Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][CH:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[CH3:34])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].C1(C2C=CC=CC=2C(NC2C=CC(C(Cl)=O)=CC=2)=O)C=CC=CC=1>>[OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([NH:25][C:26](=[O:35])[C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH3:34])=[CH:24][C:16]=2[Cl:15])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1
Reactant: OCCC1=CC=Nc2ccccc2S1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Agent: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2C=CC(CCO)Sc3ccccc32)c(Cl)c1

Procedure:
A mixture of 2-(2-hydroxyethyl)-1,5-benzothiazepine as prepared in Example 2 (0.070 g, 0.34 mM) and N,O-bis(tri-methylsilyl)acetamide (0.15 ml, 0.67 mM)was treated as described in Example 3 with 2-Chloro-4-(2-methyl-5-fluorobenzoylamino)benzoyl chloride (0.11 g, 0.32 mM) substituted for 4-(2-phenylbenzoylamino)benzoyl chloride to give the product as a white solid. m/z (MH+) 500.
Reaction SMILES: [CH:1](=[N:8][N:9]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:41])[C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[C:21]([Cl:42])[CH:20]=1)[C:10]([NH:12][CH2:13]C(OC)OC)=[O:11])C1C=CC=CC=1.Cl>C(#N)C>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([C:30]2[CH:29]=[CH:28][C:27]([CH2:26][C:22]3[C:23]([Cl:25])=[CH:24][C:19]([N:9]4[C:10](=[O:11])[NH:12][CH2:13][CH:1]=[N:8]4)=[CH:20][C:21]=3[Cl:42])=[CH:32][CH:31]=2)=[O:41])=[CH:39][CH:38]=1
Reactant: COC(CNC(=O)N(N=Cc1ccccc1)c1cc(Cl)c(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1)OC
Agent: Cl
Solvent: CC#N
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cc2c(Cl)cc(N3N=CCNC3=O)cc2Cl)cc1
Yield: 96 %

Procedure:
In 12 ml of acetonitrile was suspended 0.90 g of 1-benzylidene-2-{4-[4-(4-chlorobenzoyl)benzyl]-3,5-dichlorophenyl}-4-(2,2-dimethoxy)ethyl semicarbazide, and 0.15 g of conc. hydrochloric acid was added. The mixture was reacted at 20 to 25° C. for 1 hour, and precipitated crystals were collected by filtration to give the above-identified compound as colorless crystals (yield: 96%).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]>C1COCC1.O=[Mn]=O>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]=[O:28])=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CO)cc4)cc23)CC1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(hydroxymethyl)phenyl]-1H-indole-7-carboxamide (25 mg, 0.058 mmol) in THF (5 mL), MnO2 (160.0 mg, 1.73 mmol) was added at ambient temperature. The resulting suspension was stirred overnight, filtered through celite, and the solid rinsed with THF (3×10 mL). The filtrate was concentrated to give the title compound (15 mg, 58%) which was used in the next step without purification.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[OH:11])([CH3:3])[CH3:2].[NH2:12][C:13]1[C:14]([C:34]#[N:35])=[C:15]([CH:31]=[CH:32][CH:33]=1)OCC1CCN(C(OC(C)(C)C)=O)CC1>>[NH2:12][C:13]1[CH:33]=[CH:32][CH:31]=[C:15]([O:11][C@@H:5]2[CH2:6][C@H:7]([CH3:10])[CH2:8][CH2:9][C@H:4]2[CH:1]([CH3:3])[CH3:2])[C:14]=1[C:34]#[N:35]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(N)c2C#N)CC1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1Oc1cccc(N)c1C#N

Procedure:
Prepared as in Example 22b from (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol and 2 as a white solid (51%). MS 273 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>C(O)(=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]2=[O:16])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(I)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(I)cc1
Yield: 64.8 %

Procedure:
A solution of 2-(4-iodophenyl)ethylamine (7.08 g) and phthalic anhydride (4.24 g) in acetic acid (100 mL) was refluxed for 4 h. The solvent was evaporated and the residue triturated with ethanol (100 mL). The solid was filtered to afford the title intermediate (7.0 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:17]([CH3:16])[C@H:18]2[CH2:37][N:22]3[C:23]4[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]3[CH2:20][CH2:19]2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Product: CN(C(=O)Cc1ccc(F)c(C(F)(F)F)c1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from [4-fluoro-3-(trifluoromethyl)phenyl]acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 463.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].[OH:6][C:7]1[C:20]2[CH2:19][CH2:18][C@H:17]3[C@@H:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:29][CH:28]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>ClCCl>[ClH:5].[CH3:1][S:2]([O:6][C:7]1[C:20]2[CH2:19][CH2:18][C@H:17]3[C@@H:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCCCCN1CCC[C@H]2c3cccc(O)c3CC[C@@H]21)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1cccc2c1CC[C@H]1[C@H]2CCCN1CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Product: Cl
Reaction time: 12 h
Yield: 87.8 %

Procedure:
Methanesulfonyl chloride (0.04 ml, 0.5 mmol) was added to a stirred solution of trans-7-hydroxy-4-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline(E3, 200 mg, 0.4 mmol) and triethylamine (0.07 ml, 0.5 mmol) in dichloromethane (5 ml) at room temperature. The mixture was stirred for 12 h and then poured onto saturated aqueous K2CO3 (10 ml) and extracted onto dichloromethane (3×10 ml). The combined extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to give an off-white solid. Chromatography on silica using 50-100% ethyl acetate /pentane as elution gradient, afforded the free base of the title compound (200 mg, 94%). The free base was treated with 1M ethereal HCl in dichloromethane to afford after evaporation the title compound as a colourless solid.
Reaction SMILES: C([NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([NH:16][C:17](=[O:24])[C:18](=[O:23])[N:19]2[OH:22])=[CH:14][C:13]=1[C:25]([F:28])([F:27])[F:26])(=[O:11])=[O:10])(C(OCC)=O)=O>Cl>[OH:22][N:19]1[C:20]2[C:15](=[CH:14][C:13]([C:25]([F:28])([F:27])[F:26])=[C:12]([S:9](=[O:11])(=[O:10])[NH2:8])[CH:21]=2)[NH:16][C:17](=[O:24])[C:18]1=[O:23]
Reactant: CCOC(=O)C(=O)NS(=O)(=O)c1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Agent: Cl
Product: NS(=O)(=O)c1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Yield: 78 %

Procedure:
A suspension of 7-ethoxalylaminosulfonyl-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione (12.0 g, 28 mmol) in 150 ml of 1M hydrochloric acid was heated at reflux for 2 h with stirring. The cooled mixture was filtered and the isolated solid was washed with water and light petroleum. The crude product was recrystallized from water with decolourizing charcoal and dried in vacuo over phosphorous pentoxide for 3 h to give 7.1 g (77%) of the pure title compound. M.p. 296° C. decomp. (DSC); IR (KBr): 1700, 1615 cm-1 ; 1H-NMR (DMSO-d6): 7.67 (s, 1H, ArH), 7.77 (s, 2H, NH2), 8.26 (s, 1H, ArH), 12.2 (broad s, 2H, NH and OH); MS m/e: 325 (M+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:14][OH:15].C(N(CC)CC)C.Cl[CH2:24][CH2:25][C:26]([C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)=[O:27]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:25]([CH3:24])[C:26]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)=[O:27])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:14][OH:15]
Reactant: O=C(CCCl)c1ccco1
Reactant: OCc1ccc(N2CCNCC2)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C(=O)c1ccco1)N1CCN(c2ccc(CO)c(Cl)c2)CC1
Reaction time: 1 h

Procedure:
At ~25°, a solution of 2-chloro-4-(1-piperaziny)-benzenemethanol 3.0 g, 13.2 mmole) in 30 ml of tetrahydrofuran and 4 ml of triethylamine was added during five minutes to a solution of 3-chloro-1-(2-furanyl)-1-propanone (2.8 g. 13.3 mmole based on 75% purity). The mixture was stirred at 25° for one hour (a white precipitate formed) and was then heated under reflux for one half hour. The mixture was then filtered and the filtrate was evaporated at reduced pressure (<40°) to give an orange, heavy oil. The oil was triturated at 25° first with petroleum ether (30°-60°; two times, 50 ml) and then with diethyl ether. The orange-brown solid was collected, washed with a little diethyl ether, recrystallized from 25 ml of toluene, and finally triturated with diethyl ether (two times, 20 ml) and dried to give 3.10 g (67%), mp 95°-98° (Table 3).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.Cl[CH2:47][C:48]([NH2:50])=[O:49].C(=O)(O)[O-].[Na+]>CC(C)=O.C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:47][C:48]([NH2:50])=[O:49])[CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: NC(=O)CCl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC(N)=O)CC5)cc4)cnc32)cc1
Yield: 48.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (50 mg. 0.077 mmol) was alkylated using 2-chloroacetamide (10 mg, 0.116 mmol) and sodium bicarbonate (20 mg, 0.231 mmol) in acetone/ethanol (5/5 mL) to get 25 mg (49.01% yield) of the titled compound. MS: m/z=663.7 (M+1).
Reaction SMILES: O[CH:2]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3CCCC[O:19]3)[C:9](=[O:24])[N:8]([CH3:25])[C:7]=2[N:6]=[CH:5][C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[CH:28]=1>C(O)=O.[Zn]>[CH2:2]([C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][O:17][CH:18]=[O:19])[C:9](=[O:24])[N:8]([CH3:25])[C:7]=2[N:6]=[CH:5][C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[CH:28]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)c1cccc(Oc2cnc3c(c2C(O)c2ccccc2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Agent: [Zn]
Solvent: O=CO
Product: CC(C)c1cccc(Oc2cnc3c(c2Cc2ccccc2)c(=O)n(CCCOC=O)c(=O)n3C)c1
Temperature: 60 °C
Yield: 102.6 %

Procedure:
To a solution of 5-(hydroxy(phenyl)methyl)-6-(3-isopropylphenoxy)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 0.10 mmol) in HCOOH (3 mL) was added Zn dust (32.5 mg, 0.50 mmol). The reaction was heated at 60° C. for 2 h, cooled to RT and filtered. The filtrate was concentrated to give 3-(5-benzyl-6-(3-isopropyl phenoxy)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propylformate (50 mg, 100% yield) as an oil. LCMS: MH+ 488 and TR=1.568 min. Used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[NH:7][C:8](=S)[N:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:10]=1)[CH3:2].OO>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[CH:8][N:9]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cn(C2CCCCC2)c(=S)[nH]1
Agent: OO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cn(C2CCCCC2)cn1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
80.0 g (0.298 mol) of (1-Cyclohexyl-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)-acetic acid ethyl ester, dissolved in 200 ml acetic acid, were slowly added to H2O2 in 400 ml acetic acid at 0° C. within 90 min at 10° C. After addition the cooling was removed and the mixture was allowed stirring for 1 h. The solution was carefully poured into 80 g Na2SO3 in 300 ml water and ice. The slurry was concentrated and the acidic residue was treated with saturated aqueous K2CO3 and saturated aqueous NaHCO3 (pH 8). The mixture was extracted with AcOEt (1×400 ml, 2×150 ml). The combined organic layers were washed with brine, dried with MgSO4, concentrated and dried under reduced pressure and gave 70.0 g (0.296 mmol, 99%) of (1-Cyclohexyl-1H-imidazol-4-yl)-acetic acid ethyl ester as a brown oil which could be used without further purification in step A of Example 1.
Reaction SMILES: [C:1]([C:5]1[C:9]([CH:10]=[O:11])=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:13][C:14]([NH:16][C:17]1[S:21][C:20]2[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=2[C:18]=1[C:26]([NH:28][CH3:29])=[O:27])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([C:5]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH:28][CH3:29])=[O:27])=[O:15])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1n[nH]cc1C=O
Reactant: CNC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(NC(=O)Cn2cc(C=O)c(C(C)(C)C)n2)sc2c1CCCC2
Temperature: 60 °C
Yield: 90.7 %

Procedure:
3-Tert-butyl-1H-pyrazole-4-carbaldehyde (150 mg, 0.986 mmol), 2-(2-bromoacetamido)-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (490 mg, 1.478 mmol) and potassium carbonate (545 mg, 3.94 mmol) were mixed with DMF (5 mL) and heated for 3 h at 60° C. The reaction was partitioned between water and EtOAc. Organics were combined and purified by chromatography (0-60%, EtOAc/heptane) to give the title product as a white solid (360 mg, 0.894 mmol, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.OC1C=CC=CC=1>CC(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: BrCCCCCCBr
Reactant: Cc1ccc(N=Nc2ccc(O)cc2)cc1
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: Cc1ccc(N=Nc2ccc(OCCCCCCBr)cc2)cc1
Reaction time: 20 h

Procedure:
A 2 l three-neck flask equipped with a mechanical stirrer was charged with 42.4 g (0.2 mol) of 4-hydroxy-4′-methylazobenzene synthesized in the same manner as in the Example, 448 g (2 mol) of 1,6-dibromohexane and 212 g (1.5 mol) of potassium carbonate anhydride. To the mixture was added 800 ml of acetone and the resulting mixture was suspended by stirring. The reaction system was heated until acetone was refluxed to react hydroxybenzene with bromoalkane. After the reaction was continued for 20 hours, insoluble salts were separated by filtration and removed. The system was concentrated to a volume of about ⅓ by using a rotary evaporator. When the system was cooled in a freezing chamber, 4-(6-bromohexyloxy)-4′-methylazobenzene was produced as a crystal. After the generated product was subjected to filtration, it was washed with a small amount of cool acetone, cool ether and n-hexane in this order and then dried under reduced pressure to obtain 38.1 g of crude 4-(6-bromohexyloxy)-4′-methylazobenzene (yield: 50.8%). The resulting product was recrystallized from ethanol to obtain 32 g (yield: 42%) of 4-(6-bromohexyloxy)-4′-methylazobenzene. It was found from an analysis using high performance liquid chromatography that the purity of the product was 98.6% or more.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:19][C:15]1[CH:16]=[CH:17][C:18]2[C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=3[CH2:11][O:12][C:13]=2[CH:14]=1
Reactant: O=C(O)c1cccc(F)c1COc1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C1c2ccc(F)cc2OCc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
A mixture of 7 g of 3-fluoro-2-[(3-fluorophenyloxy)methyl]benzoic acid and 50 g of thionyl chloride is refluxed with heating for 1 hour. After cooling to room temperature, dry toluene is added and the solvent is distilled off under reduced pressure. The residue is added with dichloromethane and the mixture is cooled to 0° C. Thereto 6 g of powdery anhydrous aluminum chloride is added and the mixture is stirred for 15 minutes and then added with ice-water, followed by extraction with toluene. After drying the extract over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is subjected to silica-gel chromatography and eluted with toluene to give 4.0 g of 3,7-difluoro-6,11-dihydrodibenz[b,e]oxepin-11-one (oil). Mass spectrum m/z: 246(M+).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]([C@H:8]1CCC[N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:3]([C@H:2]1[CH2:1][CH2:6][CH2:8][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH2:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.4 %

Procedure:
n-Butyl lithium (1.6 M in hexanes) (27 mL, 43 mmol) was added to ice-cold hexamethyldisilazane (9.2 mL, 44 mmol) under a nitrogen atmosphere. The solution was stirred for 10 min and was then added to a suspension of methyl(triphenylphosphonium)bromide (15.5 g, 43 mmol) in 100 mL of THF at ambient temperature. After stirring for 1 h, the mixture was cooled to −78° C. and a solution of tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate (7.9 g, 40 mmol) in 50 mL of THF was added. The cold bath was removed and the mixture stirred overnight at ambient temperature. The reaction mixture was then quenched with saturated NH4Cl, the phases were separated, and the organic phase was washed with saturated NH4Cl, brine, dried over Na2SO4, filtered, and concentrated to give an orange oil. The oil was purified on a Biotage 40M column eluting with heptane to give tert-butyl (2R)-2-vinylpyrrolidine-1-carboxylate (5.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[O:13][C:12]2[CH:14]=[C:15]([F:22])[C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:17][C:11]=2[O:10]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>C(OCC)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[O:13][C:12]2[CH:14]=[C:15]([F:22])[C:16]([S:18]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)(=[O:20])=[O:19])=[CH:17][C:11]=2[O:10]1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1cc2c(cc1F)OC(c1ccc(F)cc1F)(c1ccc(F)cc1F)O2
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cc2c(cc1F)OC(c1ccc(F)cc1F)(c1ccc(F)cc1F)O2)N1CCCC1
Yield: 73.7 %

Procedure:
To a solution of 2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl chloride (250 mg, 0.54 mmol) in diethylether (3 mL) was added pyrrolidine (0.11 mL, 1.35 mmol, 2.5 eq.). The reaction mixture was diluted with ethyl acetate (50 mL), washed with an aqueous solution of hydrochloric acid (IN), brine and water. The organic layer was dried over sodium sulfate and the volatiles were removed in vacuo. Purification by flash chromatography afforded the title compound (198 mg, 74%) as a white foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([CH3:18])[CH:11]=1.[CH2:19](Br)[CH:20]=[CH2:21]>CC(=O)CC>[CH2:21]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([CH3:18])[CH:11]=1)[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: Cc1cc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C=O)c(C)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
31.7 g (229 mmol) potassium carbonate and 9.51 g (57.3 mmol) potassium iodide were given to a solution of 15.6 g (115 mmol) 4-hydroxy-2-methyl-benzaldehyde and 55.4 g (458 mmol) allyl bromide in 500 ml 2-butanone and stirred for 16 h at 65° C. Solvents were distilled off and the residue distributed between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated and the aqueous solution extracted once with ethyl acetate. The combined organic phases were dried and evaporated to give 19.8 g (98%) of 4-allyloxy-2-methyl-benzaldehyde.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](Br)=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[N:18]=2)[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:11]1[CH:30]=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1I.[CH:52]1([O:55][C:56]2[CH:57]=[C:58](B3OC(C)(C)C(C)(C)O3)[CH:59]=[CH:60][C:61]=2[O:62][CH:63]([F:65])[F:64])[CH2:54][CH2:53]1.C1(B(O)O)C=CC=CC=1>>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([C:58]2[CH:59]=[CH:60][C:61]([O:62][CH:63]([F:65])[F:64])=[C:56]([O:55][CH:52]3[CH2:53][CH2:54]3)[CH:57]=2)=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[N:18]=2)[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:11]1[CH:30]=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cc2cccc(OC)n2)c(Br)n(COCc2ccccc2)c1C=O
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: C[Si](C)(C)CCOCn1c(Cl)c(I)c2c(=O)[nH]ncc21
Agent: OB(O)c1ccccc1
Product: CCOC(=O)c1c(Cc2cccc(OC)n2)c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c1C=O
Yield: 105.3 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 31 except for using 875 mg (1.80 mmol) of ethyl 1-benzyloxymethyl-5-bromo-2-formyl-4-(6-methoxy-2-pyridylmethyl)-1H-pyrrol-3-carboxylate obtained in Reference example 42-(b) in place of 2-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 880 mg (2.70 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in Reference example 1-(a) in place of phenylboronic acid, respectively, whereby 1.15 g of the title compound was obtained as a yellowish oil substantially quantitatively.