Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[NH4+].C(OC(C)C)(=O)C.[N:10]1([CH2:16][CH2:17][C@@H:18]([NH2:27])[CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.F[C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][C:30]=1[S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40]>C(N(CC)CC)C.C1(C)C=CC=CC=1.ClCCl.C(COC)OC.C(O)(C)C.C(OCC)(=O)C.O1CCCC1.C(#N)C>[N:10]1([CH2:16][CH2:17][C@@H:18]([NH:27][C:29]2[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][C:30]=2[S:39]([C:42]([F:43])([F:45])[F:44])(=[O:41])=[O:40])[CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Reactant: N[C@H](CCN1CCOCC1)CSc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)OC(C)C
Product: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1

Procedure:
Scheme 2 shows two routes used to make 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (17). One route involves reacting commercially available 2-fluorobenzenesulfonyl chloride (11) with TBAF (tetra-n-butylammonium fluoride) to provide 2-fluorobenzenesulfonyl fluoride (12). The reaction is typically performed below room temperature in a solvent such as but not limited to tetrahydrofuran. 2-Fluorobenzenesulfonyl fluoride (12) can be converted to 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene (13) by reaction with Ruppert's reagent (CH3SiCF3) catalyzed by (((CH3)2N)3S)+(F2Si(CH3)3)−, also known as TASF. The reaction is typically performed at about room temperature in a solvent such as but not limited to tetrahydrofuran, dichloromethane, toluene, dimethoxyethane, or mixtures thereof. 1-Fluoro-2-((trifluoromethyl)sulfonyl)benzene (13) can be reacted with chlorosulfonic acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride (14). The reaction is typically performed at an elevated temperature before cooling for the addition of SO2Cl2, used to quench the chlorosulfonic acid. 4-Fluoro-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide (15) can be prepared from 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride (14) by reacting the latter with aqueous ammonium hydroxide. The reaction is typically performed in a solvent such as acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl alcohol, isopropyl acetate, dimethoxyethane, dichloromethane, toluene, or mixtures thereof. (1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propylamine (16), prepared as described in U.S. Pat. No. 7,390,799 B2, can be reacted with 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (15) in the presence of a base such as but not limited to triethylamine, to provide 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (17). The reaction is typically performed at elevated temperatures in a solvent such as but not limited to ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@@H:11]([CH3:15])[NH:10]1>C1(C)C=CC=CC=1>[CH3:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@@H:11]([CH3:15])[N:10]1[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Clc1ncccn1
Solvent: Cc1ccccc1
Product: C[C@@H]1CNC[C@H](C)N1c1ncccn1

Procedure:
A solution of 820 mg 2-chloropyrimidine and 1.6 g cis-2,6-dimethylpiperazine in 25 mL toluene was heated at reflux temperature for 12 hours. The solvent was evaporated the residue was basified with 5% sodium hydroxide and extracted with 2×100 mL of dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give cis-2,6-dimethyl-1-(2-pyrimidyl)-piperazine. This amine was then used to prepare 2-phenyl-4(5)-[(4-(2-pyrimidinyl)-cis-2,6-dimethylpiperazin-1-yl)-methyl]-imidazole (Compound 140), m.p. 130-135° C., according to the procedures described in Example VIII.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8]([NH:10][C:11]2[N:15]([CH2:16][CH2:17][C:18]#[C:19][CH3:20])[N:14]=[CH:13][C:12]=2[C:21]#[N:22])=[CH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].C[Al](C)C>ClCCl.CCCCCCC>[NH2:22][C:21]1[C:7]2[C:6](=[O:23])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:9][C:8]=2[N:10]=[C:11]2[N:15]([CH2:16][CH2:17][C:18]#[C:19][CH3:20])[N:14]=[CH:13][C:12]=12
Reactant: CC#CCCn1ncc(C#N)c1NC1=CC(=O)N(CCCC)C1
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC#CCCn1ncc2c(N)c3c(nc21)CN(CCCC)C3=O
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of 5-[N-(n-butyl)-2-oxo-3-pyrrolin-4-yl]amino-1-(pent-3-ynyl)-4-cyanopyrazole (0.88 g.) in dry dichloromethane (20 ml.) was added a solution of trimethylaluminium in heptane (4.2 ml. of a 1.35 M solution) while stirring at room temperature under nitrogen. After stirring overnight, the reaction was quenched by the cautious addition of 3N aqueous hydrochloric acid until gas evolution had ceased. The precipitated aluminium salts were solubilized by addition of a 10% w/v aqueous solution of sodium hydroxide and the product was extracted into EtOAc. The extract was washed with 10% w/v aqueous sodium hydroxide solution and then brine, dried (Na2SO4), and evaporated to leave a light yellow solid. Recrystallization from toluene/hexane gave the title compound as a white crystalline powder (0.5 g.): m.p. 171°-172.5°.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH3:3].[NH2:6][C:7]1[C:12]([NH2:13])=[C:11]([CH3:14])[CH:10]=[CH:9][N:8]=1>>[CH2:2]([C:1]1[NH:13][C:12]2[C:7]([N:6]=1)=[N:8][CH:9]=[CH:10][C:11]=2[CH3:14])[CH3:3]
Reactant: Cc1ccnc(N)c1N
Reactant: CCC(=O)O
Product: CCc1nc2nccc(C)c2[nH]1
Temperature: 100 °C
Yield: 90.6 %

Procedure:
A mixture of propionic acid (0.89 ml, 12 mmols), 2,3-diamino-4-picoline (1.23 g, 10 mmol) and polyphosphoric acid (40 g) was heated to 100° C. for 6 hours. Work-up of the reaction and purification of the crude product according to the procedure described in Step 1 of Example 9 gave the desired compound (1.46 g, 90%) as a tan colored solid. 1H NMR (300 MHz, CDCl3): 8.14 (d, 1H, J=5 Hz), 7.01 (d, 1H, J=5 Hz), 3.02 (q, 2H, J=7.8 Hz), 2.69 (s, 3H), 1.45 (t, 3H, J=7.8 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:18][O:19][C:20]([C:22]1([NH2:25])[CH2:24][CH2:23]1)=[O:21]>>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:25][C:22]3([C:20]([O:19][CH3:18])=[O:21])[CH2:24][CH2:23]3)=[O:14])=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: COC(=O)C1(N)CC1
Agent: Cl
Product: COC(=O)C1(NC(=O)c2ccc(N3CCC(=O)CC3)cc2)CC1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and 1-aminocyclopropane-1-carboxylic acid methyl ester hydrochloride according to the procedure of Example 154 as a gum; MS (ES) m/z: 317.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH:37]([Sn](CCCC)(CCCC)CCCC)=[CH2:38].[Cl-].[Li+].[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.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.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:22][C:16]([O:15][C:14]1[CH:24]=[CH:25][C:11]([CH2:10][CH2:9][N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:5]2[CH:4]=[CH:3][C:2]([CH:37]=[CH2:38])=[CH:7][N:6]=2)=[CH:12][CH:13]=1)([CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(Br)cn2)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(N(CCc2ccc(OC(C)(C)C(=O)OCC)cc2)Cc2ccc(C(F)(F)F)cc2)nc1
Yield: 51.3 %

Procedure:
A solution of ethyl 2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (150 mg; 0.27 mmol) in 2 ml of toluene was treated under nitrogen with tetrakis(triphenylphosphine)palladium (0) (61 mg; 0.053 mmol), vinyltributyltin (252 mg; 0.80 mmol), lithium chloride (34 mg; 0.80 mmol) and 2,6-di-tert-butyl-4-methyl-phenol (3 mg). The mixture was heated at 110C overnight. Upon cooling, the mixture was diluted with 10 ml each of ethyl acetate and water. A saturated solution of KF (10 ml) was added and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate and concentrated. Purification by radial chromatography using an ethyl acetate-hexane gradient (5–50%) afforded ethyl 2-methyl-2-(4-{2-[[4-(trifluoromethyl)benzyl](5-vinylpyridin-2-yl)amino]ethyl}phenoxy)propanoate (71 mg; 52% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([O:11]CC)=[O:10])[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Li+]>O1CCCC1.O>[N:1]1([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([OH:11])=[O:10])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CCOC(=O)c1cccc(-n2cnnn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-n2cnnn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine ethyl 3-(1H-tetrazol-1-yl)benzoate (4.93 g, 22.6 mmol) and tetrahydrofuran/water (100 mL/25 mL). Add lithium hydroxide (1.9 g, 45.2 mmol) and heat to reflux. After 2 hours, cool to ambient temperature and extract the reaction mixture five times with a 1 M aqueous sodium hydroxide solution. Combine the aqueous layers and extract with ethyl acetate. Acidify the aqueous layers with a 1 M aqueous hydrochloric acid solution (pH about 1) to give a solid. Collect the solid by filtration to give the title compound.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:34][CH2:35][C:36]2[CH:41]=[C:40](Cl)[CH:39]=[CH:38][N:37]=2)=[C:14]([C:16]2[CH:33]=[CH:32][C:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24][C:18]=3[CH:17]=2)[CH:15]=1)(=[O:9])[CH3:8].O>C(O)C>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:34][CH2:35][C:36]2[CH:41]=[C:40]([O:4][CH2:2][CH3:1])[CH:39]=[CH:38][N:37]=2)=[C:14]([C:16]2[CH:33]=[CH:32][C:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24][C:18]=3[CH:17]=2)[CH:15]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)c1ccc(OCc2cc(Cl)ccn2)c(-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOc1ccnc(COc2ccc(C(C)=O)cc2-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1

Procedure:
Potassium tert-butoxide (0.132 g) in ethanol (4 ml) was stirred for 15 min before adding 1,1-dimethylethyl 7-(5-acetyl-2-{[(4-chloro-2-pyridinyl)methyl]oxy}phenyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate, (0.4 g) and this was heated in a microwave at 110 C for 1.5 h. Water (20 ml) was added to the cooled mixture and this was extracted with DCM (2×30 ml). The combined organics were washed with brine, dried over sodium sulphate and concentrated in vacuo. The crude product was purified through silica eluting with 0-45% ethyl acetate in hexane to give the title compound, 0.16 g
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([NH2:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]([NH:17][C:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([NH:12][C:21]([C:18]3([NH:17][C:15](=[O:16])[C:14]([F:13])([F:24])[F:25])[CH2:19][CH2:20]3)=[O:22])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Reactant: NC1CCOc2cc(Br)ccc21
Product: O=C(NC1(C(=O)NC2CCOc3cc(Br)ccc32)CC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B] and A-1 [C], (rac)-7-bromo-chroman-4-ylamine has been coupled with 1-(2,2,2-trifluoroacetamido) cyclopropanecarboxylic acid (intermediate A-1 [A]) to give 1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-7-bromo-chroman-4-yl)-amide, which was subsequently reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to yield the title compound as light yellow solid. MS: 453.2 (M−H−).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH:31][CH2:32][CH2:33][OH:34]>>[OH:34][CH2:33][CH2:32][N:31]([CH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=1)[C:21](=[O:23])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11]
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cn1
Reactant: OCCNCc1ccccn1
Product: COc1ccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ncccc2C)cn1

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35]
Reactant: CCOC(=O)CCc1cc(OC)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CCC(=O)O)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
To a solution of ethyl 3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methoxyphenyl)propanoate (450 mg) in methanol (4.0 mL) and THF (8.0 mL) was added 1N aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust to pH<4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (319 mg) as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[C:6]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[NH:8][CH:9]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:2][CH2:1][CH2:3][CH2:4][C:5]1[C:6]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[C:7]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[NH:8][CH:9]=1
Reactant: N#CCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
1.80 g (6.18 mmol) of 4-(2-cyanoethyl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in step (v) above] were added to 100 ml of tetrahydrofuran and the resulting solution was slowly added dropwise with stirring at room temperature to a suspension of 469 mg (12.36 mmol) of lithium aluminum hydride in 150 ml of tetrahydrofuran. This mixture was stirred at 60° C. for 30 minutes. At the end of this time, the reaction mixture was cooled to room temperature, 25 ml of water and 0.5 ml of a 15% aqueous solution of sodium hydroxide were slowly added to the reaction mixture and the resulting mixture was then filtered. The filtrate was concentrated under reduced pressure, after which the residue was dehydrated by azeotropic distillation under reduced pressure using toluene. This azeotropic distillation was carried out three times to give 1.71 g (yield 94%) of the title compound as a white powder.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[N:11]2[C:12]=1[C:13]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)=[C:14]3[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(=O)([O-])O.[Na+]>O1CCCC1>[C:34]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]3=[C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=[C:10]4[N:11]3[C:15](=[CH:16][CH:17]=[CH:18]4)[C:14]=2[CH2:19][CH3:20])=[CH:22][CH:23]=1)(=[O:36])[CH3:35]
Reactant: CCc1c(-c2ccc(O)cc2)c2c(Cc3ccccc3)cc3cccc1n32
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCc1c(-c2ccc(OC(C)=O)cc2)c2c(Cc3ccccc3)cc3cccc1n32
Temperature: 25 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
3-Benzyl-1-ethyl-2-(4-hydroxyphenyl)pyrrolo[2,1,5-cd]indolizine (143 mg, 0.66 mmol) was dissolved in 10 ml of dry tetrahydrofuran and -.10 ml of dry pyridine and acetic anhydride (0.6 ml, 5.43 mmol) was added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into 100 ml of saturated sodium hydrogen carbonate and stirred for 20 minutes. The organic material was extracted into dichloromethane (4×50 ml), and the combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was evaporated. The crude product was purified by column chromatography over silica gel 60, using 5% of diethyl ether in petroleum ether as the eluent to afford 91 mg (35%) of 2-(4-acetoxyphenyl)-3-benzyl-1-ethylpyrrolo[2,1,5-cd]indolizine as a solid. MS(SP): m/z 393 (M+). 1H-NMR (CDCl3, 300 MHz) δ: 1.39 (t, 3H); 2.37 (s, 3H); 3.10 (q, 2H); 4.29 (s, 2H); 6.94 (s, 1H); 7.05-7.25 (m, 7H); 7.52 (d, 2H); 7.61 (dd, 1H); 7.80 (d, 1H), 7.89 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]([CH3:17])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C(=O)C>[CH3:17][N:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]1=[O:16]
Reactant: CN(C(=O)c1ccccc1)c1cccnc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)c2ccccc2c2ncccc21
Temperature: 25 °C
Yield: 91 %

Procedure:
3.94 g N-(2-chloro-pyridin-3-yl)-N-methyl-benzamide (16 mmol), 1.85 g tetrakis(triphenylphosphine) palladium (Pd(PPh3)4) (1.6 mmol), 8.48 g sodium carbonate (Na2CO3) (80 mmol), and 50 mL N,N-dimethyl acetamide (DMA) were added in a flask and reacted for 24 hr under nitrogen. After cooling to room temperature, the reaction was quenched by water. After filtration, concentration, and purification by column, 3.06 light yellow solid was obtained, with a yield of 91%.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1.Br[C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[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].CN(C)C(=O)C.O1CCOCC1>[CH3:1][S:2][C:3]1[N:8]2[N:9]=[C:10]([NH:12][C:14]3[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)=[CH:26][CH:27]=3)[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: CSc1cccc2nc(N)nn12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: CSc1cccc2nc(Nc3ccc(OCCN4CCCC4)cc3)nn12
Temperature: 150 °C

Procedure:
A microwave vial containing 5-methylsulfanyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (13.5 g, 74.9 mmol), 1-(2-(4-bromophenoxyl)ethyl)pyrrolidine (20.2 mL, 97.3 mmol), tris(dibenzylideneacetone)dipalladium (3.42 g, 3.74 mmol), xantphos (4.33 g, 7.49 mmol), sodium tert-butoxide (14.7 g, 150 mmol) and 1,4-dioxane (90 mL) was heated under microwave radiation (150° C., 10 min). N,N-Dimethylacetamide (1 mL) was added to assist with microwave absorption. The volatiles were removed under rotary evaporation and the product then purified by graduated flash column chromatography (2-10% methanol: dichloromethane) to provide a pale brown solid. Yield: 19.3 g, 70%; LCMS method: 2, RT: 2.28 min, MI: 370 [M+1]. 1H NMR (CDCl3, 300 MHz): 7.53 (d, 2H), 7.40 (d 1H), 7.26 (d, 1H), 7.10 (s, 1H), 6.93 (d 2H), 6.64 (d, 1H), 4.11 (t, 2H), 2.90 (t, 2H), 2.64 (s, 7H), 1.81 (s, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][C@@H:21]2[CH3:20])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: C[C@H]1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)cc(N2CCOC[C@@H]2C)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a solution of 4,6-dichloro-2-(methylthio)pyrimidine (585 mg, 3.0 mmol) in DCM (5 mL) was added DIPEA (1.5 mL, 9.0 mmol), followed by 3-(S)-methylmorpholine (909 mg, 9.0 mmol) dropwise. The reaction mixture was stirred at 40° C. overnight whereupon it was washed with water (10 mL), passed through a PTFE hydrophobic frit and the solvent removed in vacuo to yield a colourless oil (850 mg) used without further purification.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([S:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1)[CH:13]([CH3:15])[CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([S:16][C:17]1[N:18]=[CH:19][C:20]([C:23]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:24]=2)=[CH:21][CH:22]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)CSc1ccc(C#N)cn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CSc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 24.4 %

Procedure:
A mixture of methyl thiosalicylate (1.01 g, 6.0 mmol), 2-isobutylthio-5-cyanopyridine (1.03 g, 5.0 mmol), triethylamine (0.98 ml, 7.0 mmol) and toluene (10 ml) was refluxed under nitrogen atmosphere for 20 hrs. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (2:1, v/v) and recrystallized from ethyl acetate-isopropylether to give the titled compound (0.40 g, 23%).