Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[Cl:28][C:29]1[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[S:32][C:33]=1[Cl:34].Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:5](=[C:6](/[CH:11]=[CH:12]/[C:13]([NH:38][S:35]([C:31]3[S:32][C:33]([Cl:34])=[C:29]([Cl:28])[CH:30]=3)(=[O:36])=[O:37])=[O:15])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: Cc1c[nH]c2c(/C=C/C(=O)O)cccc12
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1c[nH]c2c(/C=C/C(=O)NS(=O)(=O)c3cc(Cl)c(Cl)s3)cccc12
Temperature: 25 °C
Reaction time: 32 h

Procedure:
(E)-3-(3-Methyl-1H-indol-7-yl)-acrylic acid (I-7) (1 mmol), 4-dimethyaminopyridine (DMAP, 2 mmol) and 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 2 mmol) in CH2Cl2 (30 mL) was added 4,5-dichloro-thiophene-2-sulfonic acid amide (1.1 mmol). The reaction mixture was stirred at room temperature for 24-40 hr. Recation mixture was diluted with another 30 ml of dichloromethane and then acidified with 10% aqueous HCl solution until pH˜1-2 (pH stripes). Organic layers was washed with saturated brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, CH2Cl2; CH2Cl2/EtOAc/hexane=1:10:20-1:20:10) to afford desired product, I-9. 1H-NMR (500 MHz, CDCl3) ESI M.S. gave (M−1): 436.4 with 88%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:22]([C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1)[C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C>[CH2:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:6]=[CH:7][C:2]=1[O:1][CH:22]([C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1)[C:23]([O:25][CH3:26])=[O:24])[CH2:13][CH3:14]
Reactant: CCCc1cc(S(N)(=O)=O)ccc1O
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(S(N)(=O)=O)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3.06 g (14.23 mmol) of the product of Step B dissolved in 25 mL of anhydrous DMF was added 4.87 g (15.0 mmol) of cesium carbonate and the reaction mixture was magnetically stirred under a nitrogen atmosphere at room temperature for 15 minutes. Methyl α-bromo-3,4-methylenedioxyphenylacetate (4.08 g, 15.0 mmol) was then added and the reaction mixture was stirred for an additional 3 hours. The reaction mixture was then partitioned between EtOAc (80 mL) and 10% aqueous citric acid (300 mL). The organic layer was separated, washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was dried in vacuo to afford 5.90 g (5.79 theoretical) of the title compound which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:47])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:47])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 50.9 %

Procedure:
Starting with 0.144 g (0.70 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.35 g (0.69 mmol) of 2-(4-bromobutoxy)-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.202 g; 63.4% overall yield) was obtained as a white solid, mp 177°-180° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH2:48]([S:50](Cl)(=[O:52])=[O:51])[CH3:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([S:50]([CH2:48][CH3:49])(=[O:52])=[O:51])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CCS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and ethanesulfonyl chloride as starting materials in 41% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.40 (s, 1H), 9.36 (s, 1H), 9.28 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.73 (s, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 3.60 (m, 2H), 3.01 (m, 2H), 2.83 (m, 6H), 2.27 (m, 2H), 1.91 (m, 1H), 1.78 (m, 2H), 1.22 (m, 2H), 1.20 (m, 3H). LCMS for C27H32ClN6O3S (M+H)+: m/z=555.2.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:11]=[C:10]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH3:13])=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: Cc1ccc(Nc2nc(Cl)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 4-methylaniline (32 mg, 0.30 mmol) by a procedure similar to example 1b and was isolated as white powder (15 mg, 30%). 1H NMR (CDCl3): 7.97-7.89 (m, 3H), 7.71 (d, J=6.6 Hz, 2H), 7.64 (ddd, J=8.4, 6.6 and 2.1 Hz, 1H), 7.33 (d, J=6.6 Hz, 2H), 2.47 (s, 3H).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[C@H:15]1[CH2:21][N:20]([CH2:22][CH2:23][S:24][CH3:25])[C:19](=[O:26])[C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:17][CH2:16]1.C(=O)([O-])[O-:36].[Na+].[Na+]>CO.O>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[C@H:15]1[CH2:21][N:20]([CH2:22][CH2:23][S:24]([CH3:25])=[O:36])[C:19](=[O:26])[C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:17][CH2:16]1
Reactant: CSCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: CS(=O)CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 18 h

Procedure:
Sodium periodate (11.3 mg, 0.053 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]-2-oxoazepan-3-ylcarbamate (22 mg, 0.053 mmol) in methanol (2 mL) and water (2 mL). After 30 min excess sodium periodate (22 mg, 0.11 mmol) was added. After 18 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 431 (M+1).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[F:13][CH2:14][CH:15]([OH:18])[CH2:16][F:17].[OH-].[Li+]>>[F:13][CH2:14][CH:15]([CH2:16][F:17])[O:18][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OC(CF)CF
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(OC(CF)CF)nc1
Temperature: 25 °C
Yield: 47 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 47% yield starting from ethyl 6-chloronicotinate and 1,3-difluoro-2-propanol. The reduction was performed using 3 equiv of lithium hydroxide, the reaction mixture was stirred at ambient temperature over night; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (d, 1 H), 8.19 (dd, 1 H), 6.99 (d, 1 H), 5.62-5.80 (m, 1 H), 4.77-4.87 (m, 2 H), 4.65-4.75 (m, 2 H); MS (ESI) m/z 216[M−H+].
Reaction SMILES: [ClH:1].Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][C@@H:55]([N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)C)CC1>>[ClH:1].[ClH:1].[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([C@@H:55]([CH3:54])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][CH2:59]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5cc(F)ccc45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106, see example 55) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4](/[C:5](=[CH:29]\[CH3:30])/[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.[H][H]>[Pd]>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([C@@H:5]([CH2:29][CH3:30])[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: C/C=C1/C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Product: CC[C@H]1C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12

Procedure:
reacting E-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid (5) with Pd/C and hydrogen gas to form 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid (6),
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[N:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=2)[C:4](=[O:23])[C:3]=1Br.[SH:25][CH2:26][C:27](O)=[O:28].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:9]([S:8][C:6]1[N:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=2)[C:4](=[O:23])[C:3]2[S:25][CH2:26][C:27](=[O:28])[NH:1][C:2]=2[N:7]=1)[CH3:10]
Reactant: CCSc1nc(N)c(Br)c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: O=C(O)CS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)SCC(=O)N2

Procedure:
A solution of 6-amino-5-bromo-2-(ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)-one (0.1 g) and mercaptoacetic acid (0.168 mL) in toluene (2 mL) was stirred at 170° C. for 2 hr under microwave irradiation. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:43])[N:9]=[C:10](SC)[C:11]([C:28]1[C:29]([F:40])=[C:30]2[C:35](=[C:36]([O:38][CH3:39])[CH:37]=1)[O:34][CH2:33][CH2:32][CH2:31]2)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=2)=[CH:15][CH:14]=1.Cl.Cl.[CH2:46]([O:48][C:49]([C:51]1[C:52]([NH:56][NH2:57])=[N:53][NH:54][CH:55]=1)=[O:50])[CH3:47]>C(N(CC)CC)C>[CH2:46]([O:48][C:49]([C:51]1[CH:55]=[N:54][NH:53][C:52]=1[N:56]1[C:8](=[O:43])[NH:9][C:10]([CH:11]([C:28]2[C:29]([F:40])=[C:30]3[C:35](=[C:36]([O:38][CH3:39])[CH:37]=2)[O:34][CH2:33][CH2:32][CH2:31]3)[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[O:21][N:20]=3)=[CH:15][CH:14]=2)=[N:57]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)c1c[nH]nc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C(F)(F)F)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)CCCO3)[nH]c1=O
Temperature: 85 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
To 5 ml of a DMF solution containing 160 mg of [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester, 87 mg of 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester bishydrochloride (Example (157b)) and 0.124 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 8 ml of methanol and 0.068 ml of acetic acid, and then 187 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (39 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([O:19]C)=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O.[OH-].[Li+].O>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CCC2c1cc(F)cc(F)c1
Yield: 52.4 %

Procedure:
The title compound was synthesized from methyl 4-(3,5-difluorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.081 g, 0.29 mmol) and lithium hydroxide monohydrate (61 mg, 1.45 mmol), according to General Procedure 7. A 1:6 mixture of water and methanol (MeOH)(3.5 mL) was used. The resulting product was purified by chromatography over silica gel (gradient 0 to 100% EtOAc in heptane over 20 min) to give the title compound 40 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.21 (ddt, 1H), 2.70-2.88 (m, 2H), 2.89-2.99 (m, 1H), 4.20 (dd, J=7.61, 6.64 Hz, 1H), 6.55 (s, 1H), 6.68-6.80 (m, 3H). 19F NMR (376 MHz, METHANOL-d4) δ ppm −112.87 (t, J=8.58 Hz). LCMS m/e 262 (M−H). 100% pure by HPLC.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)=[O:8])[CH:2]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])=[CH:16][CH:15]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc(CO)cc1)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C(=O)c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Dissolve 4-(pyridine-3-carbonyl)-benzyl alcohol (85 mg, 0.399 mmol) in dichloromethane (5 mL). Cool to 0° C. and add triethylamine (0.056 mL, 0.438 mmol) and methanesulfonyl chloride (0.033 mL, 0.438 mmol). Allow the mixture to warm to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to provide the title compound as oil (115 mg, 100%). GC-MS m/z: 291 (M4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.Cl.[CH3:11][O:12][C:13](=[O:16])[CH2:14][NH2:15]>CO.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH:15][CH2:14][C:13]([O:12][CH3:11])=[O:16])[CH:7]=[CH:8][CH:9]=1
Reactant: BrCc1cccc(Br)c1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CNCc1cccc(Br)c1
Yield: 36.5 %

Procedure:
A solution of 3-bromobenzylbromide (4.3 g, 17.2 mmol) in methanol (25 ml) and triethylamine (5 ml) is treated with glycine methyl ester hydrochloride (4.3 g, 34.4 mmol) and heated to reflux for 18 hours. The solvent is removed in vacuo and the residue chromatographed over silica gel (0-2% methanol in ethyl acetate as eluant) to give 1.62 g of a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[S:13][C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:3]=12.[OH-].[K+].[CH2:22](O)[CH3:23].C(I)C>O>[CH2:22]([N:5]1[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2](=[O:1])[C:3]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:4]1=2)[CH3:23]
Reactant: CCOC(=O)c1cnc2sc3c(c2c1O)CCCC3
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: CCI
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c3c(sc21)CCCC3

Procedure:
A mixture of 1.38 parts of ethyl 4-hydroxy-5,6,7,8-tetrahydro(l)benzothieno(2,3-b)pyridine-3-carboxylate, 11 parts by volume of 10% aqueous potassium hydroxide, 44 parts by volume of ethanol and 45 parts by volume of water and 1.5 parts by volume of ethyl iodide is refluxed for 4 hours and the product is isolated in a manner similar to that described in Example 13, whereby 1-ethyl-1,4,5,6,7,8-hexahydro-4-oxo(l)benzothieno(2,3-b)pyridine-3-carboxylic acid is obtained as crystals. Recrystallization from ethanol and, then, from tetrahydrofuran gives colorless needles melting at 218°-221° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:17][C:18]1[C:26]2[N:25]=[C:24](Cl)[NH:23][C:22]=2[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1>>[Br:17][C:18]1[C:26]2[N:25]=[C:24]([N:12]3[CH2:11][CH2:10][N:9]([C:4]4[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:14][CH2:13]3)[NH:23][C:22]=2[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The reaction of 1-(3-trifluoromethylpyridin-2-yl)piperazine (128 mg, 0.5 mmol, Fluorochem) and 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (210 mg, 0.7 mmol, Example 6b) under the conditions of Example 3c afforded the title compound as a white solid. M.p. 196° C. MS (ESI, pos. ion) m/z: 494 (M+1).
Reaction SMILES: [S:1]1[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH:3]=[C:2]1[C:13]([OH:15])=O.S(Cl)([Cl:18])=O.C(Cl)(Cl)Cl>CN(C)C=O>[S:1]1[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH:3]=[C:2]1[C:13]([Cl:18])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2oc3ccccc3c2s1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cc2oc3ccccc3c2s1

Procedure:
A suspension of 15.5 g thieno[3,2-b]benzofuran-2-carboxylic acid, 16.9 g of thionyl chloride, 150 ml of chloroform and 1 ml of dimethylformamide is refluxed 5 hours, the reaction mixture is screened and the solvent removed from the filtrate to yield thieno[3,2-b]benzofuran-2-carboxylic acid chloride as a brown solid. 5.1 g of the above mentioned acid chloride is added portionwise over 30 minutes to a stirred mixture of 2.7 g of 2-aminothiophenol, 50 ml of toluene and 5 ml of pyridine cooled in an ice bath. The mixture is then stirred at ambient temperature for 17 hours, cooled, filtered and the residue washed with ligroin to yield the amide of formula (X) ##STR18## as a brown solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:9][CH:8]=1.O>C(Cl)Cl>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCc1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCc1ccc(O)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
Boron tribromide was added dropwise, under argon to an about -78° C. solution of about 12.16 g of 4-methoxy-1-tetradecyl-benzene in about 125 ml of methylene chloride. The reaction was stirred for about 21/2 hours at about -78° C., then water was added dropwise, the organic layer separated, washed with sodium bicarbonate solution and evaporated, giving about 11.8 g of the desired title compound, mp 70°-71° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]([F:26])([F:25])[F:24])=[N:4][N:5]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20])=[CH:12][CH:11]=2)[C:6]=1[CH:7]1[CH2:9][CH2:8]1.CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>>[Cl:1][C:2]1[C:3]([C:23]([F:24])([F:26])[F:25])=[N:4][N:5]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[C:18](=[CH:29][N:30]([CH3:32])[CH3:31])[C:19](=[O:21])[CH3:20])=[CH:14][CH:15]=2)[C:6]=1[CH:7]1[CH2:8][CH2:9]1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)Nc1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)cc1
Product: CC(=O)C(=CN(C)C)C(=O)Nc1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Step-2: N-{4-[4-chloro-5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3-oxobutanamide (1.6 g, 3.98 mmol) and N,N-Dimethylformamide dimethylacetal (2.6 g, 21.9 mmol) were mixed and stirred at rt for overnight. Workup (AcOEt/H2O) followed by purification on 60-120 mesh silicagel using AcOEt and Peteher (1:1) as eluent afforded N-{4-[4-chloro-5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-2-[(dimethylamino)methylene]-3-oxobutanamide (1.3 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]([SH:8])=[N:6][C:5](=[O:9])[C:4]([OH:10])=[N:3]1.C(N(CC)CC)C.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[CH3:1][N:2]1[C:7]([SH:8])=[N:6][C:5](=[O:9])[C:4]([O:10][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3]1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cn1nc(O)c(=O)nc1S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(=O)nc1S

Procedure:
A solution of 2-methyl-3-mercapto-6-hydroxy-2,5-dihydro-1,2,4-triazin-5-one (0.8 g) in dry tetrahydrofuran (25 ml) was stirred for 30 min with triethylamine (0.835 ml) and tertbutyldiphenylsilylchloride (1.53 ml). The reaction mixture was partitioned between 1% aqueous NaHCO3 and ethyl acetate. Removal of the solvent from the dried organic layer left a residue which crystallized by trituration with light petrol affording 2-methyl-3-mercapto-6-tert-butyldiphenylsilyloxy-2,5-dihydro-1,2,4-triazin-5-one (1.34 g), m.p. 135° C. (decomp.);