Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[Cl:38][C:39]1[CH:47]=[C:46]([F:48])[C:45]([S:49](=[O:52])(=[O:51])[NH2:50])=[CH:44][C:40]=1[C:41](O)=[O:42]>>[Cl:38][C:39]1[CH:47]=[C:46]([F:48])[C:45]([S:49](=[O:51])(=[O:52])[NH2:50])=[CH:44][C:40]=1[C:41]([N:29]1[CH2:28][CH2:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30]1)=[O:42]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)c5cc(S(N)(=O)=O)c(F)cc5Cl)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 92, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with 2-chloro-4-fluoro-5-sulfamoylbenzoic acid to give the title compound. LC/MS (M+H)+: 770. Ret. time: 2.17 min. (Condition J); analytical HPLC Ret. time: 12.91 min (Condition K).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([OH:20])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)=[O:23].[CH2:39](Br)[CH:40]=[CH2:41]>>[CH2:41]([O:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:12]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:21][C:22]([NH:24][CH:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26]3)=[O:23])[CH:7]([CH2:6][C:5]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:13]=2[CH:14]=1)[CH:40]=[CH2:39]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CCC2
Reactant: C=CCBr
Product: C=CCOc1cc2c(cc1OC)CCCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide with allylbromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[CH2:29]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([CH2:41]O)[CH2:36]1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:41][CH:37]4[CH2:38][CH2:39][CH2:40][N:35]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:36]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: CCCCCCN1CCCC(CO)C1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCN1CCCC(COc2ccc(C(=O)c3c(-c4ccc(OC)cc4)sc4cc(OC)ccc34)cc2)C1
Yield: 82.2 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), 1-hexyl-3-piperidine methanol (1.69 g, 6.00 mmol), triphenylphosphine (1.57 g, 6.00 mmol), and DEAD (6.0 mmol) were converted to product by the procedure of Example 1 to give 1.41 g of the title compound. Yield: 82%. MS(FD) 572(M+). EA calculated for C35H41NO4S: C, 73.52; H, 7.23; N, 2.45. Found: C, 73.25; H, 7.08; N, 2.71.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C@@H:34]([CH3:50])[CH2:35][N:36]1[CH:40]=[CH:39][C:38]([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[C:43]([Cl:49])[CH:42]=2)=[N:37]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:49][C:43]1[CH:42]=[C:41]([C:38]2[CH:39]=[CH:40][N:36]([CH2:35][C@@H:34]([NH:33][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:23]4[N:22]=[CH:21][N:20]([C:1]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:24]=4)[CH:29]=3)=[O:31])[CH3:50])[N:37]=2)[CH:48]=[CH:47][C:44]=1[C:45]#[N:46]
Reactant: O=C(O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Yield: 128.7 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic acid (2.493 mmol, 1048 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-benzonitrile (1.918 mmol, 500 mg) using a mixture of DCM (10 ml) and DMF (1 ml) as the solvent. HBTU (0.384 mmol, 145 mg) was used instead of HOBt. The reaction mixture was diluted with DCM and washed with 1 M Na2CO3 and water. The separated organic phase was dried, filtered and evaporated. 1.637 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.12 (d, 3H), 4.17-4.52 (m, 3H), 6.75 (bs., 1H), 6.92 (d, 1H), 7.12-7.19 (m, 7H), 7.35-7.53 (m, 12H), 7.80 (d, 1H), 7.97 (bs, 1H), 8.04 (s, 1H), 8.21 (d, 1H), 13.38 (bs., 1H).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[CH:24]([C:26]1([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=O.C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([CH2:5][O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([CH2:24][C:26]5([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH2:22][CH2:23]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)C1(C=O)CCOCC1
Reactant: c1cc(OCC2CCC2)c2c(OCC3CCNCC3)noc2c1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC5CCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclobutylmethoxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 17, Step 4) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](C=O)[CH:2]=1.[Cl:9][C:10]1[C:14](C2C=NC=CC=2)=[N:13][S:12][N:11]=1.[H-].[Na+]>C1COCC1>[Cl:9][C:10]1[C:14]([C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][N:1]=2)=[N:13][S:12][N:11]=1
Reactant: O=Cc1cccnc1
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nsnc1-c1ccccn1

Procedure:
3-(3-chloro-1,2,5-thiadiazol-4-yl-pyridine (compound 1) was synthesized from 3-pyridinecarboxaldehyde following, except with slight modification, from the published procedure as provided in Sauerberg et al, Journal Medicinal Chemistry, 1992, Vol. 35, Page 2274. 3-(3-Chloro-1,2,5-thiadiazol-4-yl)pyridine was reacted with a diol (compound 2, wherein n=6, 7, 8, 9, 10 or 12) in the presence of sodium hydride in refluxing THF to yield bis[3-(pyridin-3-yl)-1,2,5-thiadiazol-4-yl]alkyl-diethers (compound 3, wherein n=6, 7, 8, 9, 19 or 12) in 75-90% yield. These diethers were treated with excess methyl iodide in acetone or chloroform to give bis-quaternary ammonium iodides (compound 4, wherein n=6, 7, 8, 9, 10 or 12) in 96-100% yield. The quaternary salts were then treated with 5 equivalents of sodium borohydride in a mixture of methanol and chloroform to yield the compounds 5, wherein n=6, 7, 8, 9, 10 or 12 in 50-60% yield. Dry hydrogen chloride gas was then bubbled through the methanolic solution of compounds 5 at 0° C. to give compounds 6, wherein n=6, 7, 8, 9, 10 or 12 in 95-100% yield.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([S:22][CH3:23])[N:12]=1.Cl.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH2:33]>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH:33][C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([S:22][CH3:23])[N:12]=1
Reactant: NNc1ccccc1Cl
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1NNc1ccccc1Cl

Procedure:
At room temperature, 16.2 mL of N,N-diisopropylethylamine was added to tetrahydrofuran (300 mL) solution of 9.4 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate and 8.3 g of 2-chlorophenylhydrazine hydrochloride, and heated under reflux for 18 hours. The solvent was concentrated under reduced pressure, water was added to this, and extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain crude ethyl 4-[2-(2-chlorophenyl)hydrazino]-2-(methylthio)pyrimidine-5-carboxylate as a yellow oily substance.
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[CH:16]1([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][N:27]=[C:22]3[NH:21][C:20]2=[O:28])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[C:12]([O:11][C:9](=[O:10])[NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([N:21]2[C:22]3=[N:27][CH:26]=[CH:25][N:24]=[C:23]3[N:19]([CH:16]3[CH2:17][CH2:18]3)[C:20]2=[O:28])[CH2:3][CH2:4]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: O=c1[nH]c2nccnc2n1C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2c(=O)n(C3CC3)c3nccnc32)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled solution (0° C.) of tert-butyl cis-4-hydroxycyclohexanecarbamate (0.682 g, 3.17 mmol, Biofine International), 1-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.5578 g, 3.17 mmol), and triphenylphosphine (1.100 ml, 4.75 mmol, Sigma-Aldrich Chemical Company) in THF (17.49 ml) was added diethyl azodicarboxylate, 40 wt. % solution in toluene (1.870 ml, 4.75 mmol, Chem Impex International) dropwise. After 10 mins, the round bottomed flask was removed from the ice bath and allowed to warm to room temperature to stir. Reaction was allowed to stir for 5 h and was then concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (0.7301 g, 1.955 mmol, 61.7% yield). LCMS showed product peak at 2.13 min (m+1=374.0). NMR showed some biproduct from DEAD reagent. Product was carried on without further purification.
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](OCCCC)=[C:12](F)[CH:11]=2)=[CH:6][C:5]=1F)C.C([Li])CCC.[C:28](=[O:33])(OC)OC.Cl>CCCCCC.O1CCCC1>[C:28]1(=[O:33])[C:6]2[C:7]([C:10]3[C:11]([CH:5]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][CH:9]=[CH:4]1
Reactant: COC(=O)OC
Reactant: CCCCOc1ccc(-c2ccc(OCC)c(F)c2)cc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=CC=C2C1=Cc1ccccc12
Temperature: -70 °C
Reaction time: 2 h

Procedure:
60 mmol of 4-ethoxy-3,3′-difluoro-4′-butoxybiphenyl (5) are introduced into 200 ml of tetrahydrofuran, and the mixture is cooled to −70° C. 120 mmol of a 1.6 M solution of n-butyllithium in hexane are added dropwise, and the mixture is stirred at this temperature for 2 hours. 60 mmol of dimethyl carbonate are subsequently added rapidly with vigorous stirring, the mixture is stirred at −70° C. for a further hour, allowed to warm to 0° C., hydrolysed with dilute hydrochloric acid and subjected to conventional work-up.
Reaction SMILES: [CH2:1]1[CH2:11]CN2C(=NCCC2)C[CH2:2]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH:20]([OH:39])/[CH:21]=[CH:22]/[C@H:23]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[N:24]2[CH2:30][C:31]#[C:32][CH2:33][O:34][CH2:35][C:36]([OH:38])=[O:37])[CH:16]=[CH:17][CH:18]=1.IC(C)C>CC(C)=O>[CH:1]([O:37][C:36](=[O:38])[CH2:35][O:34][CH2:33][C:32]#[C:31][CH2:30][N:24]1[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C@@H:23]1/[CH:22]=[CH:21]/[CH:20]([OH:39])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1)([CH3:11])[CH3:2]
Reactant: O=C(O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(C)I
Solvent: CC(C)=O
Product: CC(C)OC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Reaction time: 0.08 h
Yield: 58.8 %

Procedure:
DBU (6.6 μL, 0.044 mmol) was added to a solution of (4-{(R)-2-[(E)4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-6-oxo-piperidin-1-yl)-but-2-ynyloxy)-acetic acid (12 mg, 0.030 mmol) in acetone (0.3 mL). After 5 min, 2-iodopropane (15 μL, 0.15 mmol) was added. After 19 h, the reaction mixture was concentrated in vacuo, 0.5 M aqueous HCl (5 mL) was added and the mixture was extracted with EtOAc (3×5 mL). The combine organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2 →3% MeOH/CH2Cl2, gradient) afforded 7.9 mg (60%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[CH2:32][NH2:33].C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:33][CH2:32][C:25]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=3[O:23][CH3:22])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: O=C(O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2ccc3c(ccn3Cc3ccc(F)cc3F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of 1-(2,4-difluorobenzyl)-1H-indole-5-carboxylic acid (50 mg, 0.17 mmol, 1 equiv) in DCM (2 mL) were added the (2,4-dimethoxyphenyl)methanamine (27 μL, 0.18 mmol, 1.05 equiv) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (35 mg, 0.18 mmol, 1.05 equiv). The reaction mixture was stirred 2 h at room temperature. The solvent was removed in vacuo. The residue was dissolved in AcOEt and washed with a 0.5 N HCl aqueous solution, a saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo to afford a beige powder (56 mg, 0.13 mmol, 76%). ESI-MS (m/z): 437 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[C:13]2[CH:14]=[CH:15][C:16]([N:18]3[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)=[CH:17][C:12]=2[CH2:11][CH2:10][O:9]1)(=O)=O.[C:24]([C:26]1[CH:41]=[CH:40][C:29]2[C:30]([N:33]3[CH2:38][CH2:37][NH:36][C@H:35]([CH3:39])[CH2:34]3)=[CH:31][S:32][C:28]=2[CH:27]=1)#[N:25]>>[CH3:39][C@H:35]1[N:36]([CH2:6][CH2:7][C@H:8]2[C:13]3[CH:14]=[CH:15][C:16]([N:18]4[CH2:19][CH2:20][S:21][CH2:22][CH2:23]4)=[CH:17][C:12]=3[CH2:11][CH2:10][O:9]2)[CH2:37][CH2:38][N:33]([C:30]2[C:29]3[CH:40]=[CH:41][C:26]([C:24]#[N:25])=[CH:27][C:28]=3[S:32][CH:31]=2)[CH2:34]1
Reactant: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(N3CCSCC3)ccc21
Product: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1CC[C@@H]1OCCc2cc(N3CCSCC3)ccc21

Procedure:
Prepared by condensation of 2-[(1S)-6-(4-thiomorpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate with (3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine, as described for Example 1b). M+H=519.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:9]1[S:10][CH2:11][C:12](=[O:14])[N:13]=1.[N:15]1[C:24]2[C:19](=[N:20][C:21]([CH:25]=O)=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:9]1[S:10][C:11](=[CH:25][C:21]2[CH:22]=[CH:23][C:24]3[C:19](=[CH:18][CH:17]=[CH:16][N:15]=3)[N:20]=2)[C:12](=[O:14])[N:13]=1
Reactant: Cc1ccsc1CNC1=NC(=O)CS1
Reactant: O=Cc1ccc2ncccc2n1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1ccsc1CNC1=NC(=O)C(=Cc2ccc3ncccc3n2)S1
Temperature: 130 °C
Yield: 43.8 %

Procedure:
To a suspension of 2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one (36.2 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.20 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 10 min. The reaction mixture was then cooled to r.t. and diluted with toluene. The solid was collected by filtration and the solid was washed with toluene, MeOH and ether to give 2-[(3-Methyl-thiophen-2-ylmethyl)-amino]-5-[1,5]naphthyridin-2-ylmethylene-thiazol-4-one as a light brown solid (25.7 mg, 43.9%). HR-ES (+) m/e calcd. for C18H14N4OS2: (M+H)+ 367.0682. Found: 367.0683.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)[C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][C:14]=4[F:17])[NH:9][C:8]=3[C:6]=2[N:7]=1
Reactant: O=Cc1cccs1
Reactant: Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cccc2[nH]c3c(c12)C(c1cccs1)Oc1ccc(Cl)nc1-3
Temperature: 60 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A mixture of compound 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (60 mg, 0.224 mmol), thiophene-2-carbaldehyde (50 mg, 0.448 mmol) and PTSA (85 mg, 0.448 mmol) in toluene (1 mL) was stirred at 60° C. for 4 hours. The mixture was then diluted with water (20 mL) and extracted with EtOAc (15 mL*3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=20:1) to provide 2-chloro-7-fluoro-6-(thiophen-2-yl)-6,11-dihydropyrido[2′,3′:5,6]pyrano[4,3-b]indole (40 mg, yield: 50.0%). 1H-NMR (CDCl3, 400 MHz) δ 9.28 (s, 1H), 7.07˜7.18 (m, 5H), 6.98 (d, J=8.4 Hz, 1H), 6.81˜6.86 (m, 2H), 6.66˜6.70 (m, 1H). MS (M+H)+: 357/359.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([S:14][C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[N:18]=[CH:17][C:16]=2[C:30]([O:32]C(C)(C)C)=[O:31])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[CH:8]1([S:14][C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[N:18]=[CH:17][C:16]=2[C:30]([OH:32])=[O:31])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2SC2CCCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2ncc(C(=O)O)c2SC2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 101.5 %

Procedure:
Trifluoroacetic acid (4.72 mL, 61.46 mmol) was added to tert-butyl 5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate (Intermediate#89) (2.56 g, 6.15 mmol) in CH2Cl2 (40 mL) The resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness, re-dissolved in dioxan (20 mL) and re-evaporated to dryness to afford 5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylic acid (2.25 g, 100%) as a white crystalline solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Clc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(Cl)cccc21
Yield: 66 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 307 mg of 4-chloro-2,3-dihydro-1H-indole, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 247 mg of 2-[2-(4-chloro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].[C:9](OC(=O)C)(=[O:11])[CH3:10]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>[C:9]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: C=C(OC(C)=O)C(=O)OCC
Temperature: 120 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
First, to a mixture of ethyl pyruvate (315 g, 2.7 mol) and acetic anhydride (554 g, 5.4 mol), p-toluenesulfonic acid monohydrate (8 g) was added. Then, the mixture was stirred under a nitrogen gas stream at 120° C. for 24 hours to obtain a reaction solution. Next, acetic acid generated by a reaction with excess acetic anhydride under reduced pressure (40 to 50 mmHg) was removed from the reaction solution. Thereafter, the residue was purified by reduced pressure distillation (35 to 40 mmHg, 90 to 103° C.) to obtain ethyl α-acetoxyacrylate (250 g, yield 58%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH:20]=O)=[O:6])[CH:2]=[CH2:3].C1(P(=[CH:41][C:42]([O:44][CH3:45])=[O:43])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH2:9][C@H:8]1[CH:20]=[CH:41][C:42]([O:44][CH3:45])=[O:43])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=CC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-formylpyrrolidine (30.0 g) in tetrahydrofuran (300 ml) was added methyl (triphenylphosphoranylidene)acetate (35.2 g) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was chromatographed on a 300 g of silica gel to give (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(3-methoxy-3-oxo-1-propenyl)pyrrolidine (29.8 g) as a colorless oil.