Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][NH:9][CH2:8][CH2:7][CH:6]=1)=[O:4].Cl.[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20](Cl)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH2:10][N:9]([CH:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=3)[CH2:8][CH2:7][CH:6]=1)=[O:4]
Reactant: ClC1c2ccccc2CCc2ccccc21
Reactant: COC(=O)C1=CCCNC1
Agent: Cl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C1=CCCN(C2c3ccccc3CCc3ccccc32)C1
Temperature: 90 °C
Yield: 44 %

Procedure:
To 7.338 g (41.31 mol) of guvacoline hydrochloride (Arzneim. Forsch. 1989, 39(5), 539. ) in dioxane (100 ml) was added 5-chloro-dibenzosuberane (14.933 g, 65.39 mmol), Nal (catalytic, ˜1 g), and triethylamine (17 mL, 122.0 mmol) to give a brown heterogeneous slurry that was heated at 90° C. overnight. The solvent was then concentrated and the resultant sludge was taken up in ethyl acetate and sequentially washed with Na2HPO4 buffer (pH 4), Na2CO3 (saturated aqueous), and brine. The organics were then dried over Na2SO4 and concentrated, resulting in a brown solid which was purified by chromatography on silica gel eluting with 1-5% ethyl acetate/hexanes to give 1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester as a white solid (9.584 g, 28.74 mmol, 67%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.22 (dt, J=9.28, 2.68 Hz, 2H) 2.41 (t, J=5.56 Hz, 2H) 2.73-2.83 (m, 2H) 2.99-3.05 (m, 2H) 3.65 (s, 3 H) 3.90-4.00 (m, 2H) 4.11 (s, 1H) 6.94-6.99 (m, J=3.98, 3.98, 1.89, 1.77 Hz, 1 H) 7.05-7.11 (m, 4H) 7.13-7.21 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[C:16]([Cl:19])([Cl:18])=[CH2:17].Cl>C(Cl)Cl>[Cl:18][C:16]([Cl:19])=[CH:17][C:4]([C:3]1[C:2]([Cl:1])=[N:10][C:9]([Cl:11])=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Reactant: C=C(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
A solution of the 2,6-dichloro-nicotinoyl chloride (1.0 g, 4.76 mmol) from the previous reaction in CH2Cl2 (5 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (0.64 g, 4.76 mmol) in CH2Cl2 (20 mL). After 15 min, vinylidene chloride (0.38 mL, 0.46 g, 4.76 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was then poured over ice and was acidified using 1 N HCl (15 mL). Stirring was continued for 20 min and the product was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give 3,3-dichloro-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one (0.88 g, 68% ) as a light yellow oil: 1H-NMR (CDCl3, 300 MHz) δ8.38, d, J=8.4, 1H). 7.40 (d, J=8.4, 1H), 7.10 (s, 1H); Rf=0.5 (4:1 Hex:EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[C:21](=[O:23])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: CCNCc1cccc(C)n1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2([OH:62])[CH2:61][CH2:60][NH:59][CH2:58]2)=[CH:53][C:52]=1[CH3:63]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:59]3[CH2:60][CH2:61][C:57]([C:54]4[CH:55]=[CH:56][C:51]([F:50])=[C:52]([CH3:63])[CH:53]=4)([OH:62])[CH2:58]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cc1cc(C2(O)CCNC2)ccc1F
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(F)c(C)c3)C2)cc1Cl
Yield: 40.6 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(4-fluoro-3-methylphenyl)pyrrolidin-3-ol hydrochloride (9 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (7 mg). MS (ESI, pos. ion) m/z: calcd for C22H20ClFN2O4: 430.1096, found 430.1094.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=O)(C)(C)C.C(N(CC)CC)C.[O:29]1[C:34]2[CH:35]=[CH:36][C:37]([C:39](Cl)=[O:40])=[CH:38][C:33]=2[O:32][CH2:31][CH2:30]1>ClCCl>[S:19]1[CH2:20][CH2:21][N:17]([C:15]([C@H:9]2[NH:8][CH2:12][C@@H:11]([CH2:13][NH:14][C:39]([C:37]3[CH:36]=[CH:35][C:34]4[O:29][CH2:30][CH2:31][O:32][C:33]=4[CH:38]=3)=[O:40])[CH2:10]2)=[O:16])[CH2:18]1
Reactant: O=C(Cl)c1ccc2c(c1)OCCO2
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC[C@@H]1CN[C@H](C(=O)N2CCSC2)C1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 17D (31.6 mg, 0.1 mmol) in anhydrous dichloromethane (1 mL) was added triethylamine (0.021 mL, 0.15 mmol) followed by 2,3-dihydro-1,4-benzodioxine-6-carbonyl chloride (23.8 mg, 0.12 mmol). The mixture was shaken overnight at room temperature and concentrated under reduced pressure, MS (APCI) m/e 472 (M+H)+. The residue was dissolved in anhydrous dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was added. The mixture was allowed to stir for 5 hours at room temperature, concentrated under reduced pressure, and the residue purified by reverse-phase HPLC to provide the titled compound. MS (ESI) m/e 372 (M+H)+; 1H NMR (500 MHz, CD3OD): δ ppm 1.75-2.4 (m, 1 H), 2.74 (m, 2 H), 3.15 (m, 3 H), 3.33 (m, 1 H), 3.47 (m, 3 H), 3.75 (m, 1 H), 3.87 (m, 1 H), 4.28 (m, 4 H), 4.51 (m, 1H), 4.66 (m, 2 H), 6.90 (dd, 1 H), 7.33 (m, 2 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[C:29]([Cl:30])=[CH:28][C:12]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH2:25])[CH2:18][C@H:17]2[O:26][CH3:27])=[O:14])=[C:11]([O:31][CH3:32])[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[NH2:8][C:9]1[C:29]([Cl:30])=[CH:28][C:12]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH:25][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:18][C@H:17]2[O:26][CH3:27])=[O:14])=[C:11]([O:31][CH3:32])[CH:10]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN)C[C@H]1OC
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCNc2ncccn2)C[C@H]1OC
Temperature: 90 °C
Reaction time: 6.5 h
Yield: 35 %

Procedure:
A mixture of 1.17 parts of 2-chloropyrimidine, 5.56 parts of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide and 2.7 parts of N,N-dimethylacetamide was stirred for 6.5 hours at 90° C. After cooling, a sodium carbonate solution was added. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.4 parts (35%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[3-(2-pyrimidinylamino)propyl]-4-piperidinyl]benzamide; mp. 158.5° C. (compound 36).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:29]=[C:28]([C:27]2[CH:30]=[CH:31][C:24]([CH3:23])=[C:25]([O:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:35][N:34]=3)[CH:26]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2ccccc2Cl)cc1
Reactant: Cc1ccc(C#N)cc1Oc1ccc(C(F)(F)F)cn1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc(-c3ccccc3Cl)nn2C)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-benzohydrazonoyl chloride (1.1 g), 4-methyl-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.00 g), anhydrous iron (III) chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.50 g of desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH2:20])[CH2:15]1)=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2.C(N(CC)CC)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38]([S:41](Cl)(=[O:43])=[O:42])[CH:39]=[CH:40][C:34]=2[S:33][CH2:32]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][S:41]([C:38]3[CH:39]=[CH:40][C:34]4[S:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=4[CH:37]=3)(=[O:43])=[O:42])[CH2:15]1)=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2
Reactant: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Reactant: COc1ccc2ncc(F)c(CCN3CC[C@H](CN)C3)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(F)c(CCN3CC[C@H](CNS(=O)(=O)c4ccc5c(c4)NC(=O)CS5)C3)c2n1
Reaction time: 24 h
Yield: 91.2 %

Procedure:
To a stirred solution of [((3R)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.50 g, 1.65 mmole) in dry CH2Cl2 (25 mL) at RT was added triethylamine (0.34 mL, 2.48 mmole) and 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-sulfonyl chloride (0.47 g, 1.80 mmole). After 24 h, the reaction solution was concentrated under vacuum. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.80 g, 91%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 7.34 (m, 3H), 7.03 (d, J=9.0 Hz, 1H), 4.04 (s, 3H), 3.47 (s, 2H), 3.34 (m, 2H), 2.95 (m, 3H), 2.79 (m, 2H), 2.61 (m, 1H), 2.52 (m, 2H), 2.34 (m, 1H), 1.97 (m, 1H), 1.55 (m, 1H). LC-MS (ES) m/e 532 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[C:25]([O:24][C@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@@H:10]1[S:35][C:32]1[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=1)(=[O:27])[CH3:26]
Reactant: Cc1ccc(S)cc1
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C=O)OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@H](Sc2ccc(C)cc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a mixture of D-mannose pentaacetate (16.0 g, 0.041 mol) and p-thiocresol (7.6 g, 0.0615 mol) in CH2Cl2 (200 mL), boron trifluoride diethyl etherate (6.8 mL, 0.0533 mol) was added. The mixture was stirred overnight. The reaction mixture was then diluted with CH2Cl2 (200 mL), washed with sat. NaHCO3 (2×120 mL) and water (100 mL). The organic layer was dried over Na2SO4. The solvent was removed, and the residue was purified by column chromotography on silia gel (hexanes/EtOAc 3:1) to give product (16.2 g, 87%) as a syrup: 1HNMR (500 MHz, CDCl3), δ 7.38 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 5.49 (dd, 1H, J=2.5, 1.5 Hz), 5.42 (d, 1H, J=1.0 Hz), 5.30–5.35 (m, 2H), 4.54–4.58 (m, 1H), 4.30 (dd, 1H, J=12.5, 6.0 Hz), 4.11 (dd, 1H, J=12.0, 2.5 Hz), 2.33 (s, 3H), 2.15 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H); HRMS (M+Cs) calcd for C21H26O9SCs 587.0352. found 587.0331.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[N:11]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([N:36]([CH3:38])[CH3:37])=[N:34][CH:35]=3)=[CH:26][CH:25]=2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>C1COCC1.[Pt](=O)=O>[CH3:37][N:36]([CH3:38])[C:33]1[N:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][C:24]([N:11]3[CH:12]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[CH2:13][CH2:14][CH:10]3[C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)=[CH:29][CH:28]=2)=[CH:31][CH:32]=1
Reactant: CN(C)c1ccc(-c2ccc(N3C(c4ccc([N+](=O)[O-])cc4)CCC3c3ccc([N+](=O)[O-])cc3)cc2)cn1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)c1ccc(-c2ccc(N3C(c4ccc(N)cc4)CCC3c3ccc(N)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
The product from Example 99A (26.8 mg, 0.053 mmole) was dissolved in THF (526 L) in a round bottom flask to which was subsequently added ethanol (526 L) resulting in a yellow precipitate. To this suspension was added platinum (IV) oxide (3.16 mg, 0.014 mmole). The flask was capped with a septum and the contents vacuum degassed three times. Hydrogen was introduced via a balloon and the mixture allowed to stir at room temperature for two and one half hours. The reaction mixture was vacuum filtered through a sand and celite plug, which was rinsed with THF and methanol until the filtrate was u.v.(−). The filtrate was concentrated in vacuo to provide the title compound in quantitative yield as a white solid as a mixture of stereoisomers. MS ESI(+), m/z@450.7 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[S:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)=[O:14])[S:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(=O)O)sc1C(C)C
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1
Yield: 86.3 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylthiophene-2-carboxylic acid (86 mg, 0.406 mmol) was condensed with methyl 4-aminobenzoate (123 mg, 0.815 mmol), and the resultant was purified by silica gel chromatography [hexane-ethyl acetate (3:1)] to obtain methyl 4-[(4,5-diisopropylthiophene-2-carbonyl)amino]benzoate (121 mg, 86%) as colorless needles.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].O>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]2[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]=1[CH2:2][N:20]1[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]2[C:16]1=[O:26]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc2c([N+](=O)[O-])cccc2c1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
A mixture of 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (410 mg) and potassium phthalimide (506 mg) in N,N-dimethylformamide (10 ml) was stirred at ambient temperature for 3 hours. Then, the mixture was poured into cold water and the separated solid was collected, washed with water and dried to give 2-methyl-7-nitro-3-phthalimidomethylbenzo[b]furan (585 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2O)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79 %

Procedure:
To a 0° C. solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 332, (6.79 g, 16 mmol) in pyridine (160 mL) was added p-toluenesulfonyl chloride (3.06 g, 16 mmol). The solution was left to warm slowly to room temperature with stirring under nitrogen. After 2.5 hours, the mixture was poured into H2O with constant stirring. The resulting off-white solid was filtered, rinsed with H2O and dried to provide the desired product (yield: 6.26 g, 79%). mp 198-200° C. 1H NMR (300 MHz, DMSO d6) δ 2.35 (s, 3H), 3.28 (s, 3H), 7.20 (m, 2H), 7.52-7.64 (M, 5H), 7.70 (m, 3H), 7.89 (m, 2H), 8.32 (s, 1H). MS APCI+ 531 (M+H)+, 548 (M+H2O)+, APCI−493 (M+35)−. Anal. calc. for C24H19ClN2O6S2: C, 54.29; H, 3.61; N, 5.28. Found: C, 54.55; H, 3.46; N, 5.57.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)(O)[CH2:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccncc2)CCC2(CCN(Cc3ccccc3)C2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C1=C(c2ccncc2)CCC2(C1)CCN(Cc1ccccc1)C2
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of 2-benzyl-8-(pyridin-4-yl)-2-azaspiro[4.5]decan-8-ol (500 mg, 1.55 mmol, 1.0 eq.) (see step-7 product AMN-39) in pyridine (5 ml) was added dropwise SOCl2 (1 ml) at −10° C. and the reaction mixture was stirred at the same temperature for 10 min. After completion of the reaction (monitored by TLC), the reaction mixture was poured onto (50 g) and sat. NaHCO3 solution (10 ml) was added. The mixture was extracted with methylene chloride (50 ml). The organic layer was washed with brine (30 ml) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 2% MeOH/DCM) to yield the desired compound as a yellow semisold. Yield: 63% (300 mg, 0.987 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[S-:6].[Na+].[CH3:11][O:12][N:13]=[C:14]([C:20](=[O:23])[CH2:21]Br)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C.C(OCC)(=O)C>[CH3:11][O:12][N:13]=[C:14]([C:20](=[O:23])[CH2:21][S:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COc1cccc([S-])c1
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(=NOC)C(=O)CSc1cccc(OC)c1
Temperature: 25 °C

Procedure:
To a stirred solution of sodium 3-methoxythiophenoxide in 150 ml of ethanol (prepared by reacting 14 g of 3-methoxythiophenol with 5.94 g of sodium methoxide) were added dropwise over ten minutes 27.7 g of ethyl 2-methoxyimino-3-oxo-4-bromobutyrate. The reaction mixture was stirred at 25° C. for sixteen hours, and then the solvent was removed by evaporation under reduced pressure to give an oil. The oil was dissolved in ethyl acetate and washed several times with water. The organic layer was dried and the solvent was removed by evaporation to afford 16.28 g of ethyl 2-methoxyimino-3-oxo-4-(3-methoxyphenylthio)butyrate. NMR (CDCl3): δ1.32 (t, 3H); δ3.79 (s, 3H); δ4.05 (s, 3H), δ4.34 (q, 2H); δ6.7-7.3 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][CH:16]=[CH:15][C:14]=3[C:18]=2[OH:19])=[O:9])=[CH:4][CH:3]=1.[Cl-].[CH2:23]=[N+:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:15][C:14]=3[C:18]=2[OH:19])=[O:9])=[CH:20][CH:21]=1
Reactant: C=[N+]1CCOCC1
Reactant: O=C(NCc1ccc(Cl)cc1)c1ccc2sccc2c1O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(NCc1ccc(Cl)cc1)c1ccc2sc(CN3CCOCC3)cc2c1O
Yield: 71.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-4-hydroxy-1-benzothiophene-5-carboxamide (Preparation 14, 0.15 g), 4-methylenemorpholin-4-ium chloride (0.13 g), and anhydrous acetonitrile (5 mL) is heated at reflux for 2 hours. Upon cooling, a saturated solution of sodium bicarbonate is added until the pH=9 and this solution is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give a pink oil. Chromatography on a Biotage column eluting with 20% ethyl acetate in heptane (250 mL) and 50% ethyl acetate in heptane (500 mL) affords 140 mg (76%) of the title compound as a white solid. Physical characteristics: Mp 200° C.; MS (ESI+) for C21H21ClN2O3S m/z 417 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4C[CH2:23]4)=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:25])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(COC3C(C=C)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.C([CH:52]1[CH2:55][N:54]([S:56]([NH2:59])(=[O:58])=[O:57])[CH2:53]1)#N.N1(S(N)(=O)=O)CCC1>>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]=[CH2:23])=[CH:20][C:16]([C:17]([NH:59][S:56]([N:54]4[CH2:55][CH2:52][CH2:53]4)(=[O:58])=[O:57])=[O:19])=[C:15]([F:25])[CH:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: N#CC1CN(S(N)(=O)=O)C1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: C=Cc1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Agent: NS(=O)(=O)N1CCC1
Product: C=Cc1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2

Procedure:
Following the procedure as described in Example 230 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-2-fluoro-5-vinylbenzoic acid and 3-cyanoazetidine-1-sulfonamide with azetidine-1-sulfonamide, the title compound was obtained as colorless solid (0.13 g, 36%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.04 (d, J=12.9 Hz, 1H), 6.91 (dd, J=11.3 Hz, 17.8 Hz, 1H), 5.93 (dd, J=1.0 Hz, 17.8 Hz, 1H), 5.37 (dd, J=1.0 Hz, 11.3 Hz, 1H), 4.06 (t, J=7.7 Hz, 4H), 3.67 (s, 2H), 2.23-2.12 (m, 2H), 2.00-1.99 (m, 3H), 1.75-1.64 (m, 12H); MS (ES+) m/z 449.1 (M+1); MS (ES−) m/z 447.3 (M−1).