Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[C:6]([CH:8]=1)[NH2:7].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[C:6]([NH:7][S:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)(=[O:29])=[O:30])[CH:8]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CCCn1cnc(CSc2ccc(Cl)cc2N)c1
Solvent: c1ccncc1
Product: CCCn1cnc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Yield: 48.1 %

Procedure:
Following General Procedure B, the title compound (463 mg, 48%) was prepared from 5-chloro-2-(((1-propyl-1H-imidazol-4-yl)methyl)thio)aniline (587 mg, 2.082 mmol) and benzofuran-2-sulfonyl chloride (451 mg, 2.082 mmol) in pyridine (10 ml).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:20])[NH:12][C@H:13]([CH2:18][OH:19])[C@@H:14]([CH3:17])[CH2:15][CH3:16])[N:10]=2)[CH2:3]1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O>[OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:20])[NH:12][C@H:13]([CH2:18][O:19][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:14]([CH3:17])[CH2:15][CH3:16])[N:10]=2)[CH2:3]1
Reactant: CC[C@H](C)[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 72.8 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(1S,2S)-1-(hydroxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.34 g, 4.48 mmol) (obtained as described in Reference Example 38(3)) in dimethylformamide (67 ml) were added t-butyldimethylsilyl chloride (810 mg, 5.37 mmol) and imidazole (527 mg, 5.37 mmol) in an ice bath, and then the reaction mixture was stirred in the ice bath for 2.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (5:1→3:1) as the eluant to afford 3-hydroxy-1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.35 g, yield 97%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)=[O:33].FC1C=CC(C(F)(F)F)=CC=1NC(NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=O>>[NH2:11][C:9]1[C:10]2=[C:2]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32]([NH:31][C:22]4[CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=[CH:26][C:21]=4[Cl:20])=[O:33])=[CH:40][CH:39]=3)[C:3]([CH3:19])=[C:4]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:6]=[CH:7][N:8]=1
Reactant: Cc1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3Cl)cc2)OC1(C)C
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Product: Cc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3Cl)cc2)c2c(N)ncnn2c1CN1CCOCC1
Yield: 26 %

Procedure:
The title compound was prepared in a manner similar to the procedure described for the preparation of Example 117 Step 4, using the product of step 1, Example 119 (5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine in place of 5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and Intermediate AAL (1-[2-chloro-5-(trifluoromethyl)-phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-urea) in place of Intermediate AAN (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-urea) 44 mg (26%) of the desired product was isolated. 1H-NMR (DMSO-d6) δ 9.72 (s, 1H), 8.67-8.63 (m, 2H), 7.85 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.39-7.30 (m, 3H), 3.80 (s, 2H), 3.53-3.50 (m, 4H), 2.42-2.39 (m, 4H), 2.09 (s, 3H); MS [M+H]+=560.2; LCMS RT=2.66.
Reaction SMILES: [H-].[Na+].CC1N=NC(N2CCC(CCO)CC2)=CC=1.Cl[C:20]1[S:21][CH:22]=[C:23]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[N:24]=1>C(COC)OC.CCOCC>[Si:27]([O:26][CH2:25][C:23]1[N:24]=[CH:20][S:21][CH:22]=1)([C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:28])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCc1csc(Cl)n1
Agent: Cc1ccc(N2CCC(CCO)CC2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OCc1cscn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A suspension of sodium hydride (60%, 135 mg, 3.4 mmol) and 1-(6-methyl-3-pyridazinyl)-4-(2-hydroxyethyl)-piperidine (250 mg, 1.1 mmol) in dimethoxyethane (DME; 4 ml) was stirred at room temperature for 2 hr. A solution of 2-chloro-4-t-butyldimethylsilyloxymethylthiazole (385 mg, 1.46 mmol) in DME (1 ml) was added and the mixture stirred at reflux under argon for 5 hr then at room temperature overnight. The mixture was diluted with ether, filtered and then concentrated. The residue was chromatographed on silica gel (25 g; eluent 30%-50% ethyl acetate/hexane) to give 2-1 -(6-methyl-3-pyridazinyl)-4-piperidinylethyl-1-oxy)-4t-butyldimethylsilyloxymethylthiazole (274 mg, 54%), 1H nmr, 0.11 (s, 6H), 0.94 (s, 9H), 1.3-1.87 (m, 7H), 2.58 (s, 3H), 2.93 (t, 2H), 4.31-4.35 (m, 2H), 4.48 (t, 2H), 4,64 (s, 2H), 6.51 (s, 1H), 6.93 (d, 1H), 7.11 (d, 1H).
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[O:11][CH:12]=2)=[CH:4]1.Cl>O.CO>[S:3]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[O:11][CH:12]=2)=[CH:4]1
Reactant: COC(=O)CCCCc1nc(-c2ccsc2)co1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCc1nc(-c2ccsc2)co1
Temperature: 40 °C

Procedure:
Add solution of sodium hydroxide in water to a solution of methyl 5-(4-thiophen-3-yloxazol-2-yl)pentanoate in methanol at room temperature and heat the mixture at 40° C. for 2 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate. Wash the organic extract three times with water, dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with hexanes/ethyl acetate and collect the solids by filtration to provide the title compound: APCI mass spectrum m/z 252 [C12H13NO3S+H]+.
Reaction SMILES: Cl.[S:2]([N:12]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]1=2)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:24](OCCC(C)C)=[O:25]>C(OCC)C>[OH:25][N:24]=[C:16]1[CH2:17][CH2:18][N:12]([S:2]([C:5]2[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=2)(=[O:3])=[O:4])[C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[C:15]1=[O:19]
Reactant: CC(C)CCON=O
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CCC(=NO)C(=O)c3ccccc32)cc1
Yield: 61.2 %

Procedure:
Hydrochloric acid gas was bubbled through a cooled suspension of 1-tosyl-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one (30 g, 0.1 mol) in a dry diethyl ether (500 mL) at 0-5° C. Isoamyl nitrite (26.41 mL, 0.24 mol) was added drop wise and hydrochloric acid gas was continuously passed for 6-7 h after the addition. The precipitate that formed was filtered washed with diethyl ether and dried under reduced pressure to afford 4-(hydroxyimino)-1-tosyl-3,4-dihydro-1H-benzo[b]azepin-5 (2H)-one (21.09 g). 1H NMR: 400 MHz, CDCl3) δ: 7.79 (1H, d, J=7.6 Hz), 7.2 (1H, t, J=7.6 Hz), 7.62 (1H, d, J=8.0 Hz), 7.55 (1H, t, J=7.2 Hz), 7.39 (2H, d, J=8.4 Hz), 7.16 (2H, d, J=8.4 Hz), 4.07 (2H, t, J=6.8 Hz), 2.88 (2H, t, J=6.8 Hz), 2.342 (3H, s), 1.98 (2H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[C:27]1([S:33]([NH:1][CH2:2][C:3]([N:5]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:9](=[O:15])[N:8]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:7]3[CH:23]=[CH:24][CH:25]=[CH:26][C:6]2=3)=[O:4])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CNS(=O)(=O)c2ccccc2)c2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a solution of (3aR*,10aS*)-4-aminoacetyl-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta-[e][1,4]diazepin-10(1H)-one (0.2 g, 0.57 mmol) and benzenesulfonyl chloride (0.12 g, 0.69 mmol) in dichloromethane (10 mL) was added triethylamine (70 mg, 0.69 mmol). The mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with dichloromethane. The extract was washed with water and dried, then, the solvent was distilled off. The residue was purified by silica-gel column chromatography (dichloromethane), which was crystallized from diethyl ether to give 170 mg (yield 61%) of the titled compound, m.p. 185°-187° C.
Reaction SMILES: CS[C:3](=N)[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[OH:18][CH2:19][CH2:20][NH:21][CH:22]([CH3:26])[CH:23]([CH3:25])[NH2:24]>C(O)C>[CH3:25][CH:23]1[CH:22]([CH3:26])[N:21]([CH2:20][CH2:19][OH:18])[C:3](=[N:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[NH:24]1
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Reactant: CC(N)C(C)NCCO
Solvent: CCO
Product: CC1NC(=Nc2ccccc2N2CCOCC2)N(CCO)C1C

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea (12.5 g) and N-(2-hydroxyethyl)-1,2-dimethylethylenediamine (8 g) in dry ethanol (150 ml) was heated under reflux at 90°-95° C. for 6 days to give a dark brown oil which was purified by column chromatography on neutral alumina (250 g) using a 1:9 mixture of dichloromethane and hexane to give 4-{2-[4,5-dimethyl-1-(2-hydroxyethyl)-2-imidazolidinylideneamino]phenyl}morpholine as a colourless solid (m.p. 108°-109° C.) which was recrystallised from hexane.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:33]([NH:37][C:38](=[O:52])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:40]=1)([CH3:36])([CH3:35])[CH3:34]>C(#N)C>[C:33]([NH:37][C:38](=[O:52])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:47][CH2:48][N:49]([C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=3[F:1])[CH2:50][CH2:51]2)[CH:40]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3F)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.8 %

Procedure:
2-Fluoro-4-nitrobenzoic acid (5 g, 27.01 mmol) was dissolved in acetonitrile (150 mL) and triethylamine (7.53 mL, 54.02 mmol). N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.8 g, 40.52 mmol) was added, followed by N-tert-butyl-3(piperazin-1-ylmethyl)benzamide (7.44 g, 27.01 mmol). The reaction was stirred at room temperature for 18 hours and concentrated under vacuum. The residue was dissolved in ethyl acetate, filtered through dicalite, washed consecutively with water (×2) and brine and concentrated under vacuum. The product was purified by strong cation exchange chromatography, eluting macroporous polystyrene sulfonic acid with 2M ammonia in methanol. The resulting solution was concentrated under vacuum to afford the title compound as a pale yellow oil (2.6 g). MS (ESI) m/z 443.7 [M+H]+
Reaction SMILES: Cl[C:2]1[C:3]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[O:20]1[CH2:21][CH2:22][N:17]([C:3]2[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][N:6]=[C:5]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:4]=2)[CH2:18][CH2:19]1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cnc(Nc2cc(N3CCOCC3)c(Cl)cn2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cnc(Nc2cc(N3CCOCC3)c(-c3ccccc3)cn2)cn1
Temperature: 150 °C
Yield: 27.9 %

Procedure:
A mixture of 5-(5-chloro-4-morpholinopyridin-2-ylamino)pyrazine-2-carbonitrile (50 mg, 0.16 mmol), phenylboronic acid (38 mg, 0.31 mmol), sodium carbonate (41 mg, 0.39 mmol) and Bedford catalyst (1 mg, 0.01 mmol) in a mixture of acetonitrile-water (4:1, 2.5 mL) was heated at 150° C. by microwave irradiation for 30 minutes. The crude reaction mixture was purified by ion exchange chromatography on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated. Preparative TLC, eluting with ethyl acetate-hexane (2:3) gave 5-(4-morpholino-5-phenylpyridin-2-ylamino)pyrazine-2-carbonitrile as a yellow solid (16 mg, 28%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.CO.[BH4-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OC1CCc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
Charged 5-fluoro-2,3-dihydroinden-1-one (486 mg, 3.22 mmol), methanol (8 mL) and dichloromethane (4 mL) to a flask, the mixture was cooled to 0° C. and NaBH4 (119 mg, 3.22 mmol) was added in portions. The reaction mixture was stirred at 0° C. for 15 min, warmed up to room temperature and stirred for 30 min. Added water, extracted with ethyl acetate twice, and washed the organic phase with brine and dried with anhydrous Na2SO4, concentrated to give the title compound (488 mg, 100%). 1H NMR (400 MHz, CDCl3): δ 1.94-2.02 (1H, m), 2.46-2.55 (1H, m), 2.76-7.84 (1H, m), 3.01-3.08 (1H, m), 5.20 (2H, t, J=5.6 Hz), 6.89-6.93 (2H, m), 7.32-7.36 (1H, m).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C[O-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:36][O:35][C:32]1[N:33]=[CH:34][C:29]([NH:28][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]2)[C:5](=[O:16])[N:6]3[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:30][CH:31]=1
Reactant: COc1ccc(N)cn1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: [Pd]
Agent: C[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Nc3ccc(OC)nc3)cccc21
Temperature: 25 °C
Yield: 52.8 %

Procedure:
To an oven-dried 2-neck 25 mL round bottom flask equipped with a condenser was charged with 4′-bromo-1′-pentylspiro-(6,7-dihydrofuro-[2,3-f][1,3]benzodioxole-7,3′-indole)-2′-(1′H)-one (50.5 mg, 0.12 mmol), 5-amino-2-methoxypyridine (22.3 mg, 0.18 mmol), Pd2(dba)3 (10 mole %), BINAP (10 mole %) and sodium methoxide (12.9 mg, 0.24 mmol). The flask was flushed with nitrogen for 5 min followed by the addition of degassed toluene (5.00 mL). The reaction mixture was heated at reflux for 16 h. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (20.0 mL) and washed with saturated ammonium chloride (10.0 mL), brine (10.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The brown residue was subjected to column chromatography eluting with ethyl acetate-hexane (20% to 50%) to yield the title compound (30.0 mg) in 54% yield: MS (ES+), m/z 474.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([CH2:36][C:37]([O:39]C)=[O:38])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Na+].Cl>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([NH:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)[CH2:27][CH2:28]3)[CH:17]([CH2:36][C:37]([OH:39])=[O:38])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1NC1CCN(c2ccnc(C)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(N2CCC(NN3C(=O)CN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3CC(=O)O)CC2)ccn1
Yield: 88.4 %

Procedure:
A mixture of methyl 4-[(6-chloro-2-naphthyl)sulfonyl]-1-[[1-(2-methyl-4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazineacetate (1.17 g) obtained in Example 138 and a 2N aqueous solution of sodium hydroxide (2.0 ml) in methanol (20 ml) and 1,4-dioxane (10 m) was stirred at 40° C. for 2 hours. The reaction mixture was cooled, neutralized with 1N hydrochloric acid, and concentrated under reduced pressure. The residue was combined with saturated brine, extracted with a 10% methanol-containing dichloromethane, dried and concentrated. The residue obtained was crystallized from a mixture of ethanol and ethyl acetate to obtain the title compound (1.01 g) as colorless crystals.
Reaction SMILES: C([O-])(=O)C1C(=CC=CC=1)S.COC(=O)C1C(=CC=C(C(F)(F)F)C=1)S.[OH:26][C:27]1[C:28]2[CH:41]=[C:40](C(F)(F)F)[CH:39]=[CH:38][C:29]=2[S:30][C:31]=1[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[O:35]>>[OH:26][C:27]1[C:28]2[CH:41]=[CH:40][CH:39]=[CH:38][C:29]=2[S:30][C:31]=1[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)C=Cc1sc2ccc(C(F)(F)F)cc2c1O
Agent: COC(=O)c1cc(C(F)(F)F)ccc1S
Agent: O=C([O-])c1ccccc1S
Product: COC(=O)C=Cc1sc2ccccc2c1O

Procedure:
When the starting thiosalicylate of the above example was replaced by 5-(trifluoromethyl)thiosalicyclic acid methyl ester, methyl 3-(3-hydroxy-5-(trifluoromethyl)benzo[b]thiophene-2-yl)acrylate, an off-white solid m/z 302 (M+.) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[CH:35][CH:34]=3)[C:16]2=[CH:15][N:14]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc(N5CCN(C)CC5)cc4)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (Alfa Aesar, Cat. No. H51659). LCMS (M+H)+=499.1/501.1. 1H NMR (300 MHz, DMSO-d6) δ: 9.61 (s, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.98 (s, 1H), 3.92 (s, 6H), 3.30-3.14 (m, 8H), 2.17 (s, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[CH2:35][O:36][Si](C(C)(C)C)(C)C)[O:13][CH2:14][C:15]1[S:19][C:18](/[C:20](/[CH2:30][CH3:31])=[CH:21]/[CH:22]=[CH:23]/[C:24]([CH2:28][CH3:29])([OH:27])[CH2:25][CH3:26])=[CH:17][CH:16]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[CH2:35][OH:36])[O:13][CH2:14][C:15]1[S:19][C:18](/[C:20](/[CH2:30][CH3:31])=[CH:21]/[CH:22]=[CH:23]/[C:24]([CH2:28][CH3:29])([OH:27])[CH2:25][CH3:26])=[CH:17][CH:16]=1
Reactant: CC/C(=C\C=C\C(O)(CC)CC)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC/C(=C\C=C\C(O)(CC)CC)c1ccc(COc2ccc(CO)c(CO)c2)s1
Reaction time: 4 h

Procedure:
850 mg (1.3 mmol) of (4E,6E)-7-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-3-ethylnona-4,6-dien-3-ol are dissolved in 20 mL of anhydrous THF. 3.9 mL (3.9 mmol) of 1 M tetrabutylammonium fluoride solution are then added and the medium is stirred for 4 hours. After the usual treatment, the residue is purified by chromatography on silica gel (eluent: 2 heptane/8 ethyl acetate). (4E,6E)-7-[5-(3,4-bis-Hydroxymethyl-phenoxymethyl)-2-thienyl]-3-ethylnona-4,6-dien-3-ol is obtained in the form of a yellow oil (m=340 mg; Y=63%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH2:8][CH2:9][CH:10]=[C:11]([C:22]([OH:24])=[O:23])[CH2:12][CH2:13][C@@H:14]2[C:18](=[CH2:19])[C:17](=[O:20])[O:16][C@@H:15]2[CH:21]=1.[CH3:25]O>[Cl-].[Na+].O>[CH3:6][C:7]1[CH2:8][CH2:9][CH:10]=[C:11]([C:22]([O:24][CH3:25])=[O:23])[CH2:12][CH2:13][C@@H:14]2[C:18](=[CH2:19])[C:17](=[O:20])[O:16][C@@H:15]2[CH:21]=1
Reactant: C=C1C(=O)O[C@@H]2C=C(C)CCC=C(C(=O)O)CC[C@H]12
Reactant: CO
Agent: C=C1C(=O)O[C@@H]2/C=C(\C)CC/C=C(\C(=O)O)CC[C@H]12
Agent: C=C1C(=O)O[C@@H]2/C=C(\C)CC/C=C(\C(=O)OC)CC[C@H]12
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C1C(=O)O[C@@H]2C=C(C)CCC=C(C(=O)OC)CC[C@H]12
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (2 mL) was added slowly to a solution of the acid product of Example 1 (0.1 mmol) in 20 mL absolute methanol. The mixture was refluxed overnight, cooled to room temperature, and diluted with brine. The resultant solution was extracted with 3×20 mL CHCl3. The combined organic layers were washed with a saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography to provide the desired product in a yield of 82%.