Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][CH:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=5)[N:24]=[CH:23][CH:22]=4)[O:13][C:12]3=[O:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47].[Na+].[I-]>C1COCC1>[CH3:49][O:48][C:46](=[O:47])[CH2:45][CH2:44][N:18]([CH2:17][CH2:16][CH:14]1[O:13][C:12](=[O:33])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:15]1)[CH2:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COC(=O)CCBr
Reactant: COc1ccc2nccc(CCNCCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(CCc1ccnc2ccc(OC)nc12)CCC1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 80 °C
Yield: 42.4 %

Procedure:
A solution of the compound of Example 72 (0.2 g, 0.44 mmol) in THF (3 mL) was treated with DIPEA (0.147 mL, 2 eq.), methyl 3-bromopropionate (0.074 g, 1 eq.) and NaI (0.067 g, 1 eq.). The mixture was heated at 80° C. for 2 h, partitioned between EA and water. The org. phase was dried over MgSO4 and concentrated. The residue was purified by FC (EA) to give the title compound as a yellowish oil (0.1 g, 42% yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn](C)(C)C)[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[C:27]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:28]([O:31][CH3:32])=[N:29][CH:30]=1>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.CN(C=O)C>[NH2:23][C:14]1[CH:15]=[C:16]([C:25]2[CH:26]=[C:27]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[C:28]([O:31][CH3:32])=[N:29][CH:30]=2)[CH:17]=[C:18]2[C:13]=1[CH:12]=[N:11][N:10]2[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: COc1ncc(Br)cc1NS(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ncc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Temperature: 120 °C
Yield: 52.4 %

Procedure:
1-(Phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (4.2 g, 9.63 mmol), N-[5-bromo-2-(methyloxy)-3-pyridinyl]methanesulfonamide (3.25 g, 11.56 mmol) and Pd(PPh3)4 (1.113 g, 0.963 mmol) were weighed into a round-bottomed flask. DMF (30 ml) was added and the reaction was heated at 120° C. for 20 mins. The solvent was removed in vacuo and the crude material (9.8 g) was dissolved in DCM and loaded onto the top of a 750 g RediSep silica cartridge that was then eluted with 0-100% EtOAc/cyclohexane over 10 column volumes using the Companion XL. The product-containing fractions were combined and the solvent removed in vacuo to afford the title compound as a pale yellow solid (2.39 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].[I-:19].[Na+]>C(#N)C>[I-:19].[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N+:6]=1[CH2:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1nc2ccccc2s1
Reactant: C[Si](C)(C)CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1sc2ccccc2[n+]1CCC[Si](C)(C)C

Procedure:
2-Methylbenzothiazole (14.9 g, 0.10 moles), 3-chloropropyltrimethylsilane (15.0 g, 0.10 moles) and sodium iodide (15.0 g, 0.10 moles) were all suspended in acetonitrile (250 ml) and with stirring the mixture was heated at reflux for four days. The mixture was filtered while hot to remove sodium chloride, the solid was washed with acetonitrile and the filtrate was concentrated to dryness. The residue was stirred with ether and dried. Yield 916 g (25%) mp 203°-205°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:26]=[CH:25][C:16]2[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[N+:30]([O-:53])[CH:31]=[C:32]([Cl:52])[C:33]=1[CH2:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:26]=[CH:25][C:16]2[N:17]([CH2:21][C:22]([O:24][C@H:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:45])[F:46])=[C:39]([O:47][CH2:48][CH:49]4[CH2:50][CH2:51]4)[CH:38]=3)[CH2:34][C:33]3[C:32]([Cl:52])=[CH:31][N+:30]([O-:53])=[CH:29][C:28]=3[Cl:27])=[O:23])[C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)oc(=O)n2CC(=O)O)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1ccc2c(c1)oc(=O)n2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A mixture of 2-(6-(N-(tert-butoxycarbonyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid (0.234 g, 0.606 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.212 g, 0.505 mmol), EDC (0.290 g, 1.514 mmol) and DMAP (0.031 g, 0.252 mmol) in DCM (15 ml) was stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with 1N HCl, 1N NaHCO3 and brine. The organic phase was dried over sodium sulfate and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1) affording (S)-4-(2-(2-(6-(N-(tert-butoxycarbonyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.200 g, 0.254 mmol, 50% yield). MS/ESI+ 787.8 [MH]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH:20]([N:23]([CH3:25])[CH3:24])[CH2:19]2)=[CH:14][CH:13]=1>>[CH3:24][N:23]([CH3:25])[CH:20]1[CH2:21][CH2:22][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:2]([OH:1])=[N:3][CH:4]=3)=[CH:13][CH:14]=2)[CH2:19]1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(O)nc3)cc2)C1

Procedure:
6-Hydroxynicotinic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 326.17 (C18H22N4O2); MS (ESI): 327 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH3:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:9]=1
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: C1CCNCC1
Product: Cc1ccc(C#N)c(N2CCCCC2)c1
Temperature: 80 °C
Yield: 65 %

Procedure:
To commercially available 2-fluoro-4-methylbenzonitrile 15b (2.5 g, 18.5 mmol) was added piperidine (4 equiv., 7.3 ml) and the solution was heated at 80° C. overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 2.3 g of a white solid. Yield=65% 1HNMR (DMSO, 200 MHz) δ 1.62 (6H, m), 2.32 (3H, s), 3.07 (4H, m), 6.87 (1H, dd, J=7.8 Hz, J′=0.8 Hz), 6.95 (1H, s), 7.53 (1H, d, J=7.8 Hz)
Reaction SMILES: [N:1]1([C:6]2[CH:40]=[CH:39][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])=[CH:16][C:15]=4[CH3:37])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:41][S:42]([OH:44])=[O:43]>CN(C=O)C>[Cl:21][C:20]1[C:19]2[C:14](=[C:15]([CH3:37])[CH:16]=[C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])[CH:18]=2)[N:13]=[C:12]([S:42]([CH3:41])(=[O:44])=[O:43])[C:11]=1[CH2:10][C:9]1[CH:39]=[CH:40][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1
Reactant: CS(=O)O
Reactant: Cc1cc(C(O)(c2ccc(Cl)cc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Solvent: CN(C)C=O
Product: Cc1cc(C(O)(c2ccc(Cl)cc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(S(C)(=O)=O)nc12
Temperature: 100 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloro-8-methylquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.17 mmol, Intermediate 67), methanesulfinic acid (16.3 mg, 0.20 mmol), and DMF (2 mL) were combined in a reaction tube then sealed and heated to 100° C. and allowed to react at that temperature overnight. Analysis after overnight reaction showed only partial conversion, so additional methanesulfinic acid (13.3 mg, 0.17 mmol) was added and the vessel was resealed and heated to 100° C. for an additional 24 hours. The reaction vessel was then cooled to room temperature and solvent was removed by reduced pressure distillation. The crude residue was taken up into EtOAc, then extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C32H27Cl2N5O3S, 631.1. m/z found, 632.5 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 8.73-8.69 (m, 1H), 7.87 (dd, J=2.5, 0.6 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.65 (dd, J=1.9, 1.0 Hz, 1H), 7.60-7.57 (m, 2H), 7.37 (s, 1H), 7.35-7.30 (m, 4H), 7.20-7.16 (m, 2H), 6.44 (dd, J=2.5, 1.8 Hz, 1H), 6.37 (s, 1H), 5.06 (s, 2H), 4.48 (s, 1H), 3.39 (s, 3H), 2.92 (s, 3H), 2.74 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:13][CH2:14][CH2:15]Br)(=[O:12])[C:9]([CH3:11])=O>C(O)C>[N:1]1[C:9]([C:8]([O:13][CH2:14][CH3:15])=[O:12])=[CH:11][N:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:2]=12
Reactant: CC(=O)C(=O)OCCBr
Reactant: Nc1ncccn1
Solvent: CCO
Product: CCOC(=O)c1cn2cccnc2n1
Temperature: 75 °C
Yield: 29.8 %

Procedure:
2-Aminopyrimidine (5 g, 52.6 mmol) and bromoethyl pyruvate (90%, 7.35 mL, 52.6 mmol) were dissolved in ethanol (80 mL) and the reaction was heated to 75° C. for 16 h. The reaction was concentrated under reduced pressure and diluted with CH2Cl2 and sat aq NaHCO3. The organic layer was washed with sat aq NaHCO3 (2×) and the aq layers were extracted with CH2Cl2 (3×). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting brown oil was suspended in cold CH2Cl2 and filtered. The filter cake was washed with cold CH2Cl2 to obtain ethyl imidazo[1,2-a]pyrimidine-2-carboxylate (3 g, 30%) as a light yellow oil. The mother liquor contains a mixture of ethyl imidazo[1,2-a]pyrimidine-2-carboxylate and ethyl imidazo[1,2-a]pyrimidine-3-carboxylate (6 g, 60%) in the form of thick, black oil. This black oil was first purified by silica gel chromatography followed by recrystallization from EtOAc to obtain ethyl imidazo[1,2-a]pyrimidine-3-carboxylate (2 g, 20%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:20])[NH:13][C:12]([CH2:21][O:22][CH2:23][CH2:24][OH:25])=[C:11]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:20])[NH:13][C:12]([CH2:21][O:22][CH2:23][CH2:24][O:25][C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[C:11]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Clc1ncccn1
Reactant: CCOC(=O)C1=C(COCCO)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCCOc2ncccn2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 12.6 %

Procedure:
Sodium hydride (90 mg of an 80% by weight dispersion in oil) was added to a solution of 4-(2-chlorophenyl)-3-ethoxycarbonyl-2-(2-hydroxyethoxymethyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.60 g) in tetrahydrofuran (20 ml) and the mixture stirred at room temperature for 45 minutes and then treated with 2-chloropyrimidine (0.17 g). The mixture was stirred at room temperature for 3 days and evaporated. The residue was dissolved in ethyl acetate and the solution washed successively with 2M hydrochloric acid, 5% aqueous sodium carbonate solution and brine, dried over MgSO4 and evaporated. The residue was crystallised from ether to give the title compound (90 mg), m.p. 101°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21](OCC)=[O:22])=[CH:6][N:5]2[C:26]=1[CH3:27].[CH2:28]([NH2:31])[CH2:29][CH3:30].[C-]#N.[Na+]>CO>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([NH:31][CH2:28][CH2:29][CH3:30])=[O:22])=[CH:6][N:5]2[C:26]=1[CH3:27]
Reactant: CCCN
Reactant: CCOC(=O)c1cc(NCc2c(C)cccc2CC)c2nc(C)c(C)n2c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CCCNC(=O)c1cc(NCc2c(C)cccc2CC)c2nc(C)c(C)n2c1
Yield: 42.4 %

Procedure:
Ethyl 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylate (0.12 g, 0.33 mmol), propylamine (1.0 g, 17 mmol) and a cat. amount of sodium cyanide were refluxed in methanol (20 ml) for 24 h. An additional amount of propylamine (1.0 g, 17 mmol) was added and the reaction mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dietyl ether as eluent. Crystallization from diethyl ether gave 0.053 g (42%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@:3]1([CH:9]=[CH:10][C:11]([O: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][CH2:26][CH3:27])=[O:12])[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[H][H]>CCOC(C)=O.[Pd]>[OH:1][CH2:2][C@@:3]1([CH2:9][CH2:10][C:11]([O: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][CH2:26][CH3:27])=[O:12])[O:7][C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCOC(=O)C=C[C@]1(CO)CCC(=O)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)CC[C@@]1(CO)CCC(=O)O1
Yield: 98.2 %

Procedure:
A solution of 3.5 (0.154 g, 0.4 mmol) in EtOAc (20 mL) was treated with 10% Pd-C (0.4 g) and hydrogenated under a hydrogen balloon for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography over silica gel with EtOAc:hexanes (2:1) as eluant to give 3.3 (0.151 g, 98%) as a white solid; mp 59° C.; [α]22D +7.90° (c 1.0, CHCl3). The IR, 1H NMR, and 13C NMR were identical to those reported for the racemate 3.2. Anal. Calcd for C22H40O5 : C, 68.71; H, 10.48. Found: C, 68.81; H, 10.45.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:40][CH3:41])([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH3:39])[CH:33]=3)[CH2:30][CH3:31])=[CH:25][C:24]=2[CH3:42])=[CH:21][CH:22]=1)=[O:17].C(OCC)C>CN(C)C=O>[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:34]([CH3:39])[CH:33]=3)([CH2:30][CH3:31])[CH2:40][CH3:41])=[CH:25][C:24]=2[CH3:42])=[CH:21][CH:22]=1)=[O:17]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(-c2ccc(C(=O)OC)o2)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(=O)OC)o2)c(C)c1
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 86 %

Procedure:
t-Butyldimethylsilyl chloride (42.24 mg, 0.28 mmol) and imidazole (47.7 mg, 0.701 mmol) were added to a solution of 5-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-furan-2-carboxylic acid methyl ester (Example 19-(1); 55 mg, 0.14 mmol) in N,N-dimethylformamide (0.2 mL) at room temperature, and the mixture was stirred at room temperature for 0.2 hour. Diethyl ether was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=95/5 to ethyl acetate only) to give the title compound (61 mg, 86%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:37])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22]C(C)(C)C)=[O:21])=[C:18]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][N:9]([CH3:37])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([OH:22])=[O:21])=[C:18]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:17]=2)=[CH:12][CH:11]=1
Reactant: CN(C)c1ccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 4-(4-(dimethylamino)phenyl)-2-(4-fluoroanilino)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, ethyl acetate and water were added, and it was adjusted to pH6.5 with saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 4-(4-(dimethylamino)phenyl)-2-(4-fluoroanilino)benzoic acid 33 mg of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([Cl:15])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1.[F:23][C:24]([F:30])([F:29])[S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:16][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])[CH:5]=[C:6]([Cl:15])[C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Oc1cc(Cl)c(CN2CCCCC2)c(Cl)c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1cc(Cl)c(CN2CCCCC2)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a stirred solution of 3,5-dichloro-4-piperidin-1-ylmethylphenol (290 mg, 1.1 mmol) and pyridine (0.36 mL, 4.5 mmol) in DCM (10 mL) at −20° C. was added trifluoromethanesulfonyl chloride (0.38 mL, 2.2 mmol). After the addition was complete the reaction was allowed to warm to ambient temperature and stirred for 10 minutes. The mixture was diluted with DCM (20 mL), washed with water (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a colourless oil (334 mg, 76%). 1H NMR (CDCl3, 300 MHz): 7.26 (s, 2H), 3.66 (s, 2H), 2.53-2.44 (m, 4H), 1.58-1.48 (m, 4H), 1.50-1.34 (m, 2H).
Reaction SMILES: C([CH:3]1[CH2:26][NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4]1)C.Cl[C:28]1N=C(N)C(N)=C[CH:29]=1>>[CH2:28]([CH:26]1[NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1)[CH3:29]
Reactant: Nc1ccc(Cl)nc1N
Reactant: CCC1CNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2C1
Product: CCC1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N1

Procedure:
The titled compound was prepared analogously to Intermediate D by replacing 5-chloropyridine-2,3-diamine with 6-chloropyridine-2,3-diamine;
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[S:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1)=[O:4]>O.C(O)C>[OH:4][CH2:3][C:5]1[S:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1
Reactant: O=Cc1cc(C(=O)O)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1csc(CO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A solution of sodium borohydride (12.5 g, 330 mmol) in water (150 mL) and ethanol (100 mL) at 0° C. is charged with 5-formyl-thiophene-3-carboxylic acid (20.6 g, 132 mmol) in one portion. After warming to room temperature and stirring for 4 h, the mixture is diluted with water and the resulting precipitate vacuum filtered. The filtrate is concentrated and the resulting aqueous solution is washed with ether (2×). The aq layer is acidified with concentrated HCl and extracted with ether (3×). The combined ether extracts are dried over Na2SO4, filtered and concentrated in vacuo to give 5-hydroxymethyl-thiophene-3-carboxylic acid (14.6, 70%) as a white solid; mp 149° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.60 (s, 1 H), 8.10 (s, 1 H), 7.20 (s, 1 H), 5.52 (t, J=6.0 Hz, 1 H), 4.60 (s, 2 H).
Reaction SMILES: [NH2:1][S:2]([CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([NH:10][NH2:11])=[O:9])(=[O:4])=[O:3].[OH-].[K+].[C:18](=S)=[S:19]>C(O)C.O>[SH:19][C:18]1[O:9][C:8]([C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[CH2:5][S:2]([NH2:1])(=[O:3])=[O:4])=[N:10][N:11]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccccc1CS(N)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)Cc1ccccc1-c1nnc(S)o1
Yield: 22 %

Procedure:
To a suspension of 11.5 g of the hydrazide prepared in Example 1 in 100 ml of absolute ethanol was added a solution of 2.8 g of potassium hydroxide in 20 ml of water. After stirring several minutes, 4.8 g of carbon disulfide was added in one portion. The suspension was refluxed 4.5 hours then concentrated in vacuo. After water (about 100 ml) was added to the residue and the suspension stirred several minutes, the suspension was filtered and the filtrate was acidified with concentrated hydrochloric acid (red to litmus paper). The mixture was filtered and the residue was washed sequentially with 1×25 ml water, 1×10 ml 2-propanol and 1×10 ml ethyl ether. The suction-dried residue was recrystallized from methanol to give 3 g of the subject compound; m.p. 224°-227° C.
Reaction SMILES: C1(S([CH:10]2[CH:15](S(C3C=CC=CC=3)(=O)=O)[CH:14]3[CH2:25][CH2:26][CH:11]2[CH:12]=[CH:13]3)(=O)=O)C=CC=CC=1.[N+:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])#[C-:28].CC(C)([O-])C.[K+].Cl>O1CCCC1>[CH2:33]([O:32][C:30]([C:29]1[NH:27][CH:28]=[C:15]2[C:10]=1[CH:11]1[CH2:26][CH2:25][CH:14]2[CH:13]=[CH:12]1)=[O:31])[CH3:34]
Reactant: O=S(=O)(c1ccccc1)C1C2C=CC(CC2)C1S(=O)(=O)c1ccccc1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc2c1C1C=CC2CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A reaction system of a mixed solution of 7.76 g (20 mmol) of the resultant 5,6-bis(phenylsulfonyl)-bicyclo[2,2,2]octa-2-ene and 50 ml of anhydrous tetrahydrofuran was replaced with nitrogen. Then, 2.425 ml (22 mmol) of ethyl isocyanoacetate were added to the mixed solution, and the whole was cooled to 0° C. Potassium tert-butoxide (50 ml/l M THF solution) was dropped into the mixture in 2 hours, and the whole was stirred at room temperature for 3 hours. After the completion of the reaction, diluted hydrochloric acid was added to the reaction mixture. Then, the reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, distilled water, and a saturated salt solution in this order, and was dried with anhydrous sodium sulfate. The dried product was purified by means of silica gel column chromatography (chloroform) to yield ethyl-4,7-dihydro-4,7-ethano-2H-isoindole-1-carboxylate (3.5 g, 16 mmol, 80% yield).