Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[N:29][C:30]([O:33]C)=[CH:31][CH:32]=7)=[C:24]([C:35]([NH:37][CH3:38])=[O:36])[C:23]=6[CH:39]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.Br.CC(O)=O>CC(O)=O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30](=[O:33])[NH:29][CH:28]=7)=[C:24]([C:35]([NH:37][CH3:38])=[O:36])[C:23]=6[CH:39]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(OC)nc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: Br
Solvent: CC(=O)O
Product: CNC(=O)c1c(-c2ccc(=O)[nH]c2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 5.1 %

Procedure:
To a solution of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(6-methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (40 mg, 0.64 mmol) in HOAc (4 mL) was added HBr—HOAc (4 ml) at 0° C. Then the mixture was stirred at 80° C. for 2 hours. After the solvent was removed by vacuum, the residue was washed with Na2CO3 (a.q.), extracted with DCM, dried over Na2SO4, filtrated and concentrated in vacuo. The residue was purified by prep-HPLC to give the product 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)-2-(6-oxo-1,6-dihydropyridin-3-yl)benzofuran-3-carboxamide (20 mg, yield: 50%). 1H-NMR (MeOD, 400 MHz) δ 8.33 (s, 1H), 7.96 (q, J=9.6 Hz, 1H), 7.84 (s, 1H), 7.88 (s, 1H), 7.55 (d, J=9.6 Hz, 2H), 7.28 (d, J=9.6 Hz, 1H), 7.15˜7.21 (m, 2H), 6.87 (q, J=9.6 Hz, 1H), 6.53 (t, J=9.6 Hz, 1H), 6.06 (s, 2H), 3.31 (s, 3H), 2.95 (d, J=9.6 Hz, 3H), 2.85 (s, 3H). MS (M+H)+: 614.
Reaction SMILES: [C:1]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:3][CH2:2][C:1]([N:5]([CH3:15])[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Product: CN(C(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from N-acryloyl-N-methyl-4-nitro-aniline and N-tert.butoxycarbonyl-piperazine
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:9]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)/[C:5]/1=[CH:30]/[C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=1)(=[O:3])[CH3:2].C(O)C.[H][H]>C(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:9]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:10]=2)[C@@H:5]1[CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1cc(/C=C2/c3cc(OCc4ccccc4)c(OCc4ccccc4)cc3CCN2C(C)=O)cc(OC)c1OC
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(C[C@H]2c3cc(OCc4ccccc4)c(OCc4ccccc4)cc3CCN2C(C)=O)cc(OC)c1OC
Yield: 92.1 %

Procedure:
In 1.5 ml of methylene chloride was dissolved 100.8 mg (0.178 mmol) of (Z)-N-acetyl-6,7-dibenzyloxy-1-(3,4,5-trimethoxyphenylmethylene)-1,2,3,4-tetrahydroisoquinoline, and 7.5 ml of ethanol was further added thereto. A separately prepared solution of 2.9 mg (1.7×10-3 mmol) of Ru2Cl4 ((S)-(-)-BINAP)2N(C2H5)3 in 1.5 ml of methylene chloride was added to the above prepared solution, and the mixture was transferred to an autoclave. The mixture was subjected to hydrogenation at 23° C. for 62 hours at a hydrogen pressure of 4 kg/cm2 while stirring. After completion of the reaction, the solvent was removed by distillation, and the residue was purified by silica gel column chromatography (silica gel: 15 g, eluent: ethyl acetate/hexane=3:1 by volume) to give 92.8 mg (0.164 mmol) of (S)-N-acetyl-6,7-dibenzyloxy-1-(3,4,5-trimethoxyphenylmethyl)-1,2,3,4-tetrahydroisoquinoline in a yield of 92%. The optical rotation [α]D24 of this product was +62.8° (c=0.92, CHCl3).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCCC1CCCCO1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:34][NH:35][O:36][CH3:37].C(N(CC)CC)C>CN(C=O)C.O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:35]([O:36][CH3:37])[CH3:34])=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.7 %

Procedure:
3-Iodobenzoic acid (3.01 g, 12.1 mmol) was dissolved in DMF (30 mL), and HOBt.H2O (2.45 g, 18.1 mmol), WSC.HCl (3.02 g, 15.8 mmol), N,O-dimethylhydroxylamine hydrochloride (1.30 g, 13.3 mmol), and triethylamine (1.86 mL, 14.6 mmol) were added thereto, and then, the mixture was stirred at room temperature for 4 hours. Water (60 mL) was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and then, dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (ethyl acetate/n-heptane=100/0 to 50/50) to give 3-iodo-N-methoxy-N-methylbenzamide (3.23 g, yield: 82%).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].CO>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:1]1([N:7]2[CH:11]=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:16][CH:17]=3)[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=C(c2cn(-c3ccccc3)nn2)CCNC1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)OC(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[1-phenyl-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetra-hydropyridine (35 mg) prepared in the above 1) was dissolved in 1 ml of pyridine and 1 ml of chloroform, 32 μl of isopropyl chloroformate was added and the mixture was stirred at room temperature for 1 hour. After an excessive reagent was decomposed by addition of methanol, the reaction solution was concentrated in vacuo and the resulting residue was separated and purified by a preparative thin-layer chromatography (chloroform/methanol 60/1) to give 47 mg of the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:18])([F:17])[C:9](=O)[CH2:10][C:11]([O:13]CC)=O.C(O)(=O)C(O)=O.[CH2:25]([NH:27][NH2:28])[CH3:26]>C(O)C>[CH2:25]([N:27]1[C:11]([OH:13])=[CH:10][C:9]([C:8]([F:7])([F:17])[F:18])=[N:28]1)[CH3:26]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CCNN
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1nc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 45.0 g of potassium carbonate and 50.0 g (272 mmol) of ethyl 4,4,4-trifluoroacetoacetate in 300 mL of ethanol was cooled with a salt/ice bath to about 0° C. and to this ethylhydrazine oxalate (44.9 g, 299 mmol) was added with a spatula with stirring. After 45 min (minutes) at about 0° C., the mixture was allowed to warm to ambient temperature and stir for 1 hour. It was then heated to reflux overnights The mixture was concentrated by evaporation under reduced pressure and the residue was diluted with dichloromethane and water. The product only partially dissolved and seemed to be distributed in both phases. The layers were separated and the aqueous layer was extracted with dichloromethane and filtered. The solids obtained on filtration were extracted with dichloromethane. The dichloromethane layers and extracts were combined, washed with water (2×200 mL), and dried and the volatiles were allowed to evaporate overnight. All of the solids were combined to obtain the title compound.
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:21]=[C:22]([O:29][CH3:30])[C:23]([C:26]([OH:28])=O)=[N:24][CH:25]=2)=[O:19])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH2:37])[CH3:33].C(OC(C)C)(C)C>>[CH2:32]([O:34][C:35]([CH2:36][NH:37][C:26]([C:23]1[C:22]([O:29][CH3:30])=[CH:21][C:20]([C:18]([NH:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:16][CH:15]=2)=[O:19])=[CH:25][N:24]=1)=[O:28])=[O:38])[CH3:33]
Reactant: CCOC(=O)CN
Reactant: CCCCCCCCCCc1ccc(NC(=O)c2cnc(C(=O)O)c(OC)c2)cc1
Agent: Cl
Solvent: CC(C)OC(C)C
Product: CCCCCCCCCCc1ccc(NC(=O)c2cnc(C(=O)NCC(=O)OCC)c(OC)c2)cc1

Procedure:
5-(((4-n-Decylphenyl)amino)carbonyl)-3-methoxypyridine-2-carboxylic acid N-(ethoxycarbonylmethyl)amide was prepared from 5-(((-4-n-decylphenyl)amino)carbonyl)-3-methoxypyridine-2-carboxylic acid (m.p. 160° C., decomp.; from aqueous hydrochloric acid/THF) and glycine ethyl ester hydrochloride, m.p. 155°-157° C. (from diisopropyl ether).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16].[Cl:17][C:18]1[CH:37]=[CH:36][CH:35]=[CH:34][C:19]=1[C:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[Cl:17][C:18]1[CH:37]=[CH:36][CH:35]=[CH:34][C:19]=1[C:20]([NH:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Reactant: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](CNC(c3ccccc3)(c3ccccc3)c3ccccc3Cl)O2)c(=O)[nH]1
Temperature: 40 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
5′-Amino-2′,5′-dideoxyuridine (0.237 g, 1.04 mmol) was reacted with 2-chlorotrityl chloride (0.415 g, 1.33 mmol) in dry pyridine (5 mL) at 40° C. for 24 h. A second portion of 2-chlorotrityl chloride (0.198 g, 0.63 mmol) was added. After a further 2 h stirring at 40° C., the reaction was quenched with MeOH (2 mL). The reaction mixture was concentrated in vacuo and purified by flash column chromatography using an ISOLUTE Si column eluted with a gradient of 0→5% CH3OH in CHCl3. The fractions with Rf=0.17 (10% CH3OH/CHCl3) yielded the title compound as a white solid (85 mg, 16%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[CH:8]=2)[N:3]=1.O.[NH2:23][NH2:24]>>[N+:19]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:23][NH2:24])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)cc(-c3ccccc3Cl)c2c1
Reactant: NN
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-6-nitro-4-(o-chlorophenyl)quinoline is reacted at reflux with hydrazine hydrate to give 6-nitro-4-(o-chlorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([C:14](O)=[O:15])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Solvent: CO
Product: OCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Temperature: 5 °C

Procedure:
1-(3,4-Dichloro-phenyl)-1H-imidazole-4-carboxylic acid (20.0 g, 77.8 mmol) was treated with 1M BH3 THF complex (100 ml) and refluxed for 2 h. The mixture was cooled to 5° C. and MeOH (20 ml) was added slowly. After evaporation of all volatiles the residue was taken up in 2N HCl solution (100 ml) and refluxed for 2 h. After filtration the hot aqueous phase was slowly treated with 2N NaOH solution until pH 10. On cooling the title compound crystallizes as a white material (12.2 g, 65%). Mp. 146-147° C. (H2O), MS: m/e=242 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=O)[CH2:15][O:14][CH-]2)=[CH:8][C:7]=1[N+:18]([O-:20])=[O:19].[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:16][CH2:15][OH:14])=[CH:8][C:7]=1[N+:18]([O-:20])=[O:19]
Reactant: COCCNc1ccc(N2[CH-]OCC2=O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCNc1ccc(NCCO)cc1[N+](=O)[O-]

Procedure:
0.02 mole (5.6 g) of N-[4-(β-methoxyethyl)amino-3-nitrophenyl]oxazolidone, prepared according to Example 7, is added to 13.5 ml of 3N sodium hydroxide and 5.6 ml of 96° strength ethanol.
Reaction SMILES: [F:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][NH:27]C(=O)OC(C)(C)C)[CH2:22][CH2:21]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O>[NH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:20]([C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]4)[N:4]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Yield: 67.5 %

Procedure:
A solution of tert-butyl (1-(5-fluoro-2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (55 mg, 0.12 mmol) in TFA (3 mL) was stirred at room temperature for 60 min. TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (30 mg) MS 371.3 (M+H); UV 206.8, 274.8 nm.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[CH3:12][O:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14](=[O:35])/[CH:15]=[C:4]1/[O:6][C:1](=[O:11])[C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:3]/1=2
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C1/OC(=O)C2=C1CCCC2
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A solution of 3,4,5,6-tetrahydrophthalic acid anhydride (3.04 g) and (triphenylphosphoranylidene)acetic acid methyl ester (6.69 g) in chloroform (50.0 mL) was refluxed for 3 hours. After cooling the reaction mixture to room temperature, it was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9→3:7) to give the title compound (1.93 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[C:4]([O:13][CH2:14][CH3:15])[CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:13][CH2:14][CH3:15])[CH:3]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 114 %

Procedure:
0.2 g of ethyl 4-chloro-2-ethoxybenzoate was dissolved in 5 ml methanol, and 2 ml of 1N sodium hydroxide was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was ice-cooled and neutralized with 1N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated, to give 0.20 g of 4-chloro-2-ethoxybenzoic acid.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[S:5][C:6]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].O.C(=O)(O)[O-].[Na+]>CC(C)C(O)=O>[CH3:4][CH:8]([CH3:9])[CH2:7][NH:3][C:4]1[S:5][C:6]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc(Cc2cccc3ccccc23)sc1N
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)C(=O)O
Product: CCOC(=O)c1cc(Cc2cccc3ccccc23)sc1NCC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 191 %

Procedure:
Sodium borohydride (1.3 g) was added in 10 portions over 5 hours to a stirred solution of ethyl 2-amino-5-(1-naphthalenylmethyl)-3-thiophenecarboxylate (5.50 g) in 2-methylpropanoic acid (40 ml) at 0° C. The mixture was stirred at room temperature for 16 hours then further sodium borohydride (1.8 g) was added in 10 portions over 8 hours and stirring continued for a further 16 hours. The solution was poured into water (1000 ml), neutralized with sodium bicarbonate and extracted with ethyl acetate (2×500 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ether:hexane (1:3) to give the subtitle compound (6.20 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: ClCCN1CCCCC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a solution of 4-hydroxybenzoic acid ethyl ester (5.0 g) in N,N-dimethylformamide (50 ml) were sequentially added potassium carbonate (6.2 g) and 1-(2-chloroethyl)piperidine (8.3 g), and the solution was stirred for 1.5 hours at 60° C. The solution was filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to obtain 4-(2-piperidin-1-ylethoxy)benzoic acid ethyl ester (8.3 g). To a solution of 4-(2-piperidin-1-ylethoxy)benzoic acid ethyl ester (34g) dissolved in ethanol (200 ml) was added an aqueous solution of 2N sodium hydroxide (100 ml), and the solution was refluxed for 1 hour. Ethanol was evaporated in vacuo, water was added and stirred, the solid that was precipitated by adding 2N hydrochloric acid (180 ml) was filtered to provide the title compound (28.2 g).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 36 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.60 min, m/z=459.0 [M+H]+, m/z=457.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.73 (dd, J=8.07, 3.91 Hz, 1H) 1.77-1.89 (m, 1H) 2.55 (s, 3H) 2.88 (d, J=11.74 Hz, 1H) 3.17-3.27 (m, 2H) 3.42 (br. s, 1H) 4.19 (br. s, 1H) 4.84 (br. s, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.39 (d, J=7.83 Hz, 1H) 7.75 (dd, J=7.95, 1.83 Hz, 1H) 7.85 (d, 2H) 8.00 (d, J=2.45 Hz, 1H) 8.52 (d, J=1.96 Hz, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](N(OC)C)=[O:14])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]=CN(C)C)=[CH:21][CH:20]=3)[CH:9]=2)=[CH:4][CH:3]=1.[CH2:33]1COC[CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:14])[CH2:33][CH3:34])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:26])(=[O:31])=[O:32])=[CH:21][CH:20]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Product: CCC(=O)c1sc(-c2ccc(Cl)cc2)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Yield: 14.6 %

Procedure:
Grignard reagent (ethyl magnesium bromide, 0.67 g, 5.0 ml 1M solution in THF, 5.08 mmol) was added drop wise to a stirred solution of 5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-N-methylthiophene-2-carboxamide (compound 33d, 0.5 g, 1.01 mmol) in anhydrous THF (15 ml) at 25° C. The reaction mixture was then heated to about 70 to about 75° C. for 2 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., the reaction mixture was quenched by addition of a saturated solution of ammonium chloride (10 ml). The mixture so obtained was extracted with ethyl acetate (2×30 ml). the combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.06 g, 14.6%).