Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([F:13])[C:7]=1[F:14])[CH2:3][C:4]#[N:5].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)=O.[NH2:36][C:37]1[CH:41]=[C:40]([CH3:42])[NH:39][N:38]=1>C(#N)C>[C:4]([C:3]1[CH:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[C:41]2[C:40]([CH3:42])=[N:39][NH:38][C:37]=2[NH:36][C:2]=1[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([F:13])[C:7]=1[F:14])#[N:5]
Reactant: Cc1cc(N)n[nH]1
Reactant: N#CCC(=O)c1c(F)ccc(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Solvent: CC#N
Product: Cc1n[nH]c2c1C(c1ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc1)C(C#N)=C(c1c(F)ccc(F)c1F)N2
Yield: 81.6 %

Procedure:
To 1.1 g (5.52 mmol) of 3-oxo-3-(2,3,6-trifluorophenyl)propanenitrile diluted in 20 ml of acetonitrile are respectively added 1.60 g (5.52 mmol) of tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate and 0.53 g (5.52 mmol) of 3-amino-5-methyl-pyrazole. The reaction mixture is refluxed for 4 h then the solvent is concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 5:5) then the solid obtained is triturated in ethyl acetate and dried to yield 2.48 g (81%) of tert-butyl 4-(4-(5-cyano-3-methyl-6-(2,3,6-trifluorophenyl)-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate in the form of a yellow solid.
Reaction SMILES: CS(C)=O.[C-:5]#[N:6].[Na+].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:13]([CH:19]=1)[C:14](Cl)=[N:15][O:16][CH3:17]>C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:13]([C:14](=[N:15][O:16][CH3:17])[C:5]#[N:6])[CH:19]=1
Reactant: CON=C(Cl)c1cc(Cl)ccc1OCc1ccc(Cl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CON=C(C#N)c1cc(Cl)ccc1OCc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
Dimethyl sulfoxide (3 ml) and 95% sodium cyanide (0.31 g, 6 mmol) were added to 5-chloro-2-(4-chlorobenzyloxy)-α-methoxyiminobenzyl chloride (1.03 g, 3 mmol), and the mixture was stirred at 100° C. for 4 hours. After completion of the reaction, ethyl acetate (150 ml) was added, and the mixture was washed with saturated brine (100 ml) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 5-chloro-2-(4-chlorobenzyloxy)-α-methoxyiminophenylacetonitrile (0.92 g, 91.5%) as crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][N:4]=1.[CH2:8]([NH2:10])[CH3:9]>C1COCC1>[CH2:8]([NH:10][CH2:2][C:3]1[CH:7]=[CH:6][S:5][N:4]=1)[CH3:9]
Reactant: BrCc1ccsn1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1ccsn1

Procedure:
prepared by reaction of 3-bromomethyl-isothiazole (Buttimore D. et al J. Chem. Soc. 1965, 7274-7276) with 2M ethylamine in THF.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[N:16][CH:15]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[C:11](N)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[N:16][CH:15]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]1[CH:17]=[N:16][CH:15]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1c(OCc2ccccc2)cncc1OCc1ccccc1
Solvent: C1CCOC1
Product: O=Cc1c(OCc2ccccc2)cncc1OCc1ccccc1
Product: OCc1c(OCc2ccccc2)cncc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %
Yield: 38 %

Procedure:
To 3,5-bis(benzyloxy)isonicotinamide (1.6 g, 4.79 mmol) in THF (30 mL) was added Cp2ZrCl (3.7 g, 14.4 mmol, 3 eq.) at rt. The mixture was stirred at rt for 2 h, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-bis(benzyloxy)isonicotinaldehyde (580 mg, 38%) and (3,5-bis(benzyloxy)pyridin-4-yl)methanol (710 mg, 46%) as white solids. Data for aldehyde 1H NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 8.13 (s, 2H), 7.51-7.22 (m, 10H), 5.21 (s, 4H); LRMS (M+H+) m/z 320.1. Data for alcohol 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 2H), 7.58-7.34 (m, 10H), 5.22 (s, 4H), 4.87 (s, 1H); LRMS (M+H) m/z 322.1.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:29](=[O:30])[CH2:28][CH2:27][C@@:26]2([CH3:31])[C:13]=1[CH2:14][CH2:15][C@@H:16]1[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]1[CH2:18][CH2:19][C@@H:20]2[C:32]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>O1CCCC1.O>[CH:1]([NH:11][C:12]1[C:29](=[O:30])[CH2:28][CH2:27][C@@:26]2([CH3:31])[C:13]=1[CH2:14][CH2:15][C@@H:16]1[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]1[CH2:18][CH2:19][C@@H:20]2[C:32]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:2]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=CO
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C(NC=O)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A solution of formic acid (0.22 mL, 5.84 mmole) and acetic anhydride (0.46 mL, 4.76 mmole) is heated at reflux temperature for 2 hours under a nitrogen atmosphere. The cooled solution is diluted with tetrahydrofuran (5 mL) and a solution of 4-amino-N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide, (0.35 g, 0.91 mmole) in tetra-hydrofuran (10 mL) is added. The reaction is stirred overnight at room temperature and then diluted with water (25 mL). A gummy material separated which is extracted into diethyl ether-dichloromethane and washed with saturated aqueous sodium bicarbonate. The dried solution is concentrated to a yellow foam which is purified by flash chromatography (hexane-50% ethyl acetate then ethyl acetate) to give 4-formamido-N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide (0.25 g, 67.6%, diethyl ether).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9][C:8](=O)[N:7](C)[C:6]=2[CH:18]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])=[N:27][C:22]([NH:1][C:2]2[C:3]([O:19][CH3:20])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH:13]4[CH2:14][CH2:15]4)[CH2:9][CH2:8][NH:7][C:6]=3[CH:18]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)N(C)C(=O)CN(CC1CC1)C2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)NCCN(CC1CC1)C2

Procedure:
The title compound was prepared from 8-Amino-4-cyclopropylmethyl-7-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to example 730 (0.058 g, 42%). Mp 149-151° C.; LCMS (m/e) 538 (M); 1H-NMR (DMSO, 400 MHz) δ 8.25 (s, 1H), 8.00 (s, 1H), 7.83 (d, 1H, J=7.58 Hz),7.78 (s, 1H), 7.75 (s, 1H), 7.25 (s, 1H), 7.05 (s, 1H), 6.30 (t, 1H), 6.07 (t, 1H), 5.75 (s, 1H), 4.16-4.12 (t, 1H, J=8.08 Hz), 3.90 (s, 3H), 3.60-3.50 (q, 2H, J=11.87 Hz), 3.19 (s, 3H), 3.11 (s, 2H), 2.86 (s, 1H), 2.72 (s, 1H), 2.41-2.40 (d, 2H, J=6.57 Hz), 2.11-2.09 (d, 1H, J=8.84 Hz), 1.40-1.35 (d, 1H, J=8.84 Hz), 0.92-0.80 (m, 1H), 0.50-0.48 (d, 2H, J=7.83 Hz), 0.20-0.12 (m, 2H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13]Br.[OH-:15].[K+].S(=O)(=O)(O)O>O>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][CH2:10][CH2:11][CH2:12][CH2:13][O:15][C:4]1[CH:6]=[CH:7][CH:8]=[C:1]([OH:2])[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: [OH-]
Reactant: BrCCCCBr
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Oc1cccc(OCCCCOc2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A five neck five liter round bottom flask equipped with a mechanical stirrer, two condensers, and a dropping funnel is purged with nitrogen then charged under a nitrogen blanket with 1.5 kg (13.6 moles) resorcinol, 120 grams deionized water, and 138.75 grams (0.64 moles) 1,4-dibromobutane. The reaction slurry is slowly heated with stirring to reflux under a slow nitrogen purge; then a solution of 109 grams (1.64 moles) 85% KOH pellets in 109 grams water is added dropwise under a nitrogen blanket over a two hour period. After an additional hour of refluxing, the reaction mixture is allowed to coil enough to pour the contents into 10 liters deionized water. The water slurry is acidified with 30% sulfuric acid and allowed to stand at room temperature overnight before filtering under reduced pressure and washing with several portions of warm water. The residue, 80 grams of yellow amorphous solid, is then extracted with large quantities of boiling water to remove oils. After cooling to room temperature, the water extracts (14 liters) yield 28 grams of white, shiny platelets. HPLC analysis reveals 92% purity by peak area. Recrystallization from acetone yielded product of >98% purity by HPLC analysis with a melting point of 103° C.-106° C. (literature melting point, 105° C.-108° C.) for use in examples 10, 18 and 20. Both 1H and 13C NMR spectra are consistent with the proposed structure.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)([OH:3])=[O:2].[C:16](=O)([O-])O.[Na+].CN(C)C=O.S(OC)(OC)(=O)=O>CC(C)=O>[CH3:16][O:2][C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)=[O:3]
Reactant: O=C(O)c1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)C(=O)C1(CC1)O2
Yield: 58.5 %

Procedure:
5-Carboxyspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (2 g.) and sodium hydrogen carbonate (1.25 g.) were suspended in acetone (50 ml.) and N,N-dimethylformamide (5 ml.) and, under stirring, dimethyl sulfate (2 ml.) was added dropwise to the mixture. The reaction mixture was refluxed under heating for 24 hours, and, after cooling, the solvent was evaporated off under reduced pressure. The residue was diluted with water and the solution was extracted with ethyl acetate. The extract was washed with aqueous solution of sodium hydrogen carbonate and dried. After removing the solvent by evaporation under reduced pressure, the residue was recrystallized from methanol to give colorless needles of 5-methoxycarbonylspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.25 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[C:5]([NH2:8])=[N:6][CH:7]=1.I[C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]([CH3:25])[CH:13]=1>C(N(CC)CC)C.CN(C)C=O.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH3:25])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: COc1cc2c(I)cn(C)c2cc1OC
Reactant: C#Cc1cc(Cl)cnc1N
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(C#Cc3cc(Cl)cnc3N)cn(C)c2cc1OC
Temperature: 20 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A suspension of 0.43 g of 5-chloro-3-ethynylpyridin-2-ylamine, 0.6 g of 3-iodo-5,6-dimethoxy-1-methyl-1H-indole (example 103-f), and 0.072 g of copper iodide, in a mixture of 60 ml of triethylamine and 30 ml of dimethylformamide, is degassed with argon for 15 minutes. 0.066 g of bis(triphenylphosphine)palladium(II) chloride is added to the above suspension. The mixture is agitated at around 20° C. for approximately 6 hours; 0.075 g of 5-chloro-3-ethynylpyridin-2-ylamine is added and the mixture is agitated at this same temperature for 2 days. The mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 100 ml of water and extracted with three times 100 ml of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (50/50 by volume)]. 0.44 g of 5-chloro-3-(5,6-dimethoxy-1-methyl-1H-indol-3-ylethynyl)pyridin-2-ylamine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].Cl[C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.S(Cl)(Cl)=O>CS(C)=O.CO>[CH3:9][O:8][C:6]([C:2]1[N:1]([C:13]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=2)[CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cnc(-n2cccc2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
Methyl 1H-pyrrole-2-carboxylate (5.78 g, 46.2 mmol) was dissolved in DMSO and cooled to 10° C. NaH was added in two portions over 5 min. The reaction mixture was stirred at 10° C. for 10 min and methyl 6-chloro-5-nitronicotinate (5 g, 23.09 mmol) in DMSO (10 mL) was added slowly over 3 min. The red reaction mixture was allowed to warm to room temperature and stirred overnight. It was cooled to 0° C. and quenched with water (12 mL) and diluted with brine (50 mL). The mixture was washed with EtOAc (2×25 mL) and the aqueous layer was acidified to pH=2 with 4.5 N HCl. It was extracted with EtOAc (1×100 mL) and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow solid, which was dissolved in MeOH (100 mL) and cooled to 0° C. Thionyl chloride (45 mL, 617 mmol) was added slowly over 5 min. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature overnight. It was concentrated in vacuo and the resulting solid was triturated with ethyl acetate (300 mL). The solid was filtered off and the filtrate was concentrated in vacuo. then washed with ethyl ether to afford methyl 6-(2-(methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate (5.04 g, 16.51 mmol, 92% yield) as a yellow solid, [M+H] calc'd for C13H11N3O6, 306; found, 306.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH:18]([O:17][CH:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][O:1][C:30](=[O:31])[NH:29][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=2)=[CH:9][CH:8]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(Cc1ccc(CCO)cc1)OC(C)C
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)OCCc2ccc(CC(OC(C)C)C(=O)O)cc2)cc1

Procedure:
Using ethyl 3-[4-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([O:19][NH:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[CH2:12]([O:19][N:20]([CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])[C:10]([NH:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[S:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1CCNOCc1ccccc1
Reactant: Fc1cccc(F)c1N=C=S
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCN(OCc1ccccc1)C(=S)Nc1c(F)cccc1F

Procedure:
A solution of 19.68 g of 2,6-difluorophenylisothiocyanate and 34.1 g of N-{2-[N-(benzyloxy)amino]ethyl}phthalimide in 150 ml of benzene is heated to boiling under reflux for 6 hours. The cooled solution is separated from a slight precipitate and then evaporated in vacuo. The residual oil crystallizes from isopropyl ether. There is obtained 1-(benzyloxy)-3-(2,6-difluorophenyl)-1-(2-phthalimidoethyl)-2-thiourea of melting point 141°-143° (ether/methylene chloride).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:16])CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][F:16])[N:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1cccc(Br)n1
Solvent: ClCCl
Product: FCc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A solution of (6-bromopyridin-2-yl)methanol (5 g, 27 mmol) in dry DCM (60 mL) was added dropwise at −78° C. to a cooled solution of DAST (13 g, 80 mmol) in dry DCM (50 mL). The reaction mixture was stirred 1 h at −78° C. then 1 h at room temperature. To complete the reaction, an additional 5 mL of DAST were slowly added at −60° C. and the reaction mixture was kept overnight at room temperature. The reaction was quenched with water and the organic layer extracted with DCM, dried over MgSO4 and evaporated. Purification over silicagel chromatography (prepacked 85 g silicagel column, Cyclohexane/AcOEt: 90/10 as eluent) to afford 4.50 g of 2-bromo-6-(fluoromethyl)pyridine
Reaction SMILES: C[O-].[Na+].[CH:4](=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7].[Cl:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17]Cl.Cl>O.C1(C)C=CC=CC=1.C(O)C>[Cl:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][O:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[CH:4]=[O:12]
Reactant: O=Cc1ccccc1O
Reactant: ClC/C=C/CCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=Cc1ccccc1OC/C=C/CCl

Procedure:
To 130 lt of ethanol, 12.1 kg of sodium methoxide are added while cooling and stirring, followed by 26.5 kg of salicylaldehyde at 30°. Thereupon 33.3 kg of trans-1,4-dichloro-2-butene are added and the mixture heated to 68° for 4 hours. It is combined with 156 lt of toluene, 187 lt of water and 9.4 kg of 36% hydrochloric acid while keeping the temperature at about 30°. The precipitate formed is filtered off and washed with 16 lt of toluene. The filtrate is separated, the organic layer washed 3 times with 27 lt of water, evaporated, the residue distilled and the fraction boiling at 170°/0.2 mmHg collected, to yield the 2-(4-chloro-trans-2-butenyloxy)-benzaldehyde.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=[N:10][NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(OCC)C>C(O)(=O)C.O=[Pt]=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][NH:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=NNC(=O)c2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)N1CCC(NNC(=O)c2ccccc2)CC1
Reaction time: 12 h
Yield: 91.2 %

Procedure:
30 g (0.12 mol) of N′-(1-acetylpiperidin-4-ylidene)benzohydrazide were dissolved in 500 mL of glacial acetic acid and 1 g of PtO2 were added. The mixture was hydrogenated at 40 psi for 12 hours at room temperature. The catalyst was then filtered on celite and the filtrate evaporated in vacuo. The residue was redissolved with dichloromethane and washed with aqueous NaHCO3. The solvent was dried over sodium sulfate and removed under reduced pressure to give, after trituration with diethylether, 28.6 g (92% yield) of the title compound.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C:24]2=[O:29])=[CH:19][CH:18]=1>C(O)C.O>[OH:1][C@H:2]([CH2:3][NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C:24]2=[O:29])=[CH:21][CH:22]=1)[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Solvent: O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1

Procedure:
A suspension of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A. Gutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and 4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in ethanol/water (9:1, 140 ml) is refluxed for 14 h (the precipitate dissolves, after some time again formation of a precipitate). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. The combined mother liquors are concentrated under reduced pressure and, after addition of a second portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (2.84 g, 14.0 mmol), suspended in ethanol/water (9:1, 70 ml) and refluxed for 13 h (the precipitate dissolves, after some time again formation of a precipitate). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. Total yield: 10.14 g, 92% of theory.
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][C@H:63]1[CH2:68][CH2:67][C@H:66]([OH:69])[CH2:65][CH2:64]1>CN(C=O)C>[CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:8]([NH:62][CH:63]2[CH2:68][CH2:67][CH:66]([OH:69])[CH2:65][CH2:64]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)NC1CCC(O)CC1)C1CCCCC1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
To a solution of cyclohexyl-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetic acid (100 mg, 0.25 mmol, 1.0 equiv) in DMF (1.5 mL) was added triethylamine (51.1 mg, 70.0 μL, 0.50 mmol, 2.0 equiv) and HATU (124.7 mg, 0.33 mmol, 1.3 equiv) and the mixture stirred at 40° C. After 15 min, trans-4-amino-cyclohexanol hydrochloride (50.03 mg, 0.33 mmol, 1.3 equiv; [CAS RN 50910-54-8]) was added and stirring continued at 50° C. for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 50 mg (40%) of the title compound.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.CCOCC>[CH2:1]([O:9][C:24](=[O:25])[O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(OCCc1ccccc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 29.96 g phenethyl alcohol and 30 ml pyridine in 150 ml dichloromethane, 60.5 g benzylchloroformate was dropped in over 1 h 45 min while cooling in an ice-bath. After stirring over night at room temperature, the reaction was diluted with ether, washed with 2N HCl, NaHCO3, and water. After extraction with ether, the combined. organic layers were dried and evaporated to dryness. The residue was purified by silica gel chromatography to yield the product: 52.5 g of a colorless oil.