give a clear solution (45 minutes). Addition of HCl gas was continued for another 20 minutes with stirring whereupon a white precipitate formed. The reaction mixture was stirred overnight. The solid product was filtered, washed with toluene followed with ether and then dried under vacuum. This produced 250 g (53% yield of the tetrazole. m.p. 152°-154° C.; 1H-NMR (CDCl3): 2.40 (s, 3H), 7.19 (dd, 1H), 7.55 (m, 2H), 8.25 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:16]([OH:18])=O)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.C(Cl)(=O)C(Cl)=O.CC[N:27]([CH:31]([CH3:33])[CH3:32])C(C)C.C1(N)CC1>CN(C=O)C.C(Cl)Cl>[CH:31]1([NH:27][C:16]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)=[O:18])[CH2:33][CH2:32]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COCCCc1cc(C(=O)O)c2ccccc2c1
Agent: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCCc1cc(C(=O)NC2CC2)c2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a CH2Cl2 solution (0.1 M) of 3-[3-(methyloxy)propyl]-1-naphthalenecarboxylic acid (1 eq.) from the previous step was added at 0° C. oxalyl chloride (1.2 eq.) followed by a few drops of DMF. The resulting solution was stirred at RT for 2 h before the volatiles were removed in vacuo. The resulting residue was taken up in dichloromethane (0.1 M), cooled to 0° C. and added sequentially Hunig's base (1.2 eq.) an cyclopropylamine (1.1 eq.) dropwise. The resulting suspension was stirred at RT for 18 h. The reaction was quenched with 1 N aq. HCl and extracted with ether. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:14]([CH2:22][CH3:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[CH3:21][C:17]1[CH:16]=[C:15]([N:14]([CH2:12][CH3:13])[CH2:22][CH3:23])[CH:20]=[CH:19][C:18]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCN(CC)c1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1

Procedure:
In a manner similar to that of part A of Example 1 condensation of phthalic anhydride (60 g.) and N,N-diethyl-m-toluidine (162.8 g.) in contact with aluminum chloride (120 g.) and with chlorobenzene (360 ml.) as diluent afforded 2-(2-methyl-4-(diethylamino)benzoyl)benzoic acid (IV: Y2 = CH3, Y'4 = (CH3CH2)2N, Z4 = Z"5 = Z"6 = Z7 = H).
Reaction SMILES: [NH2:1][C:2](=S)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:9][NH2:10].C1COCC1>C(O)C>[NH2:1][C:2](=[N:9][NH2:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: NN
Reactant: CCOC(=O)C(N)=S
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(N)=NN
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-amino-2-thioxoacetate (5) (5 g, 37.5 mmol) was dissolved in ethanol and cooled to 0° C. Hydrazine in THF (1M, 37.5 mmol) was added dropwise and stirred at ambient temperature for 1 h. The reaction mixture was concentrated, white flakes of ethyl 2-amino-2-hydrazonoacetate were obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[O:7][C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=1[N+:17]([O-])=O)=O>C(O)(=O)C.[Fe]>[O:2]=[C:3]1[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=2[O:7][C:8]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=2[NH:17]1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2C(=O)OC)s1
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(s1)Oc1ccccc1C(=O)N2
Temperature: 85 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a stirring solution of compound 118 (1.918 g, 5.69 mmol) in acetic acid was added iron (2.223 g, 39.8 mmol) and the reaction mixture was stirred at 85° C. for 1 h then at 100° C. for 1 h. The mixture was cooled to room temperature, poured into 150 mL of ice-cold water and the resulting white precipitate was filtered to afford title compound 119 (1.261 g, 81%) as a beige solid. LRMS (ESI): (calc) 275.03. (found) 276.2 (MH)+.
Reaction SMILES: [CH:1]1[S:5][CH:4]=[CH:3][C:2]=1[CH2:6][NH:7][CH2:8][CH:9](O)[C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[F:16][C:15]1[C:10]([CH:9]2[CH2:8][NH:7][CH2:6][C:2]3[CH:3]=[CH:4][S:5][C:1]2=3)=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=1
Reactant: COc1cc(F)c(C(O)CNCc2ccsc2)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(C2CNCc3ccsc32)cc1OC
Yield: 56.7 %

Procedure:
1.16 g of α-[[(-3-thenyl)amino]methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol was dissolved in 11 ml of trifluoroacetic acid, and after adding thereto 0.31 ml of conc. sulfuric acid under ice cooling, the mixture was stirred for 4 hours. The reaction solution was concentrated, and chloroform and water were added to the residue. The mixture was basified by addition of 10 ml of conc. aqueous ammonia under ice cooling. The chloroform layer was collected after a separating procedure, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized form ethanol, affording 0.76 g of 7-(6-fluoro-3,4-dimethoxyphenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, m.p. 108°-111° C. (2) 0.62 g of 7-(6-fluoro-3,4-dimethoxyphenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (obtained above) was dissolved in 13 ml of dichloromethane; and to the mixture was added dropwise 12 ml of 1M borontribromide-dichloromethane solution under an argon gas stream at -30°--60° C. (internal temperature) under cooling while stirring. The mixture was stirred for 2 hours at room temperature, and to the mixture was added dropwise 20 ml of methanol under ice cooling. The solment was distilled off, and the residue was recrystallized from ethanol, affording 0.30 g of 7-(6-fluoro-3,4-hydroxyphenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrobromide.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([OH:15])=O.S(Cl)([Cl:18])=O>>[CH:8]1[CH:9]=[C:10]2[C:2]([N:3]([CH2:12][C:13]([Cl:18])=[O:15])[C:4](=[O:11])[C:5]2=[CH:6][CH:7]=1)=[O:1]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Product: O=C(Cl)CN1C(=O)c2ccccc2C1=O

Procedure:
A solution of 1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetic acid (7.00 g) and thionyl chloride (12 mL) was stirred at reflux under nitrogen for one hour. The thionyl chloride was distilled from the reaction, and the resulting crude product was further purified by distillation via a kugelrohr apparatus (BUCHI, Flawil, Switzerland). [Bp: 160°-180° C. (oven temperature) at 10 mm Hg.]The yield of the title compound was 6.88 grams (90.2%). The structure of the title compound, and of all of the compounds synthesized in each of the subsequent examples, was confirmed by 1H NMR.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[CH3:2].[H-].[Na+].[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:29][C:28]1[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5-(4-nitro-phenyl)-3-oxo-pentanoic acid ethyl ester prepared in Example FF (14.2 g, 54 mmol) in dry THF (150 mL) was added NaH (2.43 g of a 60% dispersion in oil, 57.5 mmol), and the mixture was stirred at room temperature for 45 minutes. 4-Nitrobenzyl bromide (13.9 g, 64.3 mmol) was added all at once, and the resulting suspension was stirred overnight at room temperature. Dilute HCl (2N, 100 mL) was added. The solution was extracted with EtOAc; the extracts were combined, washed with brine, and dried (MgSO4). Concentration gave a residue which was chromatographed on silica gel, eluting with 5:1 hexane:EtOAc to 1:1 hexane:EtOAc, to yield the title compound. 1H NMR (CDCl3) δ 1.11 (t, 3 H), 2.66 (m, 1 H), 2.95 (m, 3 H), 3.21 (m, 2 H), 3.75 (t, 1 H), 4.07 (m, 2 H), 7.23 (m, 4 H), 8.05 (d, 4 H).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]1=[O:19])[CH2:4][CH2:5][CH3:6].[CH2:20](I)[CH:21]=[CH2:22]>CN(C=O)C>[CH2:22]([C:7]1([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]1=[O:19])[CH:21]=[CH2:20]
Reactant: CCCCC1CCc2cc(OC)ccc2C1=O
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(CCCC)CCc2cc(OC)ccc2C1=O
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
NaH (0.32 g of a 60% dispersion in mineral oil, 8.0 mmol) was added to an ice-cold solution of 2-butyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (1.55 g, 6.7 mmol) in anhydrous DMF (30 mL). The mixture was purged with N2 and stirred at 0-5° C. for 45 minutes. Allyl iodide (0.91 mL, 10.0 mmol) was added and, after a few minutes, the cooling bath was removed and the mixture was stirred overnight at room temperature. Additional NaH (0.16 g of a 61.1% dispersion in mineral oil, 4.1 mmol) was added and the mixture was stirred at room temperature for 15 minutes. Allyl iodide (0.46 mL, 5.0 mmol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was partitioned between EtOAc and water, and the aqueous phase was back-extracted with several portions of EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40M (4×15 cm) silica gel column, eluting with 1% to 4% EtOAc in hexane, to afford 2-allyl-2-butyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone as an oil.