Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]2)[S:6][CH:7]=1.C(N(C(C)C)CC)(C)C.O=C1CCC(=O)N1[O:30][C:31]([NH:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:35]=1[CH:36]=[N:37][N:38]2C(OC)=O)=O.[OH-].[Na+]>O.CO.CN(C)C=O>[NH:38]1[C:39]2[C:35](=[C:34]([NH:33][C:31]([NH:13][C@H:10]3[CH2:11][CH2:12][C@@H:8]([C:5]4[S:6][CH:7]=[C:3]([CH3:2])[N:4]=4)[CH2:9]3)=[O:30])[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Reactant: Cc1csc([C@@H]2CC[C@H](N)C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc([C@@H]2CC[C@H](NC(=O)Nc3cccc4[nH]ncc34)C2)n1
Reaction time: 2 h
Yield: 42.9 %

Procedure:
A solution of Example 120C (89 mg, 0.41 mmol), N,N-dimethylformamide (3 mL), diisopropylethylamine (0.15 mL, 0.85 mmol) and methyl 4-((2,5-dioxopyrrolidin-1-yloxy)carbonylamino)-1H-indazole-1-carboxylate (prepared as in Org. Proc. Res. Dev., 2007, 11, 578; 135 mg, 0.41 mmol) was stirred at room temperature for 10 minutes. Methanol (6 mL) and 5N aqueous NaOH (0.24 mL, 1.2 mmol) were added and stirring continued for 2 hours at room temperature. The reaction mixture was diluted with water (10 mL), concentrated to half the volume, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% of methanol/ethyl acetate (1:10) in hexanes) to obtain the title compound (60 mg, 43%) and Example 119 (28 mg, 20%). MS (ESI+) M/Z 342 [M+H]+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[I:16][C:17]1[C:18]([CH3:30])=[C:19]([CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27])[C:20]([OH:22])=O.[CH3:31][C:32]([N:35]1[C:39]([OH:40])=[CH:38][CH:37]=[N:36]1)([CH3:34])[CH3:33].C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C.ClCCl>[CH3:31][C:32]([N:35]1[C:39]([OH:40])=[C:38]([C:20](=[O:22])[C:19]2[CH:23]=[CH:24][C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:17]([I:16])[C:18]=2[CH3:30])[CH:37]=[N:36]1)([CH3:34])[CH3:33]
Reactant: CC(C)(C)n1nccc1O
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1I
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)c2cnn(C(C)(C)C)c2O)ccc(S(C)(=O)=O)c1I
Reaction time: 1.5 h

Procedure:
A solution of 8.4 g (40 mmol) of 1,3-dicyclohexylcarbodiimide in 40 mL of acetonitrile was added to a mixture of 13.6 g (40 mmol) of 3-iodo-2-methyl-4-methylsulfonylbenzoic acid and 5.6 g (40 mmol) of 1-(1,1-dimethylethyl)-5-hydroxypyrazole in 80 mL of acetonitrile with stirring. The mixture was allowed to stir for 1 hour and was then filtered, washing the filter cake with a little acetonitrile. Triethylamine (16.8 mL, 120 mmol) and acetone cyanohydrin (1 mL, 10 mmol) were added with stirring to the filtrate. After about 1.5 hour, dichloromethane was added and the resulting mixture was washed with a mixture of 2N aqueous hydrochloric acid and saturated aqueous sodium chloride. It was then concentrated by evaporation under reduced pressure. The residue obtained was dissolved in dichloromethane and the resulting solution was extracted with dilute aqueous sodium hydroxide. The aqueous extract was acidified with concentrated aqueous hydrochloric acid and the resulting mixture was extracted with dichloromethane. Fifty mL of triethylamine was added to the dichloromethane extract and the resulting solution was washed with saturated aqueous sodium chloride solution and then several times with 2N aqueous hydrochloric acid. It was then concentrated by evaporation under reduced pressure. The residue was triturated with hexane to obtain 16.8 g (72.7 percent of theory of the title compound as a light yellow powder melting at 171-172° C.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=C[CH:2]=1.Br[C:13]1[C:22]([CH2:23][N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:21][C:20]2[C:19]([CH3:30])([CH3:29])[CH2:18][CH2:17][C:16]([CH3:32])([CH3:31])[C:15]=2[CH:14]=1.COC([SiH3])=C(OC)OC.C(N(CC)CC)C>CN1CCCC1=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([C:13]1[C:22]([CH2:23][N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:21][C:20]2[C:19]([CH3:30])([CH3:29])[CH2:18][CH2:17][C:16]([CH3:32])([CH3:31])[C:15]=2[CH:14]=1)=[CH2:2]
Reactant: CC1(C)CCC(C)(C)c2cc(Cn3cccn3)c(Br)cc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC([SiH3])=C(OC)OC
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: C=Cc1cc2c(cc1Cn1cccn1)C(C)(C)CCC2(C)C
Temperature: 90 °C
Reaction time: 17 h
Yield: 21.2 %

Procedure:
To a suspension of 2.076 g (3.99 mmol) 2-bromo-5,5,8,8,-tetramethyl-3-((pyrazol-1-yl)methyl)-5,6,7,8-tetrahydronaphthalene p-toluenesulfonate, 0.045 g (0.20 mmol) of palladium acetate, 0.122 g (0.40 mmol) of tri-o-tolulylphosphine) and 1.22 ml (7.97 mmol) trimethoxyvinylsilane in 8 ml N-methylpyrrolidinone was added 1.80 ml (12.90 mmol) triethylamine. The reaction vessel was evacuated and filled with nitrogen three times then heated to 90° C. for 1.5 hours. The reaction was cooled and stirred for 17 hours at room temperature. The resulting suspension was quenched with 1M hydrochloric acid and extracted with ethyl ether. The organic layer was washed with 1M HCl, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution with 20% ethyl acetate/hexane) to yield 0.249 g (21%) of 2-vinyl-5,5,8,8,-tetramethyl-3-((pyrazol-1-yl)methyl)-5,6,7,8-tetrahydronaphthalene (M+1=295).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[CH2:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O.C1(C)C=CC=CC=1>[OH:14][CH2:13][CH2:12][CH2:11][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: OCCCN1CCc2ccccc21
Reaction time: 23 h
Yield: 72.5 %

Procedure:
A stirred reaction mixture consisting of 22.5 ml (0.20 mole) of indoline, 29.8 ml (0.30 mole) of 3-chloropropanol, 41.4 g (0.30 mole) of potassium carbonate, 0.5 g of tetra-n-butylammonium bromide, 150 ml of toluene, and 50 ml of water was heated at reflux temperature for 5 hr. An additional 15 ml (0.15 mole) of 3-chloropropanol was added and reflux continued for an additional 23 hr. Thin layer chromatographic (TLC) analysis (10% ethyl acetate in methylene chloride) showed the reaction to be about 50% complete. Additional potassium carbonate (20 g), tetra-n-butylammonium bromide (0.5 g) and 3-chloropropanol (15 ml) were added to the reaction mixture which was then heated at reflux temperature for another 18 hr. Tlc analysis showed the reaction to be 66% complete. The mixture was diluted with water and toluene. The toluene layer was separated, washed twice with water, and then extracted twice with 2N hydrochloric acid solution. The acid extracts were washed once with toluene and combined. Toluene was added to the acid extract and the mixture basified by agitating while adding 50% sodium hydroxide solution. The organic layer was separated, washed with water, and the wash back extracted with toluene. The toluene solutions were combined, dried (sodium sulfate) and concentrated to give 25.7 g of a dark brown oil which was purified by chromatography on a 380 g column of silica gel using increasing portions of ethyl acetate in methylene chloride to elute the desired product (12.3 g).
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH:40](=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:40]([N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(N[C@@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(N[C@H](Cc1ccccc1)CN(Cc1ccccc1)C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)OCc1cncs1
Yield: 18.4 %

Procedure:
The product from Example 31D (80 mg, 0.141 mmol), benzaldehyde (17 μl, 0.170 mmol), acetic acid (10 μl, 0.166 mmol), and sodium triacetoxyborohydride (48 mg, 0.226 mmol) were processed as described in Example 27 to provide the title compound (17 mg, 18%). 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.78 (s, 2H), 7.32-7.08 (m, 15H), 5.12 (br s, 2H), 4.84 (br s, 2H), 4.12 (s, 2H), 3.13 (dd, 2H), 3.05-2.87 (m, 6H), 2.80-2.70 (m, 2H); MS (ESI+) m/z 656 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:40]=[CH:39][C:8]2[NH:9][C:10]([CH:12]([C:18]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:13](OCC)=[O:14])=[N:11][C:7]=2[CH:6]=1)#[N:4].[NH4+].[Cl-]>CO>[CH3:27][C:26]1[C:18]([CH:12]([C:10]2[NH:9][C:8]3[CH:39]=[CH:40][C:5]([C:3]#[N:4])=[CH:6][C:7]=3[N:11]=2)[CH2:13][OH:14])=[C:19]2[C:23](=[C:24]([CH3:28])[CH:25]=1)[N:22]([S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH:21]=[CH:20]2
Reactant: CCOC(=O)C(c1nc2cc(C#N)ccc2[nH]1)c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(CO)c4nc5cc(C#N)ccc5[nH]4)c(C)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaBH4 (518 mg, 13.7 mmol) was added to a solution of (±)-ethyl 2-(5-cyano-1H-benzo[d]imidazol-2-yl)-2-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)acetate (481 mg, 0.913 mmol) in MeOH (10 mL) at 23° C. The mixture was stirred at room temperature for 2 h. An additional aliquot of NaBH4 (1.03 g, 27.4 mmol) was added to the mixture. After 1 hr, sat. aq. NH4Cl was added and the resulting mixture was separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in heptane) to provide the title compound. MS (ESI+) m/z 485.2 (M+H).
Reaction SMILES: [CH:1]12[C:9](=[O:10])[O:8][C:6](=O)[CH:3]([CH2:4][CH2:5]1)[CH2:2]2.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH2:18][CH2:17]1.C(Cl)Cl.C1(C)C(C)=CC=CC=1>O>[Cl:28][C:24]1[CH:23]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:6](=[O:8])[CH:3]4[CH2:2][CH:1]([CH2:5][CH2:4]4)[C:9]3=[O:10])[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=1
Reactant: NCCCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: O=C1OC(=O)C2CCC1C2
Solvent: Cc1ccccc1C
Solvent: O
Solvent: ClCCl
Product: O=C1C2CCC(C2)C(=O)N1CCCCN1CCN(c2cccc(Cl)c2)CC1

Procedure:
1,3-Cyclopentane dicarboxylic anhydride (2.2 g., 15 mmole) and 4.0 g. (15 mmole) of 1-(4-aminobutyl)-4-(3-chlorophenyl)piperazine were combined in 300 ml. of methylene chloride and stirred for 30 minutes at room temperature. The solvent was replaced with xylene and the mixture was refluxed for 48 hours with water removal via a Dean-Stark trap. The solvent was removed in vacuum and the residue filtered through 75 g. of silica gel with 2% ethanol/chloroform as eluent. The product was concentrated in vacuum and crystallized from 50 ml. of isopropanol with addition of 4N isopropanolic HCl. Recrystallization from ethanol gave 1.6 g. of the title compound as the hydrochloride, quarter hydrate; m.p. 199°-202° C.
Reaction SMILES: N#N.C([O:5][C:6](=O)[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]1([F:22])[F:21])C.CC(C[AlH]CC(C)C)C.[OH-].[Na+]>C1COCC1.O>[F:22][C:9]1([F:21])[CH:8]([CH2:7][CH2:6][OH:5])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10]1
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCO)C(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of tert-butyl 4-(2-ethoxy-2-oxoethyl)-3,3-difluoropiperidine-1-carboxylate (177 mg, 0.57 mmol) in dry THF (5.8 mL) was added DIBAL-H (1.0 M solution in THF, 1.15 mL, 1.15 mmol) at 0° C. The reaction mixture was stirred at rt for 2 h. The mixture was cooled down to 0° C., successively treated with H2O (0.23 mL) and 2N aq. NaOH (0.45 mL). The mixture was stirred at rt for 20 min, filtered through celite, washed with EA and the filtrate concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 1:1→1:2) and the title compound obtained as a colorless oil. LC-MS-conditions 08: tR=0.74 min; [M-CH3+H]+=251.34.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:25])[C:22]([OH:24])=O)[CH:9]=1)(=[O:3])[CH3:2].CN(C(ON1N=N[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.N1CCCCC1>CN1C(=O)CCC1>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([NH:20][C:21](=[O:25])[C:22](=[O:24])[N:40]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNc1cc(NC(=O)C(=O)O)nc(-c2ccccc2)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1cc(NC(=O)C(=O)N2CCCCC2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.2 %

Procedure:
To a stirred solution of [(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetic acid (50 mg) in NMP (2.5 ml) were added HATU (51 mg) and N,N-diisopropylethylamine (25 μl). The mixture was stirred at room temperature for 15 min then piperidine (90 μl) added and the solution left for 16 hrs. After this time, the solvent was removed in vacuo. Purification via flash chromatography on silica gel using ethyl acetate as the eluent furnished the correct material (10 mg).
Reaction SMILES: C1(NC=CP(=O)(OCC)OCC)CCCCC1.[H-].[Na+].[CH2:20]([N:24]1[C:29]2[N:30]=[C:31]([CH:43]([CH3:45])[CH3:44])[C:32]([CH:41]=O)=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:28]=2[C:27](=[O:46])[NH:26][C:25]1=[O:47])[CH2:21][CH2:22][CH3:23].O.O.[C:50]([OH:55])(=O)[C:51](O)=O>O1CCCC1.O.C1(C)C=CC=CC=1>[CH2:20]([N:24]1[C:29]2[N:30]=[C:31]([CH:43]([CH3:44])[CH3:45])[C:32](/[CH:41]=[CH:51]/[CH:50]=[O:55])=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:28]=2[C:27](=[O:46])[NH:26][C:25]1=[O:47])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCn1c(=O)[nH]c(=O)c2c(-c3ccc(F)cc3)c(C=O)c(C(C)C)nc21
Reactant: O=C(O)C(=O)O
Agent: CCOP(=O)(C=CNC1CCCCC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1c(=O)[nH]c(=O)c2c(-c3ccc(F)cc3)c(/C=C/C=O)c(C(C)C)nc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.15 g (4.4 mol) of diethyl 2-(cyclohexylamino)-vinyl-phosphonate in 15 ml of tetrahydrofuran is added dropwise in the course of 10 min at 0°-5° C. under argon to a suspension of 0.25 g (8.4 mmol) of 80% strength sodium hydride in 15 ml of anhydrous tetrahydrofuran. The mixture is stirred at 0° C. for 15 min, a solution of 1.5 g (4 mmol) of the compound from Example 5 in 15 ml of tetrahydrofuran is added dropwise at 0° C. in the course of 20 min, and the mixture is stirred at room temperature for 1 h and under reflux for 20 min. The mixture is cooled, 50 ml of water are added cautiously, the mixture is extracted twice with ethyl acetate, and the combined organic phases are washed with sodium chloride solution and concentrated in vacuo. The residue is heated under reflux with a mixture of 25 ml of toluene, 35 ml of water and 2.6 g (36 mmol) of oxalic acid dihydrate for 1 h. The phases are separated, the aqueous phase is extracted with ethyl acetate, and the combined organic phases are washed with sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is crystallized from ether/petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.[BrH:10]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:10])=[CH:4][CH:3]=1
Reactant: Br
Reactant: OCc1ccc(Cl)cc1
Product: Clc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
100 ml of HBr (48%) were heated to 90° and treated portionwise with 1.43 g (0.01 mol) of 4-chlorobenzyl alcohol. The mixture was stirred for 1/4 hr. and then cooled to room temperature. The mixture was extracted with ethyl acetate and the organic phase was washed with water and saturated sodium chloride solution and dried over sodium sulfate. 1.82 g (88.6%) of 4-chloro-benzyl bromide were obtained as colorless crystals; m.p. 53°-55°.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:37])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:38])[C@@H:15]([OH:39])[C@@H:14]2[OH:40])(=O)=O)=CC=1.[CH3:41][N:42](Cl)[CH3:43].CCN(CC)CC>CN(C=O)C.O>[Cl:37][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[C@:17]1([C@H:16]([OH:38])[C@@H:15]([OH:39])[C@H:14]([OH:40])[C@@H:13]([CH2:12][N:42]([CH3:43])[CH3:41])[O:18]1)[O:19][CH2:20]2
Reactant: CN(C)Cl
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@]3(OCc4cc(Cl)c(Cc5ccc(C(C)C)cc5)cc43)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN(C)C)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
To a solution of ((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-iso-propylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (15 mg, 0.025 mmol) and dimethylamino hydrochloride (48 mg, 0.588 mmol) in DMF (1 mL), was added Et3N (67 mg, 0.662 mmol). After being stirred for 24 h at 80° C., the reaction mixture was diluted with H2O and extracted 3× with AcOEt. The combined organic layers were washed with brine prior to drying over Na2SO4. The volatiles were removed under reduced pressure. The resulting residue was purified by preparative HPLC to yield 6 mg of title compound. 1H NMR (CD3OD, 300 MHz) δ 7.41 (s, 1H), 7.24 (s, 1H), 7.13 (s, 4H), 5.18 (d, J=13.5 Hz, 1H), 5.13 (d, J=13.5 Hz, 1H), 4.17-4.02 (m, 3H), 3.76-3.75 (m, 2H), 3.46-3.18 (m, 3H), 2.90-2.81 (m, 1H), 2.76 (s, 6H), 1.22 (d, J=6.9 Hz, 6H); MS ESI (m/z) 462 (M+1)+, calc. 461.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21](=[O:23])[CH3:22])C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:20]/[C:21](=[O:23])[CH3:22])=[CH:5][CH:4]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: CC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Reaction time: 5 h
Yield: 91.8 %

Procedure:
4-(Trifluoromethyl)benzaldehyde (25.0 g, 144 mmol)(commercially available from 3B Scientific Corporation Product List (Order Number 3B4-3644)) was taken up in 500 mL of DCM. 1-Triphenylphosphoranylidene-2-propanone (48.0 g, 151 mmol) was added. After 5 hours, an additional 3 g of the Wittig reagent was added. The mixture was stirred for 10 hours. The solvent was removed under reduced pressure, and the residue was triturated with 500 mL of 5% EtOAc/hexanes. The mixture was filtered, removing a large amount of P(O)Ph3. The residue was taken up in 300 mL of 2.5% EtOAc/hexanes and filtered through a pad of silica. The mixture was concentrated under reduced pressure, and the residue was found to be (E)-4-(4-(trifluoromethyl)phenyl)but-3-en-2-one (28.3 g, 92.0% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.68-7.60 (m, 3H), 7.52 (d, J=16.43 Hz, 1H), 6.78 (d, J=16.4 Hz, 1H), 2.41 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][C:18]1[O:19][CH:20]=[CH:21][CH:22]=1>O>[CH3:17][C:18]1[O:19][C:20]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:21][CH:22]=1
Reactant: Cc1ccco1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccccc2)o1
Reaction time: 0.5 h

Procedure:
Into a flask containing benzoyl chloride (206 g) and dichloromethane (2 L) was added aluminum chloride (200 g) while stirring. After 30 minutes at ambient temperature the flask was placed in a water bath and a condenser was connected through which 2-methylfuran (210 mL) was added dropwise over 30 minutes. The resulting mixture was stirred for 7 hours then carefully poured into cold water (3 L). The organic layer was collected, washed with water and concentrated to afford (5-methylfuran-2-yl)(phenyl)methanone as an oily product (220 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]3)=[C:6]([Cl:21])[CH:5]=[CH:4][C:3]=1[N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH:28][C:29](=[O:43])/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][C:35]([C:38]([O:40]CC)=[O:39])=[CH:36][CH:37]=1.[OH-].[Na+]>C(O)C>[C:38]([C:35]1[N:34]=[CH:33][C:32](/[CH:31]=[CH:30]/[C:29]([NH:28][CH2:27][C:23]2[N:22]([C:3]3[CH:4]=[CH:5][C:6]([Cl:21])=[C:7]([CH2:8][O:9][C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[C:19]=4[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]5)[C:2]=3[Cl:1])[CH:26]=[CH:25][CH:24]=2)=[O:43])=[CH:37][CH:36]=1)([OH:40])=[O:39]
Reactant: CCOC(=O)c1ccc(/C=C/C(=O)NCc2cccn2-c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a suspension of 1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-2-[(E)-3-(6-ethoxycarbonylpyridin-3-yl)acryloylaminomethyl]pyrrole (116 mg) in ethanol was added 1N sodium hydroxide solution (0.3 ml) at ambient temperature, and the mixture was stirred at 50° C. for 2 hours. The solvent was removed in vacuo, and the residue was dissolved in water. The aqueous solution was washed with diethyl ether and adjusted to pH 5 with 1N hydrochloric acid. The resulting precipitates were collected by filtration and washed with water and diethyl ether to give 2-[(E)-3-(6-carboxypyridin-3-yl)acryloylaminomethyl]-1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]pyrrole (77 mg) as amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8].[C:9](OC)(OC)([O:11][CH3:12])[CH3:10]>CN(C=O)C>[C:7]([C:6]1[NH:5][CH:4]=[N:3][C:2]=1[N:1]=[C:9]([O:11][CH3:12])[CH3:10])#[N:8]
Reactant: COC(C)(OC)OC
Reactant: N#Cc1[nH]cnc1N
Solvent: CN(C)C=O
Product: COC(C)=Nc1nc[nH]c1C#N
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
5 g of 4-amino-5-cyanoimidazole was suspended in 10 mL of DMF and 10 mL of trimethyl orthoacetate was added, followed by stirring at 90° C. for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was dilute with ethyl acetate, and then 4.2 g of desired compound deposited as a crystal was collected by filtration. The solution was concentrated and the residue was purified by silica gel column chromatograpy (eluent: ethyl acetate) and then recrystallized from ethyl acetate-n-hexane to obtain 2.9 g of a desired compound as a crystal.