Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][CH2:44][CH2:45][OH:46].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:46][CH2:45][CH2:44][O:43][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][O:37]3)[CH:8]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2O)n1
Reactant: OCCOC1CCCCO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 134.8 %

Procedure:
A solution of intermediate 95a (1.42 g, 6.15 mmol) and triphenyl phosphine (3.22 g, 12.29 mmol) in THF (50 mL), under an atmosphere of argon was treated with 2-(tetrahydro-pyran-2-yloxy)-ethanol (1.25 mL, 9.22 mmol), followed by the dropwise addition of diethyl azodicarboxylate (1.94 mL, 12.29 mmol). The reaction mixture was then stirred at RT for 1 h. Water (0.5 mL) was added and the mixture was concentrated in vacuo. The residue was taken up in EtOAc (8 mL) and cyclohexane was added until triphenylphosphine oxide had precipitated out of solution. This was filtered and the filtrate was concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to afford the title compound as an orange/brown oil (2.98 g, >100%). LCMS (Method 3): Rt 3.20 min, m/z 360 [MH+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]4[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH:21]5[CH2:23][CH2:22]5)(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:33]=[N:32][C:31]([NH2:30])=[N:36][CH:35]=3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: O=S(=O)(C1CC1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)C5CC5)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 122. (400 MHz, CDCl3): 0.92-0.94 (2H, m, CH2), 1.11-1.12 (2H, m, CH2), 2.21 (1H, m, CH), 2.58-2.61 (4H, m, CH2), 3.29-3.32 (4H, m, CH2), 3.80-3.82 (6H, m, CH2), 3.94-3.97 (4H, m, CH2), 5.13 (2H, b, NH2), 7.23 (1H, s, ar), 9.21 (2H, s, ar). (M+H)+ 517.35
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]([NH:25][C:26](=NC(=O)OC)SC)=[O:24].C(O)(=O)C>ClC(Cl)Cl>[CH3:21][O:22][C:23](=[O:24])[NH:25][C:26]1[NH:19][C:16]2[CH:17]=[CH:18][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[O:9][CH2:10][CH2:11][O:12]3)=[CH:14][C:15]=2[N:20]=1
Reactant: Nc1ccc(C2(c3ccc(F)cc3)OCCO2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1nc2cc(C3(c4ccc(F)cc4)OCCO3)ccc2[nH]1
Yield: 42 %

Procedure:
A mixture of 5.5 parts of 4-[2-(4-fluorophenyl)-1,3-dioxolan2-yl]-1,2-benzenediamine, 6.2 parts of methyl [(methoxycarbonylamino)(methylthio)methylene]carbamate, 4.8 parts of acetic acid and 225 parts of trichloromethane is stirred and refluxed for 17 hours. The reaction mixture is evaporated in vacuo. The residue is triturated in methanol. The product is filtered off, washed with 2,2' -oxybispropane and dried, yielding 3 parts (42%) of methyl{ 5-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1H-benzimidazol-2-yl}carbamate; mp. 227.7° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([O:23]CC)=[O:22])=[C:6]2[C:20]=1[C:10]1[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:13][C:9]=1[CH2:8][CH2:7]2.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([OH:23])=[O:22])=[C:6]2[C:20]=1[C:10]1[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:13][C:9]=1[CH2:8][CH2:7]2
Reactant: CCOC(=O)c1sc(SC)c2c1CCc1sc(-c3ccccc3)nc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1sc(C(=O)O)c2c1-c1nc(-c3ccccc3)sc1CC2
Temperature: 50 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
Ethyl 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxylate (2.28 g) was suspended in a mixed solvent of ethanol (15 ml) and tetrahydrofuran (25 ml); a 2 N aqueous solution of sodium hydroxide (8.8 ml) was added at 50° C. After the reaction mixture was stirred at 50° C. for 4 hours, the solution obtained was poured over water (400 ml), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxylic acid (2.08 g, 98.6%), which was then recrystallized from chloroform-methanol. Light-yellow prisms. Melting point 255-256° C. (decomposed).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=O)[CH3:12])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:14][Mg]Br>CCOCC>[C:11]([C:10]1[C:2]([CH3:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12)([CH3:12])=[CH2:14]
Reactant: CC(=O)c1c(C)nn2ccccc12
Reactant: C[Mg]Br
Solvent: CCOCC
Product: C=C(C)c1c(C)nn2ccccc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 54.4 %

Procedure:
A 0° C. solution of 1-(2-methylpyrazolo[1,5-a]pyridin-3-yl)ethanone (1.05 g, 6.0 mmol) in ether (20 mL) was treated with 3.0 M ether solution of methyl magnesium bromide (4 mL, 12.0 mmol). The reaction was allowed to warm to room temperature and stirred for 7 hours. The reaction was quenched with 2N HCl then extracted with ethyl acetate, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (50% ethyl acetate/heptane) to give 0.562 g (55%) of brown oil as the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=7.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.19–7.15 (m, 1H), 6.82–6.78 (m, 1H), 5.20–5.19 (m, 1H), 5.04–5.03 (m, 1H), 2.42 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 148.1, 137.5, 136.1, 128.2, 123.7, 117.0, 113.7, 111.2, 110.7, 23.6, 13.6; HRMS (FAB) calcd for C11H12N2+H 173.1079. found 173.1076.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[S:23]1[C:27]([CH:28]=O)=[CH:26][C:25]2[S:30][CH:31]=[CH:32][C:24]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[S:23]1[C:27]([CH2:28][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)=[CH:26][C:25]2[S:30][CH:31]=[CH:32][C:24]1=2
Reactant: O=Cc1cc2sccc2s1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5sccc5s4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To 6 mL of a chloroform solution containing 270 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 135 mg of thieno[3,2-b]thiophene-2-carbaldehyde, 54 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 284 mg of sodium triacetoxyborohydride was added, and stirred for 18 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.31 g of 1-(2-(4-((thieno[3,2-b]thiophen-2-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].C(OC(=O)[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27]([C:29]1[S:30]C(CN)=[CH:32][CH:33]=1)=[O:28])(C)(C)C.F[C:38](F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27]([C:29]1[S:30][C:11]([CH2:12][NH:8][C:1]([NH:3][CH2:7][C:6]#[CH:38])=[O:2])=[CH:32][CH:33]=1)=[O:28]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CN)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCNC(=O)NCc1ccc(C(=O)Nc2ccccc2N)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 15.8 mg (0.288 mmol) in 1 ml THF were added 46.7 mg (0.288 mmol) 1,1′-carbonyldiimidazol. After 1 h at rt 100 mg (0.288 mmol) {2-[(5-Aminomethyl-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid t-butyl ester were added and the reaction mixture was stirred for 1 h at rt. 1.7 ml trifluoroacetic acid were added and after 16 h at rt sat. aqueous NaHCO3 was added carefully and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. The residue was purified by HPLC/MS to yield 75 mg (0.228 mmol 5-[(3-Prop-2-ynyl-ureido)-methyl]-thiophene-2-carboxylic acid (2-amino-phenyl)-amide; exact MW [M+H] calc'd: 329.11; MW found [M+H]: 329.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[C:18]([NH2:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[F:1])=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Nc1cccc2c(Nc3ccc(C(F)(F)F)cc3F)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4ccc(C(F)(F)F)cc4F)ncnc23)c1F
Yield: 16.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(2-fluoro-4-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-23, 230 mg, 0.71 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 245 mg, 0.85 mmol), oxalyl chloride (161 mg, 1.28 mmol), DMF (1 drop) and DIPEA (275 mg, 2.13 mmol) in CH2Cl2 (8 mL) to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.63 (s, 1H), 10.22 (s, 1H), 8.82-8.79 (d, J=8.1 Hz, 1H), 8.59 (s, 1H), 8.28-8.25 (d, J=9.0 Hz, 1H), 8.16 (m, 1H), 7.89-7.83 (m, 2H), 7.75-7.67 (m, 2H), 7.42-7.34 (m, 2H), 4.32-4.30 (d, J=5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 592.33 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=2)[C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2cccc(C(F)(F)F)c2)CC1
Yield: 65 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone (example 21), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (65%).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([N:11]1[C:15]([C:16]([F:19])([F:18])[F:17])=[C:14]([CH3:20])[C:13]([Br:21])=[C:12]1[C:22]([O:24]CC)=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C1COCC1.O>[CH2:4]([N:11]1[C:15]([C:16]([F:17])([F:18])[F:19])=[C:14]([CH3:20])[C:13]([Br:21])=[C:12]1[C:22]([OH:24])=[O:23])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1c(Br)c(C)c(C(F)(F)F)n1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Br)c(C(=O)O)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Yield: 85.5 %

Procedure:
Lithium hydroxide monohydrate (8.89 g, 371.6 mmol) was added to the ice cold solution of ethyl 1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (29 g, 74.32 mmol) in THF (300 mL) and H2O (100 mL) warmed to RT and then heated at 100° C. for 14 h, cooled to RT and then diluted with H2O and acidify with 6N HCl (pH-2). The aqueous layer was extracted with EtOAc (2×350 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass which was triturated with diethyl ether to afford title compound (23 g, 85.48% yield, white color solid).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]2[C:12]([CH3:17])=[C:13]([CH2:15]O)[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1.P(Br)(Br)[Br:25]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]2[C:12]([CH3:17])=[C:13]([CH2:15][Br:25])[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COCCCc1cccc2oc(CO)c(C)c12
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCCc1cccc2oc(CBr)c(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [4-(3-methoxypropyl)-3-methyl-1-benzofuran-2-yl]methanol (181 mg, 0.774 mmol) in dichloromethane (4 mL) at 0° C. was added pyridine (0.1 mL) followed by phosphorous tribromide (0.109 mL, 1.16 mmol). The cooling bath was removed and the solution was stirred for 1 hour at room temperature. After recooling to 0° C. the reaction was quenched by the addition of ice chips. The mixture was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium bromide. The solution was dried over sodium sulfate, filtered and reduced to dryness to furnish 188 mg (82%) of the [4-(3-methoxypropyl)-3-methyl-2-bromomethyl-1-benzofuran, which was directly carried on to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:47])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:28]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:20]>CC(C)=O.CN(C=O)C>[CH2:19]([O:21][C:22](=[O:47])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:12][C:4]2[CH:5]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:7]=[C:2]([Br:1])[CH:3]=2)[C:28]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:20]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CS(=O)(=O)c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
To a solution of 3-bromo-5-methanesulfonyl-phenol (1.3 g) in a mixture of acetone and DMF (2:1, 60 mL) were added potassium carbonate (7.1 g) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.7 g). The resulting mixture was stirred at 75° C. for 1 day. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (2.9 g, 87% yield). LRMS calcd for C30H41O8BrS [M+H]+ 641.2, observed 641.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2F)=[N:10][NH2:11])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: NN=C(Nc1ccc(Br)cc1)c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Brc1ccc(Nc2n[nH]c3ccccc23)cc1
Temperature: 100 °C
Yield: 25.6 %

Procedure:
To a solution of N1-(4-bromophenyl)-2-fluoro-1-benzenecarbohydrazonamide (1.2 g, 0.00391 mol) in N-methyl pyrrolidinone (25 mL), potassium tert-butoxide (0.50 g, 0.0041 mol) was added and the resulting solution was heated at 100° C. under an atmosphere of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield N-(4-bromophenyl)-N-(1H-3-indazolyl)amine (0.29 g, 0.0010 mol) as a white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]1([CH2:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[C:22](OC)=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:25][C:26]([O:28]CC)=O)(=[O:16])=[O:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:1][O:2][C:20]1[CH:21]=[CH:22][C:17]2[S:14](=[O:15])(=[O:16])[N:13]([CH2:12][CH2:11][CH2:10][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:26](=[O:28])[CH2:25][C:18]=2[CH:19]=1
Reactant: CCOC(=O)Cc1cccc(OC)c1S(=O)(=O)NCCCc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)CC(=O)N(CCCc1ccccc1)S2(=O)=O

Procedure:
Sodium Methoxide (280 mg, 5.1 mmol) and ethyl 2-[(N-3-phenylpropylamino)-sulfonyl]-3-methoxyphenylacetate (2.0 g, 5.1 mmol) are dissolved in toluene (200 mL) and the resulting solution is refluxed for 24 hours. An additional portion of sodium methoxide (60 mg, 1.1 mmol) is added and the reaction is once again refluxed for 24 hours. The reaction mixture is subsequently diluted with EtOAc (200 mL) and H2O (200 mL). The organic phase is then washed with saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo to give 6-methoxy-2-(3-phenylpropyl)-3-oxo-3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:13]/[C:14](/[CH3:20])=[CH:15]\[C:16]([O:18][CH3:19])=[O:17].[C:21]([O:27][CH2:28][CH2:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:31])(=[O:26])[CH2:22][C:23]([CH3:25])=O>CC(O)C>[CH3:25][C:23]1[NH:13][C:14]([CH3:20])=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=2[F:1])[C:22]=1[C:21]([O:27][CH2:28][CH2:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:31])=[O:26]
Reactant: O=Cc1cccc([N+](=O)[O-])c1F
Reactant: CC(=O)CC(=O)OCCN(C)Cc1ccccc1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1F
Yield: 50.7 %

Procedure:
A mixture of 330 mg of 2-fluoro-3-nitrobenzaldehyde, 252 mg of methyl 3-aminocrotonate and 506 mg of 2-(N-benzyl-N-methylamino)ethyl acetoacetate in 2 ml of 2-propanol was refluxed for 12 hours, and then the solvent was distilled off in vacuo. The residue was purified by the method of a column chromatography on silica gel to provide 492 mg of the desired compound (104).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=3)[CH:5]=2)[CH2:27][CH2:26]1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NC1CC1
Product: COc1ccc(C(=O)NC2CC2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and cyclopropylamine in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](C=O)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23](=[O:44])[CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:45]1(C)C=CC=CC=1>>[CH3:21][O:22][C:23](=[O:44])[CH:24]=[CH:45][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:8])=[O:9])[CH:11]=[CH:12]2
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: Cc1ccccc1
Product: COC(=O)C=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 110 °C

Procedure:
A mixture of 1-benzenesulfonyl-1H-indole-5-carbaldehyde CCKXIV (3.671 g, 12.866 mmol) and methyl(triphenylphosphoranylidene)acetate (5.38 g, 16.082 mmol) in toluene (80 mL) was heated to 110° C. for 68 hours. The resulting mixture was concentrated under reduced pressure and the crude residue was purified by flash chromatography (EtOAc/hexane, 20/80 to 35/65) to afford 4.479 g of 3-(1-benzenesulfonyl-1H-indol-5-yl)-acrylic acid methyl ester CCLXV as a white solid in a mixture 10/1 of (E) and (Z) diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12]O)=[CH:7][C:6]=2[CH:14]=1.CCN(C(C)C)C(C)C.CS([Cl:28])(=O)=O.C(OCC)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][Cl:28])=[CH:7][C:6]=2[CH:14]=1
Reactant: OCC1=Cc2cc(Br)ccc2CCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: ClCC1=Cc2cc(Br)ccc2CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
To a solution of (2-bromo-6,7-dihydro-5H-benzo[7]annulen-8-yl)methanol from step A5 (150 mg, 0.593 mmol) in dichloromethane (2 mL) was added DIEA (0.310 mL, 1.78 mmol) followed by methanesulfonyl chloride (0.053 mL, 0.681 mmol) at 0° C. The mixture was gradually warmed up to rt and stirred for 18 h. Diethyl ether (50 mL) was added, the mixture was washed with water, the organic layer was partioned and concentrated. The residue was purified using silica gel column chromatography (hexanes-10% EtOAc) to give 2-bromo-8-(chloromethyl)-6,7-dihydro-5H-benzo[7]annulene (135 mg, 0.497 mmol, 84% yield). 1H NMR (500 MHz, chloroform-d) δ 7.31-7.29 (m, 1H), 7.26 (dd, J=8.2, 1.8 Hz, 1H), 7.00 (d, J=7.9 Hz, 1H), 6.51 (s, 1H), 4.21 (s, 2H), 2.80-2.74 (m, 2H), 2.48 (t, J=6.7 Hz, 2H), 2.10-2.02 (m, 2H).