Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(O)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2,6-dihydroxyphenyl)-ethanone (304 mg, 2 mmol) and benzyl bromide (0.255 mL, 2.1 mmol) in DMF (10 mL) is added K2CO3 (552 mg; 4 mmol) and the mixture is stirred at RT for 18 h. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (10:1) as eluent to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:12][NH:13][O:14][CH3:15].CCN(CC)CC.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:7]
Reactant: CNOC
Reactant: COc1ncccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncccc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a cooled mixture of 2-methoxy-nicotinic acid (2 g, 13.05 mmol), N,O-dimethylhydroxylamine (1.91 g, 19.59 mmol) in CH2Cl2 (20 mL) and Et3N (7.26 mL, 15.66 mmol) was added 1-propane phosphonic acid cyclic anhydride (9.96 mL, 15.66 mmol; 50 wt % solution in EtOAc) dropwise and stirred at room temperature for 2 h. The reaction mixture was filtered, washed with CH2Cl2 (10 mL), evaporated to dryness and subjected to column chromatography (SiO2, 50% EtOAc-hexanes) to obtain 2,N-dimethoxy-N-methyl-nicotinamide (2.33 g) in 91% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[S:16][C:17]([CH:20]2[S:25][CH2:24][CH2:23][CH2:22][S:21]2)=[N:18][N:19]=1>C1(C)C=CC=CC=1>[S:21]1[CH2:22][CH2:23][CH2:24][S:25][CH:20]1[C:17]1[S:16][C:15]([NH:14][C:5](=[O:6])[C:4]2[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=2[O:12][CH3:13])=[N:19][N:18]=1
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: Nc1nnc(C2SCCCS2)s1
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)Nc1nnc(C2SCCCS2)s1
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of 1.0 g. of 2,6-dimethoxybenzoyl chloride and 1.1 g of 2-amino-5-(1,3-dithian-2-yl)-1,3,4-thiadiazole in 20 ml of toluene was heated at reflux for eighteen hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and the solvent was removed by evaporation under reduced pressure to provide a white solid. The solid was chromatographed over silica gel to provide 1.2 g (60% yield) of N-[5-(1,3-dithian-2-yl)-1,3,4-thiadiazol-2yl]-2,6-dimethoxybenzamide.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)=[CH:54][C:55]4[N:56]([CH3:64])[C:57](=[O:63])[N:58]([CH3:62])[CH2:59][C:60]=4[N:61]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:47]=[CH:48][C:49]([C:52]3[C:53]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)=[CH:54][C:55]4[N:56]([CH3:64])[C:57](=[O:63])[N:58]([CH3:62])[CH2:59][C:60]=4[N:61]=3)=[CH:50][CH:51]=2)[CH2:43][CH2:44][CH2:45]1
Reactant: CN1Cc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: CN1Cc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Yield: 117.1 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(1,3-dimethyl-2-oxo-7-phenyl-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-6-yl)phenyl)cyclobutyl)carbamate (30 mg, 0.06 mmol) was reacted to afford the title compound (28 mg, 91%). LCMS (Method D): R1=0.798 min, M-NH2=382. 1H NMR (500 MHz, MeOD): 7.45-7.39 (4H, m), 7.34 (1H, s), 7.32-7.30 (3H, m), 7.26-7.24 (2H, m), 4.67 (2H, s), 3.36 (3H, s), 3.11 (3H, s), 2.81-2.75 (2H, m), 2.63-2.57 (2H, m), 2.26-2.24 (1H, m), 1.99-1.97 (1H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([N:23]=[N+:24]=[N-:25])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([N:23]2[C:1]([C:3]3[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=3)=[CH:2][N:25]=[N:24]2)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]
Reactant: COc1cc(N=[N+]=[N-])cc(OC)c1OC
Reactant: C#Cc1ccc(OC)cc1
Product: COc1ccc(-c2cnnn2-c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 80 °C

Procedure:
To a scintillation vial was added 4-ethynyl anisole (660 mg.; 5 mmol) and 3,4,5-trimethoxyphenyl azide (1.05 g.; 5 mmol) and the mixture was heated at 80° C. for 24 hours. The crude mixture was purified by column chromatography to give 1-(3,4,5-trimethoxy-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:31]#[C:30][CH2:29][OH:32]
Reactant: C#CCO
Reactant: Clc1ccc(Cl)c(I)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: OCC#Cc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A mixture of 2,5-dichloroiodobenzene (5.00 g), copper(I) iodide (69.8 mg), triphenylphosphine (240 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (378 mg), propargyl alcohol (1.19 ml), diisopropylethylamine (12.8 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 25 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the object product (3.38 g) as a brown solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH3:14][CH:15]([CH3:38])[CH:16]([NH:21][C:22]([C:24]1[S:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=2)[N:28]=1)=[O:23])[C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17](=[O:18])[CH:16]([NH:21][C:22]([C:24]1[S:25][CH:26]=[C:27]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:2]([NH:1][C:4]3[CH:5]=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=3)=[O:3])=[CH:33][CH:34]=2)[N:28]=1)=[O:23])[CH:15]([CH3:38])[CH3:14]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)cc2)cs1)C(C)C
Yield: 79 %

Procedure:
The title compound was synthesized analogous to Example 23, using 1-isocyanato-4-(trifluoromethyl)benzene and intermediate 3. Yield: 79%; 1H NMR (DMSO-d6, 300 MHz): δ 9.14 (s, 1H), 8.99 (s, 1H), 8.80 (d, 1H), 8.32 (s, 1H), 8.06 (d, 2H), 7.66 (bs, 4H), 7.61 (d, 2H), 4.37 (s, 1H), 3.70 (s, 3H), 2.32 (m, 1H), 0.97 (s, 6H).
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(=O)=O.[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:8]([CH:7]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][C:22]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:5][CH2:6]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)CCC#Cc1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C(#Cc1ccccc1)CCN1CCC(Cc2ccccc2)CC1
Yield: 37.9 %

Procedure:
A mixture of 1-mesyl-4-phenylbut-3-yne (200 mg, 0.87 mmol), 4-benzylpiperidine (175 mg, 1.00 mmol) and K2CO3 (368 mg, 2.67 mmol) in CH3CN (10 mL) is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as an oil (100 mg, 38%): 1H NMR (CDCl3) 1.45 (m, 2 H), 1.52 (m, 1 H), 1.65 (m, 2 H), 2.05 (t, J=6.6 Hz, 2 H), 2.54 (m, 2 H), 2.68 (m, 4 H), 2.97 (d, J=11 Hz, 2 H), 7.13-7.36 (m, 10 H).
Reaction SMILES: C([N:8]1[C:13]2[N:14]([CH3:29])[C:15](=[O:28])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[C:17](=[O:18])[C:12]=2[C:11](=[O:30])[CH:10]=[C:9]1[CH3:31])C1C=CC=CC=1.[H][H]>[Pd].C(O)(=O)C>[CH3:29][N:14]1[C:13]2[NH:8][C:9]([CH3:31])=[CH:10][C:11](=[O:30])[C:12]=2[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[C:15]1=[O:28]
Reactant: [H][H]
Reactant: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)N(C)C)c(=O)n(C)c2n1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)N(C)C)c(=O)n(C)c2[nH]1
Yield: 117.4 %

Procedure:
A mixture of (R)-8-benzyl-1,7-dimethyl-3-(5-(N,N-dimethylamino)hexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (80 mg), acetic acid (10 ml) and 10% Pd/C (20 mg) was treated with hydrogen gas (50 psi) on a Parr shaker for 18 hours. The mixture was filtered through a pad of celite and the solids were rinsed with acetic acid. The combined filtrates were concentrated under reduced pressure and then coevaporated with toluene (2×50 ml) to remove remaining acetic acid to provide (R)-1,7-dimethyl-3-(5-(N,N-dimethylamino)hexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (74 mg, 99% yield) as a beige powder. 1H NMR (300 MHz, CDCl3) δ 1.15 (d, 3H), 1.20-1.50 (m, 3H), 1.52-2.00 (m, 3H), 1.97 (s, 3H), 2.40 (s, 3H), 2.55(s, 6H), 3.15 (m, 1H), 3.58 (s, 3H), 3.97 (t, 2H), 6.40 (s, 1H), 9.50 (broad s, 1H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>CC#N>[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:7][N:6]=2)=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Oc1ccc(F)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(Oc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1
Temperature: 70 °C

Procedure:
To a 5 mL round bottom flask fitted with a stirrer bar and septum was added 2 mL CH3CN and 2-methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine from from Reference Example 3 (100 mg, 0.24 mmol). Then 4-fluorophenol (10 eq., 269 mg, 2.4 mmol), K2CO3 (2 eq., 66.3 mg, 0.48 mmol) and a drop of tris[2-(2-methoxyethoxy)-ethyl]amine were added via syringe and the mixture heated at 70° C. for 2 h. By HPLC/MS, the starting material was converted to the desired product. The product was extracted from 10 mL water with 20 mL ethyl acetate, dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure. Flash column chromatography on silica gel (eluted with 90/10 hexanes/ethyl acetate) afforded 2-(4-fluorophenyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine: HPLC/MS: m/e=445 (M++1); Rt=4.53 min; 1H-NMR 400 MHz (CDCl3): δ 7.02 (d, J=9 Hz, 2H), 7.20-7.40 (m, 9H), 8.80 (s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][C:20]([CH3:31])([CH2:25][C:26](=O)[CH2:27][S:28][CH3:29])[C:21]([O:23]C)=[O:22]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:27]([S:28][CH3:29])=[C:26]2[CH2:25][C:20]([CH3:31])([CH3:19])[C:21]([OH:23])=[O:22])=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: COC(=O)C(C)(C)CC(=O)CSC
Agent: Cl
Product: CSc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the procedure of Example 10, but using 1-(p-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and methyl 2,2-dimethyl-5-methylthio -4-oxopentanoate as starting materials and hydrolysis at reflux, the title compound was prepared, mp 161°-163°.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[C:1]([C:5]1[N:6]=[C:7]([NH:10][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[C:13]=2[CH3:22])(=[O:19])=[O:20])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(N)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(C(C)(C)C)cs1
Yield: 40 %

Procedure:
The title compound was prepared from 4-tert-butyl-1,3-thiazol-2-ylamine (METHOD H) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, white foam, 273 mg (40% yield). mp 178° C.; HRMS Calcd (found) for C14H17ClN2O2S2 m/z 344.0420 (344.0408).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([C:20]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[CH:21]=2)[C:14](=[O:19])[CH:15]=[CH:16][CH2:17]Br)=[CH:6][CH:5]=1.O.[OH-].[OH:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(=O)OCC>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([C:20]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[CH:21]=2)[C:14](=[O:19])[CH:15]=[CH:16][CH2:17][O:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCCN(C(=O)C=CCBr)c2cc3ccccc3o2)cc1
Reactant: OCCN1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCN(C(=O)C=CCOCCN2CCCC2)c2cc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.3 %

Procedure:
To a solution of 4-[2-(3-benzofuran-2-yl-4-bromobut-2-enoylamino)ethoxy]benzoic acid methyl ester (300 mg, 0.654 mmol) in dry DMF (4 ml), cessium hydroxide monohydrate (121 mg, 0.72 mmol), tetrabutylammonium iodide (49 mg, 0.13 mmol) and 1-(2-hydroxy-ethyl)pyrrolidine (85 ul, 0.72 mmol) were added. The reaction mixture was stirred overnight at rt and then diluted with EA (20 ml) and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated under vacuum and the crude was purified on preparative TLC, DCM/MeOH (9/1) to give 4-{2-[3-benzofuran-2-yl-4-(2-pyrrolidin-1-yl-ethoxy)but-2-enoylamino]ethoxy}benzoic acid methyl ester (0.94 mg) as an oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:26])[C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:25])[O:13]1>>[CH3:11][C:12]1([CH3:26])[O:13][C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:4]3[CH:3]=[CH:2][S:6][C:5]=3[S:7]([NH2:10])(=[O:9])=[O:8])=[CH:18][C:17]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: CC1(C)OC(=O)Nc2ccc(-c3ccsc3S(N)(=O)=O)cc21

Procedure:
Prepared according to procedure B from 5-bromothiophene-2-sulphonamide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid: mp 258-260° C., 1H-NMR (DMSO-d6) δ10.41 (s, 1H), 7.71 (s, 2H), 7.58 (m, 2H), 7.52 (d, 1H, J=3.9 Hz), 7.48 (d, 1H J=8.16 Hz), 6.95(d, 1H J=8.16), 1.66 (s, 6H); MS m/z 337 (M−H). Anal. Calc. For C14H14N2O4S2: C, 49.69; H, 4.17; N, 8.28. Found: C, 49.90; H, 4.28; N, 8.12.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[SH:7][CH2:8][CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11]>C(=O)(O)[O-].[Na+]>[CH2:5]([O:4][C:2]([S:7][CH2:8][CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
Ethyl chloroformate (1.2 g.) is added to a solution of 3-mercaptopropanoyl-L-proline (2.03 g.) in normal sodium bicarbonate (30 ml.) and the mixture is stirred vigorously at 5° for one hour, and for two hours at room temperature. After acidification with concentrated hydrochloric acid, the mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, and concentrated to dryness to yield 1-[3-[[(ethoxy)carbonyl]thio]propanoyl]-L-proline.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][CH3:10])=[CH:6][C:5]([S:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]=[CH:17]3)=[C:4]([Cl:22])[CH:3]=1.[C:23](O)(=O)[CH3:24].O.N>Cl>[Cl:22][C:4]1[C:5]([S:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]=[CH:17]3)=[CH:6][C:7]2[N:8]([CH2:23][CH3:24])[C:9]([CH3:10])=[N:1][C:2]=2[CH:3]=1
Reactant: CCNc1cc(Sc2cccc3cnccc23)c(Cl)cc1N
Reactant: CC(=O)O
Agent: Cl
Agent: N
Solvent: O
Product: CCn1c(C)nc2cc(Cl)c(Sc3cccc4cnccc34)cc21
Yield: 58.5 %

Procedure:
5-(4-Amino-5-ethylamino-2-chlorophenylsulfanyl)isoquinoline 210 mg (0.6 mmol) was dissolved in 6N hydrochloric acid 3 ml, acetic acid 0.1 ml was added, and the mixture was heated and refluxed overnight. The reaction mixture was neutralized with ammonia water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and 5-chloro-1-ethyl-6-(5-isoquinolylsulfanyl)-2-methyl-1H-benzo[d]imidazole 130 mg (58.5%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1([CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O.COC(=O)CCC1(CC)CCCCC1=O.C(C12CCC(=O)[N:43]3C1=C([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=13)CCC2)C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1([CH3:13])[C:7]2[NH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:8]=2[CH2:9][CH2:10][CH2:11]1
Reactant: CCC12CCCc3c1n(c1ccccc31)C(=O)CC2
Reactant: COC(=O)CCC1(C)CCCCC1=O
Agent: CCC1(CCC(=O)OC)CCCCC1=O
Product: COC(=O)CCC1(C)CCCc2c1[nH]c1ccccc21

Procedure:
In the same manner but replacing 1-methyl-2-oxocyclohexanepropionic acid methyl ester with an equivalent amount of 1-ethyl-2-oxocyclohexanepropionic acid methyl ester, described in Example 6, 3a-ethyl-1,2,3,3a,4,5-hexahydro-6H-pyrido[3,2,1-jk]carbazol-6-one, mp 97°-99° C., and 1-ethyl-1,2,3,4-tetracarbazole-1-propionic acid methyl ester, νmaxCHCl3 1738 cm-1 are obtained.
Reaction SMILES: [NH2:1][C:2](=[O:21])[CH2:3][NH:4][C:5]1[C:10]([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=[CH:7][N:6]=1>C(O)CO.CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:4]([CH2:3][C:2]([NH2:1])=[O:21])[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:10]3[N:11]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)cc1
Solvent: CO
Solvent: OCCO
Product: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 190 °C
Yield: 24.8 %

Procedure:
A mixture of N-[2-[(2-amino-2-oxoethyl)amino]-3-pyridinyl]-4-chlorobenzamide (6.0 g, 0.02 mole) in 150 ml of ethylene glycol was heated at 190° C. for 40 minutes. The precipitate, which formed, was filtered off and washed with water. The filtrate was diluted with water to produce a second crop. The first crop was heated to boiling in 300 ml of methanol, filtered through a Celite pad, seeded, and refrigerated overnight. The crystalline precipitate was filtered, washed with cold methanol, and dried under high vacuum at 60° C. overnight to give 1.42 g (25%) of title compound, mp 270°-1° C.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH:7]=O)#[N:2].[SH2:15].[Na].Cl>CN(C)C=O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:5]2[O:4][C:3]([C:1](=[S:15])[NH2:2])=[CH:7][C:6]=2[CH:9]=1
Reactant: S
Reactant: COc1ccc(OCC#N)c(C=O)c1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2oc(C(N)=S)cc2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a solution of 2-cyanomethoxy-5-methoxybenzaldehyde (420.0 g) in N,N-dimethylformamide (2.1 l), sodium hydrogen sulfide (281.5 g) was added over 16 minutes and stirred for 3 hours and 20 minutes below 8° C. After being stirred for 1 hour at 40° to 47° C., the mixture was poured into ice-water (10.5 l) with stirring. The resulting mixture was neutralized with 6N-aqueous hydrochloric acid and further stirred for 30 minutes. The resulting precipitates were collected by filtration, washed with water (1 l×5 times) and dried at 50° C. under reduced pressure to give 5-methoxy-2-benzofurancarbothioamide (408.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]3[C:12](=[O:17])[C:13](I)=[CH:14][CH:15]=[C:10]3[N:9]2[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])(=[O:28])=[O:27])=[CH:4][CH:3]=1.[CH3:36][S:37]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)(=[O:39])=[O:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]3[C:12](=[O:17])[C:13]([C:44]4[CH:43]=[CH:42][CH:41]=[C:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH:45]=4)=[CH:14][CH:15]=[C:10]3[N:9]2[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: O=c1c(I)ccc2n1[C@H](c1ccc(Cl)cc1)[C@H](c1ccc(Cl)cc1)N2S(=O)(=O)c1ccccc1F
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CS(=O)(=O)c1cccc(-c2ccc3n(c2=O)[C@H](c2ccc(Cl)cc2)[C@H](c2ccc(Cl)cc2)N3S(=O)(=O)c2ccccc2F)c1

Procedure:
rac-cis-2,3-Bis-(4-chloro-phenyl)-1-(2-fluoro-benzenesulfonyl)-6-(3-methanesulfonyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one was prepared according to general method D by reaction of rac-cis-2,3-bis-(4-chloro-phenyl)-1-(2-fluoro-benzenesulfonyl)-2,3-dihydro-6-iodo-1H-imidazo[1,2-a]pyridin-5-one with 3-(methylsulfonyl)phenylboronic acid. The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 669.0; the expected mass is 668. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:15])=[C:5]([C:10]([O:12]CC)=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2].[OH-].[Na+]>O1CCCC1.O>[C:1]([C:3]1[C:4]([I:15])=[C:5]([C:10]([OH:12])=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1sc(C(=O)O)c(I)c1C#N
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of ethyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (3.40 g, 10 mmol) in tetrahydrofuran (80 mL) and water (16 mL) was added a solution of 1.00M sodium hydroxide in water (30 mL). The solution was allowed to stir overnight. The reaction was quenched with a solution of 1N hydrogen chloride in water (50 mL) and diluted with water (400 mL). The resultant precipitate was filtered, washed with water (2×100 mL) and dried in a vacuum oven to give 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylic acid (2.6 g, 79%) as a white solid. LCMS: (FA) ES+ 326. 1H NMR (400 MHz, d6-DMSO) δ: 14.1-13.8 (bs, 1H), 2.75 (s, 3H).