Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:16]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:7][CH2:8][N:9]([S:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:24])=[O:23])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)N2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
4-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.646 g) dissolved in methylene chloride (10 ml) under an argon atmosphere were treated with DMAP (0.673 g) at RT, the mixture was cooled to 0° C. and morpholine-4-sulfonylchloride (0613 g) in methylene chloride (2 ml) was added dropwise. The mixture was stirred for 12 h at RT then partitioned between methylen chloride and 1 M HCl. The layers were separated, the organic layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 50%) to give 4-(2-methoxy-ethyl)-1-(morpholine-4-sulfonyl)-piperidine-4-carboxylic acid ethyl ester, (0.68 g) as a light yellow solid. MS (ESI): 365.17 (MH+).
Reaction SMILES: CI.[Mg].[NH:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl-].[NH4+]>CCOCC.O>[NH:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:15]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:16]
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CI
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
Methyl iodide (42.60 g.) in dry ether (150 ml.) was added to a stirred mixture of magnesium turnings (7.30 g.) in dry ether (50 ml.) at such a rate that gentle reflux was maintained. After completion of the addition the mixture was stirred at room temperature for 30 minutes and then pyrrole (20.13 g., 0.44 mole) was added at such a rate that gentle reflux was maintained. After completion of the addition the mixture was heated under reflux with stirring for 30 minutes and then cooled to 0° C. A solution of cyclohexane carboxylic acid chloride (44.0 g., 0.30 mole) in dry ether (100 ml.) was added dropwise with stirring and the resulting mixture was heated under reflux with stirring for 30 minutes. The mixture was cooled and a solution of ammonium chloride (20 g.) in water (200 ml.) was added with stirring. The organic layer was separated, washed once with 0.5 N sodium hydroxide solution (50 ml.), twice with water (100 ml.) and dried over sodium sulphate. The ether was evaporated to give a viscous oil which was distilled to give cyclohexyl pyrrol-2-yl ketone (31.5 g.), B.P. 162°-165° at 15 mm., M.P. 83°-84°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:26])[CH:4]=[N:3]1
Reactant: C1CCNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Yield: 82.9 %

Procedure:
A mixture of 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 223 μmol), pyrrolidine (148 μl, 1.79 mmol), propylphosphonic anhydride (50% in ethyl acetate, 329 μl, 558 μmol) and N,N-diisopropylethylamine (114 μl, 669 μmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The solvent is evaporated and the residue triturated with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water and dried affording 1-methyl-N-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(pyrrolidine-1-carbonyl)-1H-pyrazole-5-carboxamide (77 mg, 82.9%) as a light brown solid. mp.: 226-8° C. MS: m/z=417.3 (M+H+).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[C:38]([O:37][C:35]([N:6]1[C@H:5]([C:3]([OH:4])=[O:2])[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reaction time: 0.25 h

Procedure:
(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (1.0 g) was dissolved in 60 mL of THF-MeOH (1:4) and the mixture cooled on an ice bath. 2 N aqueous LiOH (5 eq.) was added and the mixture was stirred on ice for 15 minutes and then at room temperature for 14 hours. The pH of the mixture was adjusted to about 2 with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. DCM was added and mixture was again concentrated (900 mg). LCMS: m/z 587.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:39])[CH2:37][CH3:38].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28]([NH:39][CH2:36][CH2:37][CH3:38])=[O:34]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCN
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (5.13 g) was dissolved in chloroform (100 ml) and triethylamine (50 ml), and a solution of triphosgene (4.59 g) in chloroform (3 ml) was then added to the solution. The mixture was stirred for 30 min. Next, n-propylamine (2.74 g) was added to the reaction solution, and the mixture was stirred for additional 2 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (50/1) to give 4.14 g (yield 64%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:19]2[CH:24]=[C:23]([O:25][CH2:26][CH3:27])[C:22]([O:28][CH2:29][CH3:30])=[CH:21][C:20]=2[OH:31])[CH2:11][NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:5][CH:4]=1)#[N:2].C(=O)(O)[O-].[K+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][O:31][C:20]1[CH:21]=[C:22]([O:28][CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[CH:24][C:19]=1[CH:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:11][NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])[CH3:43]
Reactant: CCCS(=O)(=O)NCC(Nc1ccc(C#N)cc1)c1cc(OCC)c(OCC)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)NCC(Nc1ccc(C#N)cc1)c1cc(OCC)c(OCC)cc1OCC(=O)OCC
Reaction time: 67 h
Yield: 65.5 %

Procedure:
Propane-1-sulfonic acid [2-(4-cyano-phenylamino)-2-(4,5-diethoxy-2-hydroxy-phenyl)-ethyl]-amide (100 mg, 0.223 mmoles) was dissolved in dimethylformamide (1.5 ml) and treated with solid potassium bicarbonate (22 mg, 0.223 mmoles) followed by ethyl bromoacetate (0.37 ml, 0.223 mmoles). The reaction was stirred under N2, for 67 hours. Thin-layer chromatography showed presence of a new product with a higher Rf. The reaction was quenched in water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The residue was submitted to flash chromatography (ethyl acetate:methylene chloride 1:9) to yield 78 mg of {2-[1-(4-cyano-phenylamino)-2-(propane-1-sulfonylamino)-ethyl]-4,5-diethoxy-phenoxy}-acetic acid ethyl ester. 1HNMR (CHCl3): 7.35 (d, 2H), 6.81 (s, 1H), 6.57 (d, 2H), 6.43 (s, 1H), 4.81 (t, 1H), 4.68 (ABq, 2H), 4.56 (t, 1H), 4.26 (q, 2H), 4.05 (q, 2H), 3.95 (m, 2H), 3.54 (t, 2H), 2.98 (m, 2H) 1.80 (m, 2H) 1.42 (t, 3H), 1.32 (t, 6H), 1.02 (t, 3H). MS (M+H): 534.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].FC(F)(F)S(O[CH2:19][C:20]([F:23])([F:22])[F:21])(=O)=O.O>CN(C=O)C.[Cl-].[Na+].O>[F:1][C:2]1[C:9]([O:10][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccc(O)c1F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCC(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A stirred solution of 2-fluoro-3-hydroxybenzonitrile (800 mg, 5.83 mmol) in DMF (10 mL) at 0° C. was treated portionwise with NaH (280 mg, 7.00 mmol) (60% oil dispersion). The reaction mixture was then stirred for 0.5 h and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1490 mg, 6.42 mmol) was added. The reaction was allowed to warm to rt overnight with stirring. The reaction mixture was then treated with water (40 mL) and brine (5 mL) and extracted with ethyl acetate (˜50 mL). The organic extract was washed with water, dried over anhydrous Na2SO4, filtered and conc. in vacuo to afford a residue which was purified via silica gel chromatography (10% to 30% ethyl acetate/hexanes) to yield the title compound as a white solid (1040 mg, 81%). 1H NMR (400 MHz, MeOD) δ ppm 7.56 (td, 1 H), 7.47-7.38 (m, 1 H), 7.38-7.24 (m, 1 H), 4.73 (q, 2 H); m/z 220.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH:11]([F:13])[F:12])=[CH:9][C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=3)=[N:7][C:6]=12.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>>[F:12][CH:11]([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[C:6]2[N:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:9]=1
Reactant: CCOc1cccc(-c2cc(C(F)F)n3ncc(Br)c3n2)c1
Reactant: C#C[Si](C)(C)C
Product: CCOc1cccc(-c2cc(C(F)F)n3ncc(C#C[Si](C)(C)C)c3n2)c1
Yield: 96.1 %

Procedure:
Prepared from 3-bromo-7-difluoromethyl-5-(3-ethoxy-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.19 step 3a) (20.0 g, 54 mmol) and commercially available trimethylsilylacetylene (15 mL, 109 mmol) as described in example C.1 step 3a to give the title compound (20 g, 95%) as a light brown solid. MS (ISP) 386 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([O-])=O.N[C:12]1[CH:17]=CC=[CH:14][CH:13]=1.ClCN1CCCC1=O>>[CH2:17]([S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1])[CH2:12][CH2:13][CH3:14]
Reactant: O=[N+]([O-])c1ccccc1S
Reactant: Nc1ccccc1
Agent: O=C1CCCN1CCl
Product: CCCCSc1ccccc1N

Procedure:
2-Butylmercaptoaniline was prepared from -2-nitrothiophenol by a two-step reaction sequence consisting of alkylation followed by reduction. The aniline then was condensed with N-chloromethyl-2-pyrrolidone to yield the desired product.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:4]=[N:3][CH:2]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:5]4[CH:4]=[N:3][CH:2]=[N:1][CH:6]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1cncnc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cncnc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl pyrimidin-5-ylcarbamate (100 mg, 0.369 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (87.4 mg, 0.369 mmol), diisopropylethylamine (0.0643 ml, 0.369 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 2.5 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (26.3 mg, 19.5%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:4][CH:3]=1.OC1C=CC(C2CC(C3C=CC(O)=CC=3)CCC=2)=CC=1.C(C(C)=O)C(C)C.CC(C1C=CC=CC=1)=C>C(OCC)(=O)C.[C].[Pd].C1CCCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2=CC(c3ccc(O)cc3)CCC2)cc1
Agent: [Pd]
Agent: C=C(C)c1ccccc1
Agent: Oc1ccc(C2=CCCC(c3ccc(O)cc3)C2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CC(=O)CC(C)C
Product: Oc1ccc(-c2cccc(-c3ccc(O)cc3)c2)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 33 %

Procedure:
2.6 g of the 91% pure mixture of 1,3-bis(4-hydroxyphenyl)-1-cyclohexene and 1,5-bis(4-hydroxyphenyl)-1-cyclohexene obtained in Step (B), 15.6 g of methyl isobutyl ketone, 3.5 g of α-methyl styrene, and 0.2 g of 5% palladium carbon were introduced to an autoclave and agitated for 6 hours at 150° C. After the end of reaction, the reaction liquid was filtered to remove the 5% palladium carbon, and then the filtrate was condensed. The residue was dissolved in 3.2 g of ethyl acetate, after which 7.5 g of cyclohexane was added to the mixture and the separated crystal was filtered out and dried to obtain 1.9 g of 4,4″-dihydroxy-m-terphenyl of 99% purity (high-speed liquid chromatography).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl.CCN(C(C)C)C(C)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH:17]3[CH2:18][CH2:19][N:20]([C:29]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:30])[CH2:21][CH2:22]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCN(C1CCNCC1)C1CCc2ccc(OC)cc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (200 μL of 0.025 M in dichloromethane, 50 μmole) was added 200 μL of 0.25 M solution of morpholine 4-carbonyl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 24 h at 25° C. under N2. Concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford {4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone 1 (11.9 mg), [M+H]+=461.
Reaction SMILES: [C:1]([C:3](=[C:9]([S:12][CH3:13])SC)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1>C(O)C>[C:1](/[C:3](=[C:9](/[NH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)\[S:12][CH3:13])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Solvent: CCO
Product: CCOC(=O)/C(C#N)=C(\NCc1ccc(OC)cc1)SC
Yield: 121.3 %

Procedure:
Ethyl 2-cyano-3,3-bis(methylthio)acrylate (3.8 g, 17.49 mmol) was dissolved in 70 mL ethanol and (4-methoxyphenyl)methanamine (2.88 g, 20.99 mmol) was added. The reaction was stirred at reflux for 2 h. The solvent was evaporated to give 6.5 g (100% yield) of the title compound that was used in the next step without any further purification. Purity 80%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Li])(C)(C)C.CCCCC.[B:25](OC)([O:28]C)[O:26]C>O1CCCC1>[CH2:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:25]([OH:28])[OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: COB(OC)OC
Reactant: CCCCCCCc1ccccc1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCc1ccccc1B(O)O

Procedure:
Following General Procedure A and using 1-bromo-2-heptyl-benzene (Intermediate 67, 0.4 g, 1.56 mmol), 4 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (1.84 mL, 3.1 mmol) and trimethyl borate (0.45 mL, 3.1 mmol), the title compound was obtained (0.27 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:23])[CH3:22]
Reactant: COc1ccc(S)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Sc1ccc(OC)cc1

Procedure:
To stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) and anhydrous K2CO3 (10 gm, excess) in dry acetone (100 ml), ethyl 2-bromo-propionate (3.6 gm, 20 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 8 hours with good stirring. At the end, reaction was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated The residue was extracted with chloroform and washed with H2O and 0.5 N NaOH solution. The organic layer was further washed well with water, dried over MgSO4, filtered and concentrated to afford 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester as a light yellow oil. Yield 4.5gms (94%); MS; 241 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5].[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)([O-:19])=[O:18].N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.O>[C:2]([C:3](=[CH:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=1)[C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])(=[O:1])[CH3:16]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)NCC=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)NCC=Cc1ccccc1

Procedure:
1.03 g (4.74 mmol) of 3-oxo-N-(3-phenyl-2-propene-1-yl)butyramide, 723 mg (4.78 mmol) of 3-nitrobenzaldehyde and 0.2 ml (2.02 mmol) of piperidine were heated under reflux in the presence of a catalytic amount of p-toluenesulfonic acid in 30 ml of benzene overnight while water was removed. Ethyl acetate was added to the reaction mixture. After washing with 2 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous sodium sulfate. After the concentration under reduced pressure, the residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: C(OC([CH:8]1[NH:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[C:20](=[O:23])([O-:22])[O-].[K+].[K+].[I-].[K+].Br[CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>CC(=O)CC>[C:11]([O:22][C:20]([N:14]1[CH2:13][CH2:12][C:15]2[CH:16]=[C:17]([O:19][CH2:29][C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=3)[CH:18]=[CH:11][C:10]=2[CH2:9][CH2:8]1)=[O:23])([CH3:18])([CH3:12])[CH3:10]
Reactant: CC(C)(C)OC(=O)C1CCc2cc(O)ccc2CN1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cc1

Procedure:
7-Hydroxy-1,2,4,5-tetrahydro-benzo[c]azepine-3-carboxylic acid tert-butyl ester (WO 02/40471) (5.27 g, 20.0 mmol), potassium carbonate (8.30 g, 60.0 mmol) and catalytic potassium iodide were suspended in butanone (100 ml). Methyl 4-(bromomethyl)benzoate (5.5 g, 24.0 mmol) dissolved in butanone (50 ml) was added dropwise after which the reaction mixture was stirred at reflux for 24 hours. The reaction mixture was cooled, the solids were filtered and then washed with acetone. The filtrate was concentrated in vacuo and the crude mixture was purified by column chromatography eluting with a mixture of ethyl acetate:hexane (1:4) to afford the title compound (D3). MS (ES+) m/e 344 [(M+H)—CO2tBu]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].S(OC)(O[CH3:16])(=O)=O.O.[OH-].[Li+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([O:11][CH3:16])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COS(=O)(=O)OC
Reactant: N#Cc1cc(Br)c(O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(C#N)cc1Br
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A mixture of 5-bromo-2-chloro-4-hyroxybenzonitrile (compound 87, 38.1 g, 164 mmol), dimethyl sulfate (20.1 mL, 213 mmol), and lithium hydroxide monohydrate (8.93 g, 213 mmol) in THF (500 mL) was refluxed overnight. The mixture was cooled to ambient temperature and then diluted with EtOAc. The EtOAc solution was washed with water and brine prior to drying over anhydrous MgSO4. Filtration and removal of the voletiles under reduced pressure left the crude product which was purified by column chromatography (5-40% EtOAC/hexanes) to yield 5-bromo-2-chloro-4-methoxybenzonitrile (30.7 g, 76%) as a white solid.