Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9](=[O:18])[N:8]2[CH2:19][C:20]([OH:22])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:26])=O>C1C=CC=CC=1>[C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9](=[O:18])[N:8]2[CH2:19][C:20]([Cl:26])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CN1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: O=C(Cl)CN1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Yield: 100 %

Procedure:
A suspension composed of (4,5-cis-diphenyl-2-oxo-3-oxazolidinyl)acetic acid (29.1 g, 97.9 mmol), oxalyl chloride (18.6 g, 147 mmol) and benzene (120 ml) was refluxed for 2 hours. When the suspension became homogeneous, the solvent was distilled off. By the above procedure there was obtained the title compound (30.9 g) as light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][N:10]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)(=[O:16])=[O:15])[N:9]=2)=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([N:10]2[CH2:11][CH2:12][CH2:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCCC(c3ccc(Cl)cc3)=N2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(S(=O)(=O)N2CCCC(c3ccc(Cl)cc3)=N2)cc1
Temperature: 80 °C

Procedure:
(4-Chlorophenyl)-1-(4-nitrobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine (2.12 g, 5.60 mmol) was suspended in acetic acid at 80° C. Iron filings (3.0 g) were added to this suspension and the resulting reaction mixture was heated at 80° C. for 30 minutes and filtered. Upon cooling the title compound precipitated out of this mixture as a solid: mp 205°-206° C.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[CH:27][S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[C:28]([CH3:29])=[CH:27][S:26][C:16]=2[N:17]=1
Reactant: Cc1csc2nc(-c3ccccn3)nc(Cl)c12
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1csc2nc(-c3ccccn3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:8]1=[O:20])[CH3:2].O.NN>CO.[Ni]>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:7]([CH2:6][CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])[C:8](=[O:20])[CH2:9][CH2:10]2
Reactant: CCN(CC)CCCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CCN(CC)CCCN1C(=O)CCc2cc(N)ccc21
Temperature: 25 °C

Procedure:
1-(3- (Diethylamino)propyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (93 mg, 0.305 mmol) in dry methanol (5 mL) was treated with Ra—Ni (slurry in water, ˜0.05 g) followed by hydrazine hydrate (95 uL, 3.05 mmol) at room temperature and the resulting mixture was refluxed for 30 minutes. The reaction was cooled to room temperature, filtered through a celite bed, washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5:97.5). Yield: 62 mg of yellow oil (74%). 1H NMR (CDCl3) δ: 6.87 (d, J=8.4 Hz, 1H), 6.56 (dd, J=2.7, 8.4 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 3.91 (m, 2H), 2.81-2.76 (m, 2H), 2.61-2.54 (m, 2H), 2.52-2.46 (m, 6H), 1.78-1.61 (m, 2H), 1.01 (t, J=7.2 Hz, 6H). MS (ESI): 276.2 (M+1).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:31].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[C:32]([CH:33]=[CH:34][CH:35]=3)[C:30]#[N:31])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C#N)c2)C1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 66, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (40%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]=1[S:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>>[CH2:20]([O:19][C:17]1[CH:16]=[CH:15][C:14]([S:27][C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)=[C:13]([NH:12][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: Clc1ccnc2ncccc12
Product: Oc1ccc(Sc2ccc(OCc3ccccc3)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (100 mg, 0.559 mmol) was reacted with 4-(2-amino-4-benzyloxy-phenylsulfanyl)-phenol (224 mg, 0.559 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (mg, %). 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.14 (s, 2H), 6.31 (d, J=6.99 Hz, 1H), 6.61-6.69 (m, 2H), 7.08-7.23 (m, 5H), 7.32-7.46 (m, 5H), 7.92 (dd, J=8.46, 4.41 Hz, 1H), 8.47 (d, J=6.99 Hz, 1H), 9.10-9.21 (m, 2H), 9.77 (s, 1H), 11.14 (s, 1H); MS (ESI+) m/z 452 (M+H−TFA)+; (ESI−) m/z 450 (M−H−TFA)−.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].N1C=CC=CC=1.[O:15]([CH2:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:23](=[O:24])[CH2:22][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CCN(CC)CCN
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)COc1ccccc1
Yield: 66.3 %

Procedure:
First, 20 milliliters (0.05 mole) N,N-diethylethylene diamine, 50 milliliters methylene chloride, and 5.2 milliliters (0.065 mole) pyridine were combined in a flask. Next, 10.24 grams (0.06 mole) phenoxy acetyl chloride was added at -60° C. with stirring. The temperature was allowed to rise to 0° C. The reaction mixture was then washed with a 200 milliliter portion of water and a 100 milliliter portion of saturated sodium carbonate solution. The organic solution was stripped in vacuum to yield 8.3 grams of the desired product. nD30 1.5118.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:14])[CH:9]=[C:8]2[C:3]=1[CH:4]([CH2:28][CH2:29][C:30]([O-])=[O:31])[CH2:5][CH:6]1[CH2:27][CH2:26][CH2:25][CH2:24][N:7]12>CCOCC>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:14])[CH:9]=[C:8]2[C:3]=1[CH:4]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:5][CH:6]1[CH2:27][CH2:26][CH2:25][CH2:24][N:7]12
Reactant: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)N1CCCCC1CC2CCC(=O)[O-]
Solvent: CCOCC
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)N1CCCCC1CC2CCCO

Procedure:
A 125 ml., round bottomed flask equipped with a magnetic stirrer and nitrogen inlet is thoroughly flushed with dry nitrogen. Lithium aluminum hydride, 158 mg. (4.2 mmole) and 50 ml. of dry ethyl ether were added and the suspension stirred and cooled in an ice bath. To the cooled mixture is added slowly 1.89 g. (4.2 mmole) methyl dl-3-[7-hydroxy-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]-quinolin-6-yl]propionate dissolved in 20 ml. of ether. The cooling bath is removed and the reaction mixture is stirred at room temperature for 12 hours. Ethyl acetate, 50 ml., is cautiously added to quench the reaction. The resulting mixture is washed with 50 ml. each of saturated sodium bicarbonate solution, brine and water. The organic layer is dried over anhydrous magnesium sulfate, solvent evaporated in vacuo. The residue is purified by chromatography on silica gel.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][N:6]1[C:10]([CH2:11]O)=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[N:7]1>CCOCC>[Br:2][CH2:11][C:10]1[N:6]([CH3:5])[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:9]=1
Reactant: BrP(Br)Br
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO
Solvent: CCOCC
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
PBr3 (0.15 mL, 1.60 mmol) was added to a solution of alcohol 72 (0.205 g, 0.75 mmol) in Et2O (10 mL) at 0° C. The mixture was stirred at room temperature for 16 h, cooled to 0° C., quenched with ice and diluted with Et2O (100 mL). Chromatography of the organic portion on silica gel (eluting with CH2Cl2) gave 5-(bromomethyl)-1-methyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazole (73) (0.212 g, 85%) as a white solid: mp 70-71° C.; 1H NMR (CDCl3) δ 7.76 (d, J=8.9 Hz, 2H), 7.22 (d, J=8.9 Hz, 2H), 6.55 (s, 1H), 4.50 (s, 2H), 3.94 (s, 3H). APCI MS m/z 335, 337 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:29](=S)(OCC)[S-:30].[Na+]>C(O)C>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:13]2[C:3]3[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][CH:11]=[CH:12][C:2]=3[N:1]=[C:29]2[SH:30])=[CH:16][CH:17]=1)#[N:28]
Reactant: CCOC(=S)[S-]
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(S)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 80.2 %

Procedure:
A mixture of ethyl 3-amino-2-[(2′-cyanobiphenyl-4-yl)-methyl]aminobenzoate (5.6 g) and sodium O-ethyl dithiocarbonate (7.3 g) in ethanol (50 ml) was heated for 8 hours under reflux. The reaction mixture was concentrated and the residue was dissolved in water. The solution was adjusted to pH 3-4 with hydrochloric acid. Precipitating crystals were collected by filtration, followed by recrystallization from ethanol to afford yellow crystals (5.0 g, 80%), m.p. 225-227° C.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[CH3:6][S:7](Cl)(=[O:9])=[O:8].C(N(CC)CC)C>CCOCC>[CH3:6][S:7]([O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OCC1CC1
Temperature: 25 °C
Yield: 104.2 %

Procedure:
Cyclopropylcarbinol (27.4 g; 0.373 mol) and methanesulfonyl chloride (47.56 g; 0.407 mol) in dry ether (250 ml) was cooled to -20° C. under dry nitrogen. Triethylamine (59 ml; 0.42 mol) is added dropwise over 45 min with external cooling so that the reaction temperature remained below -15° C. The reaction mixture was allowed to warm to room temperature over 2 h and then filtered. The solid material is washed with ether. The solutions were combined and evaporated, to afford crude cyclopropylmethyl methanesulfonate (58.36 g) as a pale yellow liquid, which was used without further purification. NMR - d(CDCl3 ; 60 MHz) 0.3-1.5 (5H, m), 3.0 (3H, s) and 4.0 (2H, d, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([CH3:14])[N:3]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21].[OH-].[Na+]>C(Cl)Cl>[CH3:14][C:4]1[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)(=[O:21])=[O:22])=[O:25])[N:7]=[C:6]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=1
Reactant: O=C=NS(=O)(=O)c1cccs1
Reactant: COC(=O)COc1cc(C)nc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccs2)n1
Reaction time: 3 h

Procedure:
To a dry stirred solution of 18 parts of methyl (2-amino-6-methylpyrimidin-4-yloxy)acetate in 300 parts of methylene chloride at ambient temperature was added 20 parts of 2-thiophenesulfonylisocyanate. The solution was allowed to stand for 3 hours and was then poured onto ice. The pH of the aqueous layer was adjusted to 11 with sodium hydroxide solution and the methylene chloride layer was separated therefrom. The aqueous layer was neutralized with aqueous hydrochloric acid and then extracted with methylene chloride. The extract was dried and stripped of solvent to yield 8 parts of methyl [6-methyl-2-[(2-thienylsulfonyl)aminocarbonylamino]pyrimidin-4-yloxy]acetate, m.p. 114°-120°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C:9](=[O:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@@H]2CC(=O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Reaction time: 20 h
Yield: 78.2 %

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-Azido-3-hydroxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII-1) (960 mg, 2.78 mmol) in DCM (18 mL) was added PCC (2.40 g, 50% on silica gel) at 0° C. and stirring was continued at 23° C. for 20 h. The reaction mixture was placed on a silica gel column and the product was eluted with DCM to yield (1S,2R,5R,6S)-2-azido-3-oxo- bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (IX-1) (746 mg, 78%) as a white solid. 1H-NMR (250 MHz, CDCl3) □1.27 (3H, t, J=7.2 Hz), 1.62 (1H, t,J=3.4 Hz), 2.29 (1H, m), 2.44 (1H, dd,J=7.7, 3.1 Hz), 2.55 (1H, d, J=19.2 Hz), 2.98 (1H, dd, J=19.2, 5.6 Hz), 4.13 (2H, q, J=7.2 Hz), 5.29 (2H, s), 7.36-7.40 (5H, m); MS[ISP]361 (M+NH4+); mp 46-48° C.; □D20 +210.910 (c=1.07, CHCl3).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+].[OH-].[Na+]>O>[CH3:10][C:4]1[CH:3]=[C:2]([OH:12])[CH:7]=[N:6][C:5]=1[S:8][CH3:9]
Reactant: O=S(=O)(O)O
Reactant: CSc1ncc(N)cc1C
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ncc(O)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
A slurry of 5-amino-3-methyl-2-methylsulfanylpyridine (20.3 g, 132 mmol) in 20 wt percent aqueous sulfuric acid (170 mL) was cooled to −2° C. via an ice/salt water bath. A solution of sodium nitrite (9.1 g, 132 mmol) in water (30 mL) was added dropwise, maintaining the internal temperature at or below 1° C. After stirring for an additional 20 minutes, the reaction mixture was cautiously poured in portions into a rapidly stirred, hot (100° C.) solution of 20 wt. percent aqueous sulfuric acid (330 mL). Stirring was continued for 10 minutes, then the mixture was allowed to cool to room temperature. The reaction was washed with methylene chloride (3×200 mL), then the pH of aqueous layer was raised to 4-5 (in the cold) with 50 wt percent aq. sodium hydroxide (ca. 160 mL). A precipitate consisting of both a white solid and a reddish brown oil had formed. Additional 20 wt percent aq. sodium hydroxide was added, raising the pH to 6 and resulting in more precipitate/oil formation. The mixture was cooled and filtered, collecting the white solid, while the majority of colored oil remained in the mother liquor. The collected solid was taken up in 5 percent aq. sodium hydroxide (300 mL) and washed with ether (2×100 mL) to remove impurities and unreacted starting material. The aqueous portion was then treated with activated charcoal, filtered through celite, and the pH adjusted to 5-6 with glacial acetic acid. The precipitate was collected by filtration and dried in vacuo affording an off-white powder, 14 g, 90 mmol, 68 percent yield.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[ClH:5].[S:6]1(=[O:13])(=[O:12])[CH2:10][CH2:9][CH:8](N)[CH2:7]1>>[ClH:5].[OH:2][CH2:1][CH2:3][NH:4][CH:8]1[CH2:9][CH2:10][S:6](=[O:13])(=[O:12])[CH2:7]1
Reactant: NC1CCS(=O)(=O)C1
Reactant: NCCO
Agent: Cl
Product: O=S1(=O)CCC(NCCO)C1

Procedure:
The procedure of Example 1 was repeated substituting 95 percent monoethanolamine (28.6 parts) for the ammonium hydroxide of Example 1. A sticky solid was filtered after treatment with hydrochloric acid, and upon drying in vacuo over P2O5 weighed 59.6 g. (78.5 percent of theory) m.p. 122°-124° C.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([CH2:11][N:12]2[C:17](=[O:18])[C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][C:14]3[CH2:24][S:25][CH2:26][CH2:27][C:13]2=3)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Cl>O>[CH:5]1([CH2:11][N:12]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:14]3[CH2:24][S:25][CH2:26][CH2:27][C:13]2=3)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)c1cc2c(n(CC3CCCCC3)c1=O)CCSC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c(n(CC3CCCCC3)c1=O)CCSC2

Procedure:
4M sodium hydroxide solution (15.2 mL, 60.8 mM) was added to a methanol (30 mL) solution of ethyl 1-cyclohexylmethyl-2-oxo-1,5,7,8,tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carboxylate (AA08, 8.16 g, 24.3 mmol), which had been obtained in Example 8, at room temperature, and the mixture was heated and refluxed for 30 minutes. The reaction mixture was diluted with water (100 mL) and washed with ether (100 mL). 5M hydrochloric acid (13 mL, 65 mmol) was added to the water layer, the precipitated crystal was separated by filtration and washed with water, and the brown crystal of 1-cyclohexylmethyl-2-oxo-1,5,7,8,tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carboxylic acid (6.78 g) was obtained. The crystal was recrystallized from ethanol-water to give light brown crystalline powder (AA09, 6.30 g, 84.3%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2>>[O:33]=[C:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=3)[CH:24]=2)[NH:29]1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: O=C1CCc2cc(O)ccc2N1
Product: N#Cc1ccc(N(CCOc2ccc3c(c2)CCC(=O)N3)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 6-hydroxy-3,4-dihydro-2(1H)-quinolinone with the following exceptions: PPh3 was used instead of PBu3 and purification of the title compound consisted of flash chromatography (EtOAc/hexanes) followed by RP-HPLC (MeCN/H2O with 0.1% TFA): 1H NMR (400 MHz, acetone-D6) δ 8.96 (bs, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.49 (d, J=2.7 Hz, 1H), 7.41 (dd, J=8.9, 2.7 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.79 (d, J=2.6 Hz, 1H), 6.74 (dd, J=8.6 Hz, 1H), 4.62 (q, J=9.0 Hz, 2H), 4.31 (t, J=5.3 Hz, 2H), 4.16 (t, J=5.3-Hz, 2H), 2.88 (partially resolved dd, J≈7.5, 7.0 Hz, 2H), 2.44 (dd, J=8.6, 6.4 Hz, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH2:36]([O:54][CH2:55][C@H:56](O)[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:48]\[CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].C1(P([N:81]=[N+:82]=[N-:83])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:36]([O:54][CH2:55][C@@H:56]([N:81]=[N+:82]=[N-:83])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:48]\[CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOC[C@H](O)CCCCCCCCC
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC[C@H](CCCCCCCCC)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triphenyl phosphine (14.4 g, 55 mmol) was dissolved in THF and cooled to 0° C. under nitrogen. Di-tertbutyl azodicarboxylate (13.7 g, 59.5 mmol) was added slowly and the reaction was stirred for 30 mins. Then the alcohol (20 g, 45.8 mmol) was added dropwise and allowed to stir for 10 mins, then diphenyl phosphorylazide (15.1 g, 55 mmol) was added and allowed to stir overnight, warming to ambient temperature. The reaction was evaporated to dryness in vacuo and directly loaded onto a silica gel column and eluted with 0-10% ethyl acetate/hexane gradient to provide (2S)-2-azidoundecyl(9Z,12Z)-octadeca-9,12-dien-1-yl ether which was carried directly into the next reaction without characterization.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[F:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1>CO>[NH:4]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([C@@H:15]3[C@@H:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[F:27])[C@@:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[C@@H:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2cccc(-c3nnn[nH]3)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CO
Product: CC(C)(C)C[C@H]1N[C@H](C(=O)Nc2cccc(-c3nnn[nH]3)c2)[C@@H](c2cccc(Cl)c2F)[C@]1(C#N)c1ccc(Cl)cc1F

Procedure:
Rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide (690 mg) was resolved on a Berger SFC machine under 100 bar, 30° C. with 10% of methanol on an O.D. column gave two separated peaks. Peak 1, 256 mg (undesired), peak 2, 186 mg (desired).
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[C:5]2[N:6]([C:10](I)=[C:11]([CH2:13][O:14][CH3:15])[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]2=[C:23]([CH:39]=1)[O:24][CH2:25][C:26]1[CH:36]=[C:35]([CH:37]=[O:38])[CH:34]=[CH:33][C:27]=1/[C:28]/2=[C:29](/[CH3:32])\[C:30]#[N:31]>>[F:1][CH:2]([F:17])[O:3][C:4]1[C:5]2[N:6]([C:10]([CH:37]([OH:38])[C:35]3[CH:34]=[CH:33][C:27]4/[C:28](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:39][C:23]=5[O:24][CH2:25][C:26]=4[CH:36]=3)=[C:11]([CH2:13][O:14][CH3:15])[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: COCc1nc2c(OC(F)F)cccn2c1I
Product: COCc1nc2c(OC(F)F)cccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 77.6 %

Procedure:
[step 4] Using 8-(difluoromethoxy)-3-iodo-2-(methoxymethyl)imidazo[1,2-a]pyridine (700 mg, 1.98 mmol) obtained in step 3 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (290 mg, 0.988 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(8-{[8-(difluoromethoxy)-2-(methoxymethyl)imidazo[1,2-a]pyridin-3-yl](hydroxy)methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (400 mg, 78%) was obtained.