Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[NH:23]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2B(O)O)=[N:26][N:25]=[N:24]1>>[CH3:19][CH2:18][CH2:17][CH2:16][C:15]([N:7]([C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[NH:23][N:24]=[N:25][N:26]=2)=[CH:22][CH:21]=1)=[O:20]
Reactant: OB(O)c1ccccc1-c1nnn[nH]1
Reactant: CCCCC(=O)N(Cc1ccc(Br)cc1)[C@H](C(=O)O)C(C)C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C

Procedure:
WO 2005/102987 provides the reaction of 4-Bromobenzylic bromide and hydrochloride methylester of L-valine methylester in an aprotic solvent and organic or an inorganic base to give methylester of N-(4-bromobenzyl)-L-valine which is deprotected to give N-(4-bromobenzyl)-L-valine. This on acylation with valeryl chloride yields N-(4-bromobenzyl)-N-valeryl-L-valine. Valsartan is prepared by the reaction of N-(4-bromobenzyl)-N-valeryl-L-valine and 2-(1H-tetrazole-5-yl)phenylboronic acid in palladiumtetrakistriphenylphosphine.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:7][CH:8]=1.[CH2:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][CH2:24][C:25]#[CH:26]>CCCCCCC>[C:27]1([CH2:22][CH2:23][CH2:24][C:25]#[C:26][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(C(F)(F)F)c2)cc1
Solvent: CCCCCCC
Product: FC(F)(F)c1cccc(C#CCCCc2ccccc2)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 3-trifluoromethyl-phenyl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (140 mg, 97%); 1H NMR δ (CDCl3): 7.66 (s, 1H), 7.61-7.7.49 (m, 2H), 7.46-7.36 (m, 1H), 7.35-7.16 (m, 5H), 2.79 (t, J=7.15 Hz, 2H), 2.43 (t, J=7.20 Hz, 2H), 1.93 (p, J=7.11 Hz, 2H); LCMS m/z: 288.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH2:14][OH:15])=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cn(-c2ccccc2)nc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A mixture of (3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methanol (5.61 g), active manganese dioxide (15.00 g) and tetrahydrofuran (75 ml) was stirred overnight at room temperature. Manganese dioxide was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (5.03 g, yield 90%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 153–154° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12]O)=[CH:6][C:5]=1[N:14]([CH3:16])[CH3:15].N12CCCN=C1CCCCC2.C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12][N:43]=[N+:44]=[N-:45])=[CH:6][C:5]=1[N:14]([CH3:16])[CH3:15]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CNC(=O)c1cc(C#N)c(CO)cc1N(C)C
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)c1cc(C#N)c(CN=[N+]=[N-])cc1N(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.2 %

Procedure:
After dissolving N1-methyl-5-cyano-2-(dimethylamino)-4-(hydroxymethyl)benzamide (849 mg, 3.6 mmol) in tetrahydrofuran (20 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.77 ml, 5.1 mmol) and diphenylphosphoryl azide (1.1 ml, 5.1 mmol) were added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (755 mg) as a faint yellow powder. (80% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: COc1cc2c(cc1OC)CC(=O)CC2
Product: COc1cc2c(cc1OC)CC(NCc1ccccc1)CC2

Procedure:
The title compound is prepared analogously to Example L by reacting 6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-one with benzylamine. Mp: 237°-238° C.
Reaction SMILES: CI.[CH2:3]([S:5]([C:8]1[C:9]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH3:4].[C:28](=O)([O-])[O-].[K+].[K+].CC(C)=O>O.CN(C=O)C>[CH2:3]([S:5]([C:8]1[C:9]([C:14]([N:16]([CH3:28])[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=2)=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCS(=O)(=O)c1cccnc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cccnc1C(=O)N(C)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
0.50 g of methyl iodide was added to a mixture of 0.20 g of 3-ethylsulfonyl-N-(4-trifluoromethoxyphenyl)picolinamide (Compound of Present Invention 21), 0.12 g of potassium carbonate and 3 mL of acetone, and the mixture was stirred at room temperature for 1 hour. 1 mL of DMF was added to the reaction mixture, and the mixture was stirred at 60° C. for 2 hours. Water was poured to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.19 g of 3-ethylsulfonyl-N-methyl-N-(4-trifluoromethoxyphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 39).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=1.F[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([N+:32]([O-:34])=[O:33])=[CH:24][CH:23]=1.[NH4+].[Cl-]>CN(C=O)C>[N+:32]([C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([O:3][CH:4]([CH3:20])[CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH:7]=2)=[CH:23][CH:24]=1)([O-:34])=[O:33]
Reactant: CC(O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(Cc1ccnc(NC(=O)OC(C)(C)C)c1)Oc1ccc([N+](=O)[O-])c2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
Sodium hydride (119 mg, 2.97 mmol) was added to a stirred solution of tert-butyl 4-(2-hydroxypropyl)pyridin-2-ylcarbamate (47) (250 mg, 0.991 mmol) in DMF (6 mL) at 0° C., under nitrogen and after 45 min a solution of 1-fluoro-4-nitronaphthalene (14) (189 mg, 0.991 mmol) in DMF (6 mL) was added dropwise, over 2 min. The resulting dark-brown reaction mixture was stirred at 0° C. for 5 min, and was then warmed to RT. After 70 min, a saturated aqueous solution of NH4Cl (3 mL) was added and the mixture was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g; 0-70% EtOAc in isohexane, gradient elution) to afford the title compound (48) (293 mg, 65%) as an orange foam: m/z 424.0 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][O-:2].[Na+].O.[OH-].[Na+].[Br-].[C:8]([C:11]1[CH:12]=[C:13]([CH2:20][N+](C)(C)C)[CH:14]=[N:15][C:16]=1[C:17]([OH:19])=[O:18])([OH:10])=[O:9]>CO>[CH3:1][O:2][CH2:20][C:13]1[CH:12]=[C:11]([C:8]([OH:10])=[O:9])[C:16]([C:17]([OH:19])=[O:18])=[N:15][CH:14]=1
Reactant: C[O-]
Reactant: C[N+](C)(C)Cc1cnc(C(=O)O)c(C(=O)O)c1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1cnc(C(=O)O)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
A mixture of 25% sodium methoxide in methanol (270 g, 1.25 mol) and [(5,6-dicarboxy-3-pyridyl)-methyl]trimethylammonium bromide, dimethyl ester (Ia) (347 g, 1.00 mol) in methanol (650 ml) is heated at reflux for 1 hour under nitrogen. Water (1 l) and sodium hydroxide (80.0 g, 2.0 mol) are added and the reaction mixture is distilled until the pot is 100-105° C. The reaction mixture is cooled to room temperature, treated with sulfuric acid to adjust the pH to a value from 1.5 to 2 and filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven to obtain the title product as a white solid (mp 161-162° C.) which is greater than 99% pure by HPLC analysis.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH2:8][CH2:7][NH:6][C:5]1=[O:21].Br[CH2:23][CH2:24][C:25]([N:27]([O:29][CH3:30])[CH3:28])=[O:26]>CN(C)C=O>[CH3:30][O:29][N:27]([CH3:28])[C:25](=[O:26])[CH2:24][CH2:23][N:6]1[CH2:7][CH2:8][N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH:4]([CH3:3])[C:5]1=[O:21]
Reactant: CC1C(=O)NCCN1c1cccc(OC(F)(F)F)c1
Reactant: CON(C)C(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)CCN1CCN(c2cccc(OC(F)(F)F)c2)C(C)C1=O
Reaction time: 1 h
Yield: 105.5 %

Procedure:
NaH (55% dispersion in mineral oil, 24 mg, 0.56 mmol) was added at 0° C. to a solution of 3-methyl-4-(3-trifluoromethoxy-phenyl)-piperazin-2-one (example 41D; 127 mg, 0.46 mmol) in N,N-dimethylformamide (3 mL), then after 5 min a solution of 3-bromo-N-methoxy-N-methyl-propionamide (Patent Application US 2007249589; 100 mg, 0.51 mmol) was added. After 30 min the ice bath was removed and the reaction mixture was allowed to reach RT over 1 h, then partitioned between EtOAc and 10% aq. KHSO4 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the title compound (189 mg) which was directly used in the next step. Light yellow oil, MS: 390.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:26])[N:21]=1.C1(C)C(C)=CC=CC=1>CO>[Cl:26][C:22]1[N:21]=[C:20]([NH:19][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])[CH:25]=[N:24][CH:23]=1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1cncc(Cl)n1
Solvent: Cc1ccccc1C
Solvent: CO
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O
Reaction time: 8 h
Yield: 65.4 %

Procedure:
A mixture of 9.0 g (33 mmols) of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 4.36 g (33 mmols) of 2-amino-6-chloro-pyrazine and 1200 ml of xylene was refluxed for 24 hours in a nitrogen atmosphere. The methanol formed by the reaction was removed with the aid of a 4 Å molecular sieve arranged in a Soxhlet attachment. After cooling and standing overnight, the crystals were filtered off and recrystallized from dioxane. 7.91 g (64% of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[C:5]([NH:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:4]=1.[CH:36]([N:39]([CH:50]([CH3:52])[CH3:51])[CH2:40][CH2:41][NH:42][C:43](N1C=CN=C1)=[O:44])([CH3:38])[CH3:37]>>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][C:43]([NH:42][CH2:41][CH2:40][N:39]([CH:50]([CH3:52])[CH3:51])[CH:36]([CH3:37])[CH3:38])=[O:44])=[N:4][C:5]=2[NH:21][CH2:22][CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2
Reactant: NCc1nc(NCC2c3ccccc3-c3ccccc32)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Product: CC(C)N(CCNC(=O)NCc1nc(NCC2c3ccccc3-c3ccccc32)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)C(C)C

Procedure:
The title compound was prepared from (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(9H-fluoren-9-ylmethyl)amino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydro-3,4-furandiol (Preparation 13) and N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 27) in a similar procedure to Example 3.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:40])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35][N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35][N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:40])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (77 mg, 0.3 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (112 mg, 0.36 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (61 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[O:10][CH2:11][CH2:12][CH2:13][O:14]2)=[CH:7][CH:8]=1)=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C2OCCCO2)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(C2OCCCO2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-methylsulfanyl-phenyl)-[1,3]dioxane (2 g, 9.5 mmol) in DCM (50 mL) at 0° C. is added m-CPBA (2.46 g, 10.5 mmol). The mixture is stirred at 0° C. for 1 h after which Ca(OH)2 (770 mg, 10.5 mmol.) is added. The reaction is stirred an additional 30 min, then the reaction mixture is diluted with DCM and filtered through celite. The filtrate is collected and concentrated to give 2-(4-methanesulfinyl-phenyl)-[1,3]dioxane as a white solid.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:7]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6](C2C=CC(OC)=CC=2)[C:5]1=[O:24])=[N+:2]=[N-:3]>O.C(#N)C>[N:1]([C@H:4]1[C@@H:7]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:6][C:5]1=[O:24])=[N+:2]=[N-:3]
Reactant: COc1ccc(N2C(=O)[C@@H](N=[N+]=[N-])[C@H]2C=Cc2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: [N-]=[N+]=N[C@@H]1C(=O)N[C@@H]1C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
To a solution of 10.22 g of ceric ammonium nitrate in 13 ml of water at 0° C. is added 1.99 g of (±)-(cis)-3-azido-1-(4-methoxyphenyl)-2-oxo-4-(2-phenylethenyl)azetidine dissolved in 65 ml of acetonitrile during a 15 minute period (additional 10 ml of acetonitrile is used for rinse). The mixture is stirred for an additional 15 minutes at 0° C., diluted with 750 ml of ethyl acetate, washed with water (six 600 ml portions), dried over anhydrous sodium sulfate, and stripped of solvent to give an oil. The crude product is chromatographed on 90 g of silica gel, eluting first with 250 ml of 30% ethyl acetate/petroleum ether, then 50% ethyl acetate/petroleum ether. Fractions (50 ml each) 11-16 are combined and evaporated to give 802 mg of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:31][CH3:32])=[C:22]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=1)#[CH:17]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:17]#[C:16][C:18]2[CH:19]=[CH:20][C:21]([O:31][CH3:32])=[C:22]([NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(OC)c(NC(=O)C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Yield: 83.1 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloropyrimidine (860 mg, 5.76 mmol), anhydrous degassed TH F (100 mL), dichlorobis(triphenylphosphine)-palladium(II) (81 mg, 0.12 mmol), copper(I) iodide (13 mg, 0.07 mmol), and triethylamine (1.26 g, 13 mmol). After heating the reaction at 60° C. for 30 min, N-[5-ethynyl-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (560 mg, 2.30 mmol) was added dropwise as a solution in THF (10 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ESIMS (M+H)+=356.
Reaction SMILES: O.[I-:2].[I-].[I-].[I-].[CH:6]1[C:19]2[C:10](=[S+:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1.[CH:20]1[C:33]2[C:24](=[S+:25][C:26]3[C:31]([N:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][CH:21]=1.[CH:34]1[C:47]2[C:38](=[S+:39][C:40]3[C:45]([N:46]=2)=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:37]=[CH:36][CH:35]=1.C1[C:61]2C(=[S+]C3[C:59]([N:60]=2)=CC=CC=3)C=CC=1.[CH3:62][NH:63][CH3:64]>CO>[I-:2].[I-:2].[I-:2].[CH3:31][N:32]([CH3:33])[C:8]1[CH:7]=[CH:6][C:19]2[C:10]([CH:9]=1)=[S+:11][C:12]1[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:18]=2.[CH3:59][N:60]([C:36]1[CH:35]=[CH:34][C:47]2[C:38]([CH:37]=1)=[S+:39][C:40]1[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=1)[N:46]=2)[CH3:61].[CH3:62][N:63]([C:22]1[CH:21]=[CH:20][C:33]2[C:24]([CH:23]=1)=[S+:25][C:26]1[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=1)[N:32]=2)[CH3:64]
Reactant: c1ccc2[s+]c3ccccc3nc2c1
Reactant: CNC
Agent: [I-]
Solvent: CO
Solvent: O
Product: CN(C)c1ccc2nc3ccccc3[s+]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of phenothiazine-5-ium tetraiodide hydrate (0.417 g, 0.57 mmol) in methanol (10 ml) was stirred at room temperature and treated dropwise with a solution of dimethylamine (1.14 mmole) in methanol (2 ml). The mixture was stirred at room temperature for 3 hrs until the starting materials was consumed, as monitored by TLC (silica, CH3OH/TEA). The precipitate was filtered and washed with small amount of methanol, afforded a black solid, 0.30 g (84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2)c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2)c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A mixture of 1-benzyl-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (500 mg, 1.68 mmol), pivaloyl chloride (0.250 mL, 2.02 mmol), 4-dimethylaminopyridine (21 mg, 0.168 mmol) and triethyl amine (0.468 mL, 3.36 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 h; then the reaction mixture was diluted with EtOAc, washed with saturated NaCl solution and subsequently the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified with column to give the desired product as a clear oil (599 mg, 93%). 1H NMR (200 MHz, CDCl3): δ (ppm)=8.62 (s, 1H), 7.31-7.20 (m, 6H), 6.53-6.51 (m, 1H), 5.40 (s, 2H), 4.41 (q, 2H, J=7.3 Hz), 1.47 (s, 9H), 1.41 (t, 3H, J=7.3 Hz).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>[Pd].CCO>[NH2:17][C:12]1[CH:11]=[C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)c2ccccc2)ccc1O
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1cc(S(=O)(=O)c2ccccc2)ccc1O
Yield: 47.4 %

Procedure:
4-Benzenesulfonyl-2-nitro-phenol (6.37 g, 22.8 mmol), Pd/C (5%, 3 mg) and 1 mL of water were added to a flask, after which 45 mL of EtOH was added. The reaction mixture was stirred and purged with H2 (1 Atm). The reaction mixture was stirred under H2 for 4 hours, then filtered through celite. The filtrate was concentrated in vacuo to yield a crude oil, which was purified by flash chromatography (0-15% “magic base” (6:1:0.1 methylene chloride:methanol:ammonia) in dichloromethane) to afford 2-amino-4-benzenesulfonyl-phenol (2.695 g, 39%). MS: 250 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH:6][C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:17]([CH:20]=3)[C:18]#[N:19])[CH:10]=[CH:9][N:8]=2)[CH:3]=[N:2]1>C(#N)C>[CH3:22][O:21][CH2:16][CH2:15][N:1]1[CH:5]=[C:4]([NH:6][C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:17]([CH:20]=3)[C:18]#[N:19])[CH:10]=[CH:9][N:8]=2)[CH:3]=[N:2]1
Reactant: N#Cc1cc(-c2ccnc(Nc3cn[nH]c3)n2)ccc1OC1CCOCC1
Solvent: CC#N
Product: COCCn1cc(Nc2nccc(-c3ccc(OC4CCOCC4)c(C#N)c3)n2)cn1
Temperature: 90 °C

Procedure:
16 mg of 5-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-2-(tetrahydropyran-4-yloxy)benzonitrile are dissolved in 1 ml of dried acetonitrile in a 50 ml flask provided with magnetic stirrer, condenser and drying tube, 9 mg of bromoethyl methyl ether and 28 mg of Cs2CO3 are added, and the suspension is stirred at a bath temperature of 90° C. The reaction mixture is stirred at 90° C. for 5 hours and at room temperature overnight.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:26]=[C:25]([CH3:27])[C:21]2[N:22]=[CH:23][NH:24][C:20]=2[C:19]=1[CH2:28][CH3:29]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CO>[CH2:28]([C:19]1[C:20]2[NH:24][CH:23]=[N:22][C:21]=2[C:25]([CH3:27])=[CH:26][C:18]=1[N:17]=[C:8]=[S:9])[CH3:29]
Reactant: CCc1c(N)cc(C)c2nc[nH]c12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1c(N=C=S)cc(C)c2nc[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of di-2-pyridyl thionocarbonate (0.72 g, 3.11 mmol) and 4-dimethylaminopyridine (0.02 g) in ethyl acetate (50 mL) is added dropwise a solution of 5-amino-4-ethyl-7-methylbenzimidazole (0.42 g, 2.39 mmol) in ethyl acetate (20 mL) and methanol (5 mL). The mixture is stirred at room temperature for 3 hours, then rotary evaporated. The residue is purified by filtration on a short pad of silica gel, eluting with ethyl acetate, to afford 4-ethyl-5-isothiocyanato-7-methylbenzimidazole as a tan solid.