Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:10]([CH3:13])([O-:12])=[O:11].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:13][N+:10]([O-:12])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, step 1, 2-chloro-benzaldehyde (5 g, 35.7142 mmol) in ethanol (161 mL) was reacted with nitro methane (1.93 mL, 35.7142 mmol) and 10N NaOH (1.35 g, 33.9607 mmol). The resulting mixture was stirred at 0° C. for 1 hr to afford 4.5 g of the product (75.73% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])OCC.O.[NH2:15][NH2:16]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])[NH:15][NH2:16]
Reactant: NN
Reactant: CCOC(=O)Nc1ccccc1F
Solvent: CCO
Solvent: O
Product: NNC(=O)Nc1ccccc1F
Reaction time: 72 h

Procedure:
A mixture of ethyl N-(2-fluorophenyl)carbamate (8.3 g, 45.4 mmol) and hydrazine hydrate (13.6 g, ca. 14 ml) in 40 ml of absolute ethanol is heated to reflux. After 3 days, the reaction mixture is concentrated, and the solid is filtered, washed with water and with ether and dried to give 4-(2-fluoro-phenyl)semicarbazide.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1.[OH:14][CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1>>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([N:17]2[CH2:18][CH2:19][CH2:20][CH:15]([OH:14])[CH2:16]2)=[O:12])=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1
Reactant: OC1CCCNC1
Reactant: Nc1ncc(Cl)cc1/C=C/C(=O)O
Product: Nc1ncc(Cl)cc1/C=C/C(=O)N1CCCC(O)C1

Procedure:
The title compound was prepared from (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoic acid and 3-hydroxypiperidine as a white solid:
Reaction SMILES: [C:1]([S:4][CH:5]([CH:10]([C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:7](O)=[O:8])(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.[NH2:43][CH2:44][C:45]([NH2:47])=[O:46].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([S:4][CH:5]([CH2:6][C:7]([NH:43][CH2:44][C:45]([NH2:47])=[O:46])=[O:8])[CH:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[O:16])(=[O:3])[CH3:2]
Reactant: NCC(N)=O
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)NCC(N)=O)SC(C)=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A mixture of 3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid (E5, Isomer A; 226 mg, 0.5 mmol), N-ethyl-N1 -dimethylaminopropylcarbodiimide hydrochloride (116 mg, 0.6 mmol), 1-hydroxybenzotriazole (90 mg, 0.58 mmol), glycinamide hydrochloride (64 mg, 0.58 mmol) and diisopropylethylamine (0.2 ml, 1.14 mmol) in dichloromethane was stirred at 5° C. for 2 h then at room temperature overnight. The mixture was cooled in ice and the solid was collected by filtration and washed well with dichloromethane. The solid was triturated with 1M citric acid, then filtered, washed with water and dried. Recrystallisation from methanol/ether gave the title compound as a single isomer (Isomer A), 75 mg (30%) mp 218°-219° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[OH:30])[CH2:23][CH2:22][CH2:21]4)[C:14]3=[O:31])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C.O>[Cl:36][CH2:35][CH2:34][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:20]1([NH:19][C:15]2[C:14](=[O:31])[N:13]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=3[CH3:12])[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:32])[CH:18]=[CH:17][N:16]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CCC2)c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CCC2)c1=O
Temperature: 90 °C

Procedure:
To N-cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 268f, 0.874 g) in acetonitrile (17 mL) was added 1-bromo-2-chloroethane (1.68 mL) and cesium carbonate (6.61 g) and the reaction heated at 90° C. for 18 h. Ethyl acetate and water were added and the organic layer separated, washed with water, brine, dried (MgSO4), filtered and the solvent removed in vacuo. Purification (SiO2 chromatography eluting with 50-70% ethyl acetate/iso-hexane) gave the subtitle product (304 mg). The drying agent was re-washed with dichloromethane (2×50 mL) and the solvent removed to afford further subtitle product (472 mg).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[C:26]([C:28]([NH:30][C:31]4[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=4[F:38])=[O:29])[CH:25]=[CH:24][C:23]=3[F:39])[CH:18]=[CH:17][N:16]=2)[NH:12][CH:11]=1)=[O:9])C.Cl.O>O1CCCC1>[F:39][C:23]1[CH:24]=[CH:25][C:26]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[F:38])=[O:29])=[CH:27][C:22]=1[O:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:13]2[NH:12][CH:11]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:9])[CH:14]=2)[CH:20]=1
Reactant: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCC=O)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(3,3-diethoxypropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide (250 mg, 0.43 mmol) in 10 ml of tetrahydrofuran was added 1 ml of 1M HCl (1.0 mmol). The mixture was stirred at room temperature for 60 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 205 mg, 94%.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:8][CH2:9][F:10].[OH:11][C:12]1[N:13]=[CH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[N:16][CH:17]=1.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[F:10][CH2:9][CH2:8][O:11][C:12]1[N:13]=[CH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[N:16][CH:17]=1
Reactant: COC(=O)c1cnc(O)cn1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(OCCF)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.4 %

Procedure:
Cesium carbonate (6.34 g) and 1-iodo-2-fluoroethane (2.26 g) were added to a solution of methyl 5-hydroxypyrazine-2-carboxylate (1 g) in DMF (30 mL), and the mixture was stirred at room temperature for 20 hours. Aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (200 mg).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:39]([O-:41])=[O:40])=[C:33]([CH2:35][C:36]([OH:38])=[O:37])[CH:34]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[Si](C=[N+]=[N-])(C)(C)[CH3:43].CCCCCC>CN(C=O)C.CO.O>[CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:39]([O-:41])=[O:40])=[C:33]([CH2:35][C:36]([O:38][CH3:43])=[O:37])[CH:34]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(CC(=O)O)c3)S(C)(=O)=O)c(C3CC3)cc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(CC(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 2 h
Yield: 70 %

Procedure:
To a stirred solution of 2-(5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrophenyl)acetic acid (2.00 g, 3.44 mmol) in 10 mL of 1:1 DMF/MeOH was added 2 M TMS-diazomethane in hexane (0.786 g, 6.88 mmol) at 0° C. and reaction mixture stirred for 2 h. The reaction was diluted with water and extracted into EtOAc. The ethyl acetate solution was washed with water, dried over sodium sulfate and evaporated to dryness to give the title compound in 70% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.04 (d, J=9.19 Hz, 1H) 7.88 (br. s., 0H) 7.80 (t, J=6.06 Hz, 2H) 7.46 (s, 1H) 7.44 (br. s., 1H) 7.28 (dd, J=9.18, 1.95 Hz, 1H) 7.08-7.18 (m, 3H) 6.13 (br. s., 1H) 3.88 (s, 2H) 3.62 (s, 3H) 3.29 (s, 3H) 2.93 (d, J=2.93 Hz, 3H) 2.88 (s, 2H) 2.79 (d, J=1.76 Hz, 1H) 1.82-1.93 (m, 1H) 0.67-0.98 (m, 3H) 0.49 (br. s., 1H). LCMS (m/z, ES+)=596 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)#[N:25]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:29]4[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: N#Cc1ccc(O)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(C#N)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure A by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 4-cyanophenol (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in acetonitrile. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.94-2.04 (m, 4H), 2.95-3.05 (m, 2H), 4.08-4.11 (m, 2H), 4.98-5.04 (m, 1H), 7.58-7.60 (m, 2H), 7.99-8.01 (m, 2H), 8.37 (s, 1H), 8.56 (s, 1H). Mass spectrum MH+=421.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1[C:28]([C:29]([OH:31])=O)=[C:27]([CH2:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:26][N:25]=1.C(N(C(C)C)C(C)C)C.[C:50]1([CH:56]2[CH2:60][CH2:59][NH:58][CH2:57]2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:23][C:24]1[C:28]([C:29]([N:58]2[CH2:59][CH2:60][CH:56]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:57]2)=[O:31])=[C:27]([CH2:32][C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:40])[O:26][N:25]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1noc(CC(=O)c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(CC(=O)c2ccccc2)c1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of TBTU (0.48 g, 1.5 mmol, 1.5 eq.) in DMF (2 mL) was added to a mixture of 3-methyl-5-(2-oxo-2-phenylethyl)isoxazole-4-carboxylic acid (0.24 g, 1 mmol, 1 eq), N-ethyl-N-isopropylpropan-2-amine (0.18 mL, 1 eq) and 3-phenylpyrrolidine (0.15 g, 1 eq) in DMF (1 mL). The resulting solution was stirred at room temperature. Chloroform (25 mL) was added and the solution was washed with water and 1 M HCl, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2 1:2 heptane/EtOAc) to afford the title compound. MS (ESI, POS. ION) M/Z Calcd for C23H22N2O3: 374.1630, found 374.1632.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[N+:16]([O-])([O-])=O.[Na+]>C(O)(=O)C.O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:14]3[N:15]=[N:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1cccnc1Nc1cccc(Br)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1cccc(-n2nnc3cccnc32)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.2 %

Procedure:
Compound 2 (3.8 g, 14.4 mmol) was dissolved in a mixture of acetic acid (4 ml), water (4 ml) and methylene chloride (4 ml). The mixture was cooled to 0° C., then sodium nitrate (1.29 g, 18.7 mmol) was slowly added. Upon completion of the addition of sodium nitrate, the mixture was brought to room temperature and stirred for 20 minutes. The intended product was confirmed by LC-MS. Methylene chloride (30 ml) was added to the solution and the solution was then washed with water (3×30 ml). The organic layer was dried over magnesium sulfate and then evaporated to provide the title compound (2.9 g, 73%). [M+H] calc'd for C11H7BrN4, 274; found, 274.
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[Cl:5][C:6]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:7]=1[CH:8]=[CH:9][S:10](Cl)(=[O:12])=[O:11]>>[Cl:5][C:6]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:7]=1[CH:8]=[CH:9][S:10]([N:3]=[C:1]([NH2:4])[CH3:2])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)C=Cc1c(Cl)cccc1Cl
Reactant: CC(=N)N
Product: CC(N)=NS(=O)(=O)C=Cc1c(Cl)cccc1Cl

Procedure:
Reaction of acetamidine with 2,6-dichlorostyrylsulfonyl chloride according to the procedure of Example 29 (b) affords N'-[(2,6-dichlorostyryl)sulfonyl]acetamidine, m.p. 154.5°-158.5° C. (corr.), from absolute ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:15][CH3:16])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:6]Cl.[C-:17]#[N:18].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:17]#[N:18])[CH:8]=[C:9]([S:15][CH3:16])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: [C-]#N
Reactant: CCCOc1c(OC)cc(CCl)cc1SC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1c(OC)cc(CC#N)cc1SC
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
To 16 g of 3-methoxy-5-methylthio-4-propoxybenzyl chloride in 100 ml of dry DMF was added 5 g (0.10 mole) sodium cyanide. The mixture was stirred for about 48 hours at room temperature under N2. The solution was filtered, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography to yield 14.5 g of 3-methoxy-5-methylthio-4-propoxyphenyl acetonitrile as an oil. (95% yield).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[N:18]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][C:20](=O)[CH2:19]2.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:1]([CH:3]=[C:20]1[CH2:21][CH:22]2[CH2:25][N:18]([CH2:24][CH2:23]2)[CH2:19]1)#[N:2]
Reactant: O=C1CC2CCN(C1)C2
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC2CCN(C1)C2
Temperature: 25 °C

Procedure:
Diethyl cyanomethylphosphonate (5.67 g, 0.032 mole) in THF (75 ml) was added over 10 minutes to a stirred solution of potassium tert-butoxide (3.60 g, 0.032 mole) in THF (75 ml) at 0° C. The reaction mixture was then cooled to -20° C. before dropwise addition of 1-azabicyclo[3.2.11octan-3-one* (3.64 g, 0.029 mole) in THF (50 ml) over 15 minutes. The mixture was allowed to warm to room temperature, stirred for 1h, and then poured into 20% aqueous potassium carbonate (150 ml) and extracted with ethyl acetate (3×200 ml). The combined organic extracts were dried (Na2SO4) and evaporated to give the title compound (D11) as a 6:5 mixture of E and Z isomers (3.88 g, 90%). The isomers could be separated chromatographically on silica using 3% methanol/chloroform as eluant to give in order of elution the Z-isomer and the E-isomer as oils.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1.NN>C(O)C.CCOCC>[F:36][C:34]([F:35])([F:37])[C:32]1[CH:31]=[C:5]([CH:4]=[C:3]([C:2]([F:39])([F:38])[F:1])[CH:33]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][NH2:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Agent: NN
Solvent: CCO
Solvent: CCOCC
Product: NCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-1,3-dihydroisobenzofuran-1-yl)ethyl)isoindoline-1,3-dione (250 mg, 0.455 mmol) in ethanol (2 mL) was added hydrazine (0.100 mL, 3.2 mmol). The resulting solution was heated to 45° C. and held there for 3 h. The reaction was cooled to room temperature, diluted with ether, and filtered to remove the precipitate which was discarded. Concentration of the mother liquor gave 175 mg (92%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.74 (s, 1H), 7.63 (s, 2H), 7.28 (m, 2H), 7.21 (m, 1H), 7.16 (m, 1H), 5.11 (s, 2H), 4.61 (qAB, JAB=12.8 Hz, 2H), 3.65 (qAB, JAB=9.8 Hz, 2H), 2.73 (m, 1H), 2.54 (m, 1H), 2.13 (ddd, J=14.4, 8.6, 5.8 Hz, 1H), 2.00 (ddd, J=14.3, 8.6, 5.8 Hz, 1H), 1.55 (bs, 2H); 13C-NMR (CDCl3, 126 MHz) δ 141.4, 141.3, 139.9, 131.7 (q, J=33.6 Hz), 128.2, 127.5, 127.1, 123.4 (q, J=273 Hz), 121.7, 121.4, 121.1, 90.0, 76.8, 72.8, 72.0, 40.4, 37.4. Mass spec.: 420.14 (MH)+. Accurate mass spec.: m/z 420.1391 [MH]+, Δ=1.7 ppm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][C:13](Cl)=C)([CH3:4])([CH3:3])[CH3:2].[C:16]1(N(CC)CC)C=CC=CC=1>CCOC(C)=O>[C:1]([C:5]1[C:6]2[S:11][C:12]([CH3:13])=[CH:16][C:7]=2[CH:8]=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(Cl)CSc1ccccc1C(C)(C)C
Reactant: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc2cccc(C(C)(C)C)c2s1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 1-tert-Butyl-2-(2-chloro-allylsulfanyl)-benzene (5.66 g, 23.58 mmol) in PhNEt2 (50 mL) is refluxed overnight. It is cooled to rt, diluted with EtOAc (100 mL), washed with 1.0 M HCl (3×100 mL); dried with Na2SO4; filtered and concentrated. The resulting crude material is purified by chromatography gives the title compound (4.69 g, 23.01 mmol, 98%). 1H NMR (CDCl3): δ 1.54 (s, 9H), 2.59 (d, J=1.3 Hz, 3H), 6.99 (q, J=1.3 Hz, 1H), 7.21-7.29 (m, 2H), 7.53 (dd. J=7.4, 1.3 Hz, 1H) ppm. ES-MS (m/z): calcd for C13H16S (M+1)+: 205.3. found: 205.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:12].CS(C)=[O:27]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=[O:27])=[C:10]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[CH:20]=1
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1-c1ccccc1CBr
Reactant: CS(C)=O
Product: O=Cc1ccccc1-c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
The starting material is prepared as follows: The solution of 3.2 g of 2-(o-bromomethylphenyl)-5-chloro-2'-fluorobenzophenone in 40 ml of freshly distilled dimethylsulfoxide is heated for 30 minutes in an oil bath at 178°. After cooling, the solution is partitioned between diethyl ether and water, the ethereal layer washed again with water and saturated aqueous sodium chloride, and evaporated. The residue is taken up in 40 ml of methylene chloride and the solution treated with 2.6 g of pyridinium chlorochromate for 2 hours at 25°. The mixture is diluted with 100 ml of diethyl ether, filtered through a bed of infusorial earth and the filtrate evaporated, to yield the 2-[4-chloro-2-(2-fluorobenzoyl)-phenyl]-benzaldehyde.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].[Br:14][CH2:15][CH2:16]Br.[H-].[Na+]>CN(C=O)C>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:16][CH2:15][Br:14])[C:5]1=[O:13])([CH3:3])=[CH2:2]
Reactant: BrCCBr
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCBr)c2ccccc21

Procedure:
1-Isopropenylbenzimidazolone (J. Davol, J. Chem. Soc., 1960, 308) was alkylated with 1,2-dibromoethane using sodium hydride in DMF. The product was purified by chromatography and crystallization from cyclohexane to give 1-isopropenyl-3-(2-bromoethyl)benzimidazolone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]([O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)[CH2:26][CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH2:25][CH2:26][CH3:27])[CH:34]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CCCOc1cccc(B(O)O)c1
Product: CCCOc1cccc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 16 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-propoxy phenyl boronic acid (47 mg, 0.26 mmol) to give the title compound (10 mg, 16%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).