Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N)(=[S:24])C.Cl.[OH-].[Na+]>O.CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[S:24])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: CC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=S)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C

Procedure:
20.0 g (67 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile and 10.06 g (134 mmol) of thioacetamide are heated to 90° together with 100 ml of dry N,N-dimethylformamide, whereupon the mixture is saturated with dry hydrogen chloride at this temperature for 5 hours. The mixture is cooled to room temperature and poured into 2.5 l of water. The mixture is neutralized to pH 7 with sodium hydroxide solution and the precipitated product is filtered off under suction. The material on the suction filter is taken up in methylene chloride, insoluble material is filtered off and the filtrate is washed with water, dried over magnesium sulphate and concentrated in half. By suction filtration and recrystallization from ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbothioamide of melting point 247°-248°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]3[NH:30][CH:31]=[N:32][C:28]=3[CH:27]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:35].C(N1C=CN=C1)([N:38]1C=CN=C1)=O.N>CN(C)C=O>[NH2:1][C:2]1[C:3]([Cl:35])=[CH:4][C:5]([S:9]([NH:12][CH:13]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]3[NH:30][CH:31]=[N:32][C:28]=3[CH:27]=2)[C:14]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]([NH2:38])=[O:24])[CH2:20][CH2:21]2)=[O:15])(=[O:11])=[O:10])=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(Cl)cc(S(=O)(=O)NC(Cc2ccc3[nH]cnc3c2)C(=O)N2CCC(C(=O)O)CC2)cc1Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Reaction time: 12 h

Procedure:
540 mg (1 mMol) of 4-amino-N-[1-(1H-benzimidazol-5-yl-methyl)-2-(4-carboxy-piperidin-1-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide are dissolved in 10 ml of absolute dimethylformamide and combined, with stirring, with 180 mg (1.1 mMol) of carbonyldiimidazole. After about one hour 2 ml of ethanolic ammonia solution are added dropwise and the mixture is stirred for a further 12 hours. It is then evaporated down, the residue is mixed with water and extracted twice with ethyl acetate. The organic phase is washed twice with aqueous saline solution, dried with sodium sulphate and evaporated down. The residue is purified over a silica gel column, the evaporated eluate is triturated with ether and suction filtered.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:14]([CH3:13])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.7 %

Procedure:
To a solution of 6-Bromoindole (1.82 g, 9 mmol) in DMF at 0° C. was added NaH (446 mg, 18 mmol). The mixture was allowed to warm to room temperature and stirred for 15 min. The reaction was then cooled to 0° C., MeSO2Cl (1.55 g, 13.5 mmol) added and the mixture stirred at this temperature for 1.5 h before being quenched with ice and diluted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous Na2SO4. The crude residue was purified by flash chromatography to give the title product as a white solid (782 mg, 29% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)[CH:5]=[N:6][C:7]=1[Cl:8].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>N1C=CC=CC=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)=[CH:3][C:2]=1[NH:1][S:29]([C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N)c3)cc2s1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(Cl)cc4)c3)cc2s1
Yield: 23.4 %

Procedure:
N-(6-(5-amino-6-chloropyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.040 g, 0.13 mmol) was dissolved in pyridine (1 ml), then 4-chlorobenzene-1-sulfonyl chloride (0.026 g, 0.13 mmol) was added to the mixture while stirring. The mixture was allowed to stir under inert atmosphere for 3 days. The progress of the reaction was monitored by LC/MS, which showed product. The mixture was diluted with DCM and saturated sodium bicarbonate solution. The organic layer was extracted with DCM (3×20 ml). Combined organics, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by ISCO silica-gel chromatography in a gradient of 0-10% Methanol/DCM. The fractions with desired material were combined and concentrated in vacuo. The residue was diluted with ethyl acetate and allowed to stir 10 minutes. The precipitate was collected by filtration and washed with 1:1 ethyl acetate/hexanes to give N-(6-(6-chloro-5-(4-chlorophenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.015 g, 24% yield) as a white crystalline solid. MS (ESI pos. ion) m/z: 494 (MH+). Calc'd exact mass for C20H14Cl2N4O3S2: 493. 1H NMR (400 MHz, DMSO-d6): 2.23 (s, 3H), 5.73 (s, 1H), 7.48-8.17 (m, 7H), 8.84 (s, 1H), 8.62 (s, 1H), 12.45 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N+](=[CH2:15])=[N-]>>[CH3:15][O:11][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: CSc1ccc(CC(=O)O)cc1
Product: COC(=O)Cc1ccc(SC)cc1

Procedure:
(4-Methylsulfanyl-phenyl)-acetic acid was treated with an etheral solution of diazomethane until completion of esterification. The solvent was evaporated, the residue triturated in hexane/ether, and filtered to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([Cl:29])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[F-].[Cs+].CO[CH2:34][CH2:35]OC.CO>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:3]1[C:2]([CH:34]=[CH2:35])=[CH:17][CH:16]=[C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(OCc1ccccc1)c1c(NS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1Cl
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)OCc2ccccc2)c1Cl

Procedure:
A mixture of Example 226E (160 mg, 0.32 mmol), dibutyl vinylborate (88 mg, 0.48 mmol), CsF (146 mg, 0.96 mmol), Pd(PPh3)4 (37 mg, 0.03 mmol), DME (3.2 mL) and methanol (1.6 mL) was purged with argon, sealed in a vial and microwaved at 150° C. for 240 seconds. The mixture was diluted with ethyl acetate (50 mL), washed with brine, dried (Na2SO4), filtered, concentrated and purified on a Biotage silica gel cartridge (40 g) with 10% ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 446 (M+H)+, 463 (M+NH)+, 468 (M+Na)+; (ESI(−)) m/e 444 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.76 (m, 3H), 7.38 (m, 7H), 7.10 (d, 1H), 6.93 (dd, 1H), 5.86 (d, 1H), 5.51 (d, 1H), 5.26 (s, 2H).
Reaction SMILES: [CH3:1][S-:2].[Na+].[NH2:4][C:5]1[C:6](Cl)=[N:7][C:8]([Cl:11])=[N:9][CH:10]=1>CO>[NH2:4][C:5]1[C:6]([S:2][CH3:1])=[N:7][C:8]([Cl:11])=[N:9][CH:10]=1
Reactant: C[S-]
Reactant: Nc1cnc(Cl)nc1Cl
Agent: [Na+]
Solvent: CO
Product: CSc1nc(Cl)ncc1N
Yield: 35 %

Procedure:
Sodium methanethiolate (0.342 g) was added to a solution of 5-amino-2,4-dichloropyrimidine (1 g) in methanol (5 ml) and the mixture was heated at reflux for 2 hours. Volatile material was then removed by evaporation and water (1 ml) was added. The suspended solid was collected by filtration, washed with hexane (10 ml) and dried under vacuum to give 5-amino-2-chloro-4-methylthiopyrimidine (0.3 g); 1H NMR (CDCl3): 2.55 (s, 3H), 7.75 (s, 1H); mass spectrum (+ve CI): 175 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[I:30]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[I:30])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4nccc34)CC2=O)cc1
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4ncc(I)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(R)-4-((R)-1-((6-chloropyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (216 mg, 0.522 mmol) was dissolved in acetonitrile (10.0 mL) and N-iodosuccinimide (124 mg, 0.548 mmol) was added. The solution was stirred at room temperature for 5 minutes. The reaction was diluted with DCM. The organic layer was washed with 1M NaOH followed by an aqueous solution of sodium thiosulfate. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to afford (R)-4-((R)-1-((6-chloro-3-iodopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:7])=[N:4][O:5][N:6]=1.C(OCC)C.[Cl-].[CH:14]1([C:17](O)=[O:18])[CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([NH:7][C:17]([CH:14]2[CH2:16][CH2:15]2)=[O:18])=[N:4][O:5][N:6]=1
Reactant: Cc1nonc1N
Reactant: O=C(O)C1CC1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1nonc1NC(=O)C1CC1
Reaction time: 0.5 h

Procedure:
5 g (about 0.05 moles) of 4-methyl-3-aminofurazan, 50 ml of ethyl ether and 4 ml of pyridine are then loaded into a 100 ml glass reactor. This is cooled to a temperature of from 0° to 10° C. and 5 ml (0.06 moles) of the chloride of cyclopropanecarboxylic acid are added under agitation. Heating is then carried out under reflux for about one hour. After cooling of the reaction mass, the ether is evaporated and the residual solid is transferred into about 100 ml of water. Slight heating is effected for about 30 minutes and then the mass is cooled and filtered, the solid being washed with water. The solid obtained is dried in an oven at 90° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([CH:35]([CH3:37])[CH3:36])[C:12]2[O:16][C:15]([C:17]3[CH:33]=[CH:32][C:20]([C:21]([NH:23][CH2:24][C@H:25]4[O:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:22])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:34]=1)#[N:8].Br[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=1>CO>[C:7]([C:9]1[CH:10]=[C:11]([CH:35]([CH3:37])[CH3:36])[C:12]2[O:16][C:15]([C:17]3[CH:33]=[CH:32][C:20]([C:21]([NH:23][CH2:24][C@H:25]4[O:31][CH2:30][CH2:29][N:28]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=5)[CH2:27][CH2:26]4)=[O:22])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:34]=1)#[N:8]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CCNCCO4)cc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CCN(Cc5cccc(C(F)(F)F)c5)CCO4)cc3)oc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a mixture of 36 mg of potassium carbonate in methanol (3 ml) was added 37 mg of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-[(7S)-1,4-oxazepan-7-ylmethyl]benzamide (INTERMEDIATE 20) followed by 1-(bromomethyl)-3-(trifluoromethyl)benzene (13 μl). The mixture was heated to 70° C. and stirred for 8 h, and then cooled and added directly to a 40M samplet for purification via column chromatography on a Biotage Horizon 40M column, eluting with 1 column volume of 100% hexanes, followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes, followed by 4 column volumes of 100% ethyl acetate, to provide the title compound (28 mg, 56%). Mass spectrum (ESI) 577.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.4 Hz, 2H), 7.96 (d, J=6.0 Hz, 2H), 7.94 (s, 1H), 7.61 (s, 1H), 7.52 (m, 3H), 7.44 (t, J=7.5 Hz, 1H), 6.65 (bs, 1H), 3.96 (m, 2H), 3.81 (m, 2H), 3.70 (s, 2H), 3.68 (m, 2H), 3.48 (sept, J=7.0 Hz, 1H), 3.25 (m, 1H), 2.74 (m, 2H), 2.01 (m, 1H), 1.82 (m, 1H), 1.46 (d, J=7.0 Hz, 6H).
Reaction SMILES: OC1C=CC([C:8]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:9]=2[C:10]([O-:12])=[O:11])=CC=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:17][C:15]2[CH:16]=[CH:8][C:9]([O:12][C:10](=[O:11])[C:9]3[CH:8]=[CH:16][C:15]([O:17][C:24](=[O:25])[C:23]4[CH:27]=[CH:28][C:20]([C:19]([F:29])([F:30])[F:18])=[CH:21][CH:22]=4)=[CH:14][CH:13]=3)=[CH:13][CH:14]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])c1ccc(O)cc1-c1ccc(O)cc1
Product: O=C(Oc1ccc(OC(=O)c2ccc(C(F)(F)F)cc2)cc1)c1ccc(OC(=O)c2ccc(C(F)(F)F)cc2)cc1

Procedure:
4-(4-trifluoromethylbenzoyloxy)-benzoic acid-4-(4-trifluoromethylbenzoyloxy)-phenyl ester is prepared as in Example 6 from 4-hydroxyphenyl-4-hydroxybenzoate and 4-trifluoromethylbenzoyl chloride. Yield: 12.9 g (80% of the theoretical). A liquid crystalline phase was observed under a polarization microscope in the temperature range from 180° to 340° C.
Reaction SMILES: Cl[C:2]1[C:3]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[NH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[N:22]=1>>[N:5]1[C:4]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:3]=2[C:2]([NH:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[N:22]=2)=[N:7][CH:6]=1
Reactant: Clc1ncnc2c1oc1ccccc12
Reactant: NCCNc1ccnc(N)n1
Agent: Cl
Product: Nc1nccc(NCCNc2ncnc3c2oc2ccccc23)n1

Procedure:
4-Chloro-benzo[4,5]furo[3,2-d]pyrimidine (50 mg, 0.244 mmol) and the product of Example 1E (72 mg, 0.318 mmol) were treated under the conditions of Example 1F to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.59-3.85 (m, 4H) 6.03 (d, J=7.12 Hz, 1H) 7.52 (t, J=7.46 Hz, 1H) 7.58-7.67 (m, 1H) 7.67-7.88 (m, 4H) 8.11 (d, J=7.12 Hz, 1H) 8.28-8.44 (m, 1H) 8.82 (t, J=5.43 Hz, 1H) 11.69 (s, 1H); MS (ESI+) m/z 322.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([O:10][CH2:11][O:12][CH3:13])[CH:3]=1.C(Cl)(Cl)(Cl)[Cl:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:15])=[C:4]([O:10][CH2:11][O:12][CH3:13])[CH:3]=1
Reactant: COCOc1cc(Cl)ccc1CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCOc1cc(Cl)ccc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
4.69 g of 4-chloro-2-methoxymethoxybenzyl alcohol [prepared as described in step (b) above] were dissolved in 80 ml of tetrahydrofuran, and then 7.11 g of carbon tetrachloride and 12.14 g of triphenylphosphine were added to the resulting solution. The resulting mixture was stirred at room temperature for 1 hour and then heated under reflux for 2.5 hours. At the end of this time, any insoluble substance was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.38 g (yield 66%) of the title compound as an oily substance.
Reaction SMILES: Cl[C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]2[O:9][C:8]([C:10]3[S:11][CH:12]=[CH:13][N:14]=3)=[N:7][C:6]=2[CH:15]=1.[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[Sn](Cl)Cl>C(O)C>[NH2:16][C:3]1[C:2]([S:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:15][C:6]2[N:7]=[C:8]([C:10]3[S:11][CH:12]=[CH:13][N:14]=3)[O:9][C:5]=2[CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc2oc(-c3nccs3)nc2cc1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1cc2oc(-c3nccs3)nc2cc1Sc1ccc(O)cc1
Temperature: 70 °C

Procedure:
To a flask equipped with a magnetic stir bar and vigreux column was added the product from Example 349A, 4-mercaptophenol, potassium carbonate, and ethanol. The mixture was refluxed for 2 hours followed by addition of tin dichloride while the mixture was maintained at 70° C. After heating overnight the mixture was then cooled and filtered through silica, eluting with 10% CH3OH/CHCl3. The organic layer was then concentrated under vacuum and subjected to purification via Reverse phase (C-18) column chromatography (3% to 100% CH3CN/H2O with 0.1% TFA) to provide the title product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: N#Cc1ccc(F)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(C#N)cc2)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a solution of 4-fluorobenzonitrile (2.0 g) and 1-methylpiperazine (2.5 g) in dimethylsulfoxide (30 ml) was added potassium carbonate (4.6 g), and the solution was stirred for 1 hour at 120° C. Water was added thereto followed by stirring, the solution was 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 provide 4-(4-methylpiperazin-1-yl)benzonitrile (2.34 g). This compound (1.1 g) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (1.1 g).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH2:10]([O:9][C:7](=[O:8])[C:6](=[CH:14][N:15]([CH3:17])[CH3:16])[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)C(C)C
Product: CCOC(=O)C(=CN(C)C)C(=O)C(C)C
Yield: 50 %

Procedure:
A mixture of ethyl isobutyrylacetate (15 mmol, 0.42 mL) and N,N-dimethylformamide dimethyl acetal (37.5 mmol, 5 mL) was heated to reflux for 16 hours, then cooled. The volatiles were removed in vacuo to give 1.60 g of 2-dimethylaminomethylene-4-methyl-3-oxo-pentanoic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].Cl.[NH2:15][NH:16][C:17]([NH2:19])=[O:18].[OH-].[Na+]>CC(N(C)C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([S:10]([NH:15][NH:16][C:17]([NH2:19])=[O:18])(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8]
Reactant: NNC(N)=O
Reactant: Cc1cc(S(=O)(=O)Cl)cc(C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: Cc1cc(S(=O)(=O)NNC(N)=O)cc(C)c1O
Temperature: 0 °C

Procedure:
11 g (0.05 mol) of 3,5-dimethyl-4-hydroxybenzenesulphonic acid chloride and 6 g (0.05mol) of semicarbazide hydrochloride are first introduced into 50 ml of dimethylacetamide. 10 ml of 10 N sodium hydroxide solution are added dropwise to this white suspension over the course of 15 minutes at 40° C., whilst stirring. Since the reaction is exothermic, slight cooling must be applied. The mixture is then stirred for a further 4 hours at 40° C. After cooling to 0° C., the sodium chloride which has precipitated is filtered off and the filtrate is concentrated completely under reduced pressure. The residue is dissolved in a small amount of water and is cooled to 0°-5° C. Hereupon, 3.5-dimethyl-4-hydroxybenzenesulphonylsemicarbazide, of melting point 243° C. (with decomposition), crystallises out.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9](O)=[O:10].Cl.Cl.[CH3:24][N:25]([CH3:33])[C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>>[CH3:24][N:25]([CH3:33])[C:26]1[CH:27]=[C:28]([NH:29][C:9](=[O:10])[C:8]([C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Agent: Cl
Product: Cc1cc(C)c(C(C(=O)Nc2cccc(N(C)C)c2)=C2C(=O)Nc3ccccc32)[nH]1
Yield: 25.1 %

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydroindol-3-ylidene)-acetic acid (90 mg) was reacted with 3-dimethylaminoaniline dihydrochloride (85 mg) using method B to give 32 mg (25%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1/C=C\C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1/C=C\C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A solution of tert-butyl (Z)-4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)vinyl]piperidine-1-carboxylate (0.0374 g, 0.100 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0146 g, 0.100 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((Z)-2-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}vinyl)piperidine-1-carboxylate (0.0387 g, 77%).