Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O.C(OCC)(=O)C>C(O)C>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCc1ccc(Br)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
Potassium cyanide (630 mg) was added to an emulsion of 4-bromo-1-bromomethyl-2-trifluoromethylbenzene (3.86 g) in ethanol (15 mL)-water (5 mL), and the mixture was stirred at 70° C. for three hours and 15 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel C-200; elution solvent:heptane:ethyl acetate=9:1) to obtain 2.28 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21]O>>[C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Temperature: 170 °C

Procedure:
Methyl oleate was prepared as follows: A reactor was charged with 500 grams oleic acid, 58 grams methanol and 5 weight percent (based on the oleic acid) of the catalyst of Example I. Heating was begun to 140° C. and a water/methanol mixture began distilling at about 80° C. Subsurface addition of methanol (29 grams/hour) was begun while heating to 170° C. The reaction was terminated when the acid value of the reaction mixture reached about 1 . The methyl oleate, after filtering with a diatomaceous earth filter aid, had an acid value of 0.9 and contained less than 1 ppm titanium.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1.[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[O:16][C:15]([CH2:17][N:33]2[CH2:34][CH2:35][CH:30]([C:26]3[CH:25]=[C:24]([NH:23][C:21](=[O:22])[CH:20]([CH3:19])[CH3:36])[CH:29]=[CH:28][CH:27]=3)[CH2:31][CH2:32]2)=[CH:14][CH:13]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2Cl)o1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4ccc(C(F)(F)F)cc4Cl)o3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-[2-chloro-4-(trifluoromethyl)phenyl]-2-furaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 505.0 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N+:14]([O-])=[CH:13][C:12]=3[C:8]=2[C:7]([CH:18]=[O:19])=[CH:6][CH:5]=1>C(O)(=O)C.ClCCl.[Fe]>[F:20][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([CH:18]=[O:19])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)F)c2oc3cc[n+]([O-])cc3c12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=Cc1ccc(OC(F)F)c2oc3ccncc3c12
Yield: 65 %

Procedure:
To a well stirred suspension of 6-(difluoromethoxy)[1]benzofuro[3,2-c]pyridine-9-carbaldehyde 2-oxide (1.0 g, 3.6 mmol) in acetic acid (15 mL) was added iron powder (800 mg, 14.28 mmol) and the mixture was stirred at about 60° C. for about 15-30 minutes. Excess acetic acid was removed under reduced pressure. The residue obtained was diluted with dichloromethane (50 mL) and filtered through a celite bed and the filtrate was washed with water (3×25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified through a silica gel column using ethyl acetate in dichloromethane as an eluent to give 6-(difluoromethoxy)[1]benzofuro[3,2-c]pyridine-9-carbaldehyde as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=O)C2C(=CC=CC=2)C1=O.[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[C:23]([C:30]2[N:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:22]=1.ClC1[N:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:25]([C:24]2[CH:28]=[CH:29][C:21]([CH3:20])=[CH:22][C:23]=2[C:30]2[N:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:27])[C@@H:3]1[CH2:8][NH:9][C:17]1[N:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc(C(=O)O)c(-c2ncccn2)c1
Product: Cc1ccc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c(-c2ncccn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A389 using 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione, 4-Methyl-2-(pyrimidin-2-yl)benzoic acid and 2-chloro-5-(trifluoromethyl)pyrimidine. 1H NMR (500 MHz, CD3OD) δ 9.00-6.70 (m, 8H), 5.15-2.85 (m, 5H), 2.45-0.65 (m, 11H); ESI MS (M+H) 471.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=O)[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][OH:24].Cl.N1C=CC=CC=1>CCO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=[N:23][OH:24])[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCC(=NO)c1ccc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure P, 1-(5,6-diphenyl-pyridin-2-yl)-propan-1-one (Compound 76, 90 mg, 0.31 mmol), NH2OH—HCl (87 mg, 1.25 mmol) and pyridine (272 mg, 0.27 mmol) in EtOH (2 ml) were reacted to give title compound as a white solid.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[NH:13][CH:14]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:16]=1[C:17]([NH2:19])=[O:18].O>C(O)C>[CH:1]([NH:11][C:12]1[NH:13][CH:14]=[C:15]([C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[C:16]=1[C:17]([NH2:19])=[O:18])=[O:2]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCO
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1NC=O
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A solution of 2 cm3 (52.9 mmol) of formic acid in 5 cm3 (52.9 mmol) of acetic anhydride is added, at a temperature close to 25° C., to a solution of 0.3 g (1.21 mmol) of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in 5 cm3 of absolute ethanol. After stirring for 2 hours at this temperature, the reaction medium is poured into 100 cm3 of water. The suspension is then filtered. The solid is drained, dried to give 0.257 g of 2-formylamino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in the form of a green powder. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm), from 6.22 to 8.53 (very broad m, 2H); 6.78 (d, J=3.0 Hz, 1H); 7.64 (d, J=9.0 Hz, 2H); 8.19 (d, J=9.0 Hz, 2H); 8.32 (d, J=1.5 Hz, 1H); 10.55 (broad s, 1H); 11.6 (broad s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]1([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:17](=[O:27])[C:16]([C:28](OCC)=[O:29])=[C:15]2[OH:33].C(N(C(C)C)C(C)C)C>O1CCOCC1.CCOC(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]1([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:17](=[O:27])[C:16]([C:28]([NH:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[O:29])=[C:15]2[OH:33]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCCC2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCCC2)C1=O
Temperature: 80 °C
Yield: 12.3 %

Procedure:
tert-Butyl 2-aminoacetate hydrochloride (901 mg, 5376 μmol) was added to a mixture of ethyl 6′-chloro-4′-hydroxy-2′-oxo-spiro[cyclohexane-1,1′-naphthalene]-3′-carboxylate (1.20 g, 3584 μmol) in 1,4-dioxane (3584 μL) and N-ethyl-N-isopropylpropan-2-amine (1873 μL, 10753 μmol). The resulting mixture was heated at 80° C. for 2 hours. The resulting mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (185 mg) as a light yellow solid after purification via preparatory HPLC. MS (m/z)=364 (M+H-tBu)+.
Reaction SMILES: O1CCN([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)CC1.[N+:13]([CH2:16][CH2:17]OC(=O)C)([O-:15])=[O:14].[OH2:22].Cl>C(#N)C.CCOC(C)=O>[N+:13]([CH2:16][CH2:17][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1=[O:22])([O-:15])=[O:14]
Reactant: CC(=O)OCC[N+](=O)[O-]
Reactant: O
Reactant: C1=C(N2CCOCC2)CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1CCCCC1CC[N+](=O)[O-]

Procedure:
To a solution of 1-morpholino-1-cyclohexene (51 g; 300 mmol) in 120 mL anhydrous acetonitrile at 0-4° C. was added the 2-nitroethylacetate product of Example 2a (37.8 g, 293 mmol) dropwise. The resulting red solution was stirred under N2 atmosphere in an ice bath for 2½ hrs. The red solution was then stirred at ambient temperature under an N2 atmosphere overnight. Water (100 mL) was added to the red solution over a 10-15 minute period. The temperature rose from 20 to 29° C. with the first 200 mL of water, but then dropped to 27° C. by the end of the addition. This was then acidified with aqueous HCl. The dark red reaction mixture was diluted with 85 mL of EtOAc and the layers separated. The light orange water layer (bottom) was extracted again with 50 mL of EtOAc. The combined EtOAc layers were washed with saturated brine (2×85 mL), dried (MgSO4), filtered and concentrated to afford 45 g of 2-(2-nitroethyl)cyclohexanone as a red oil.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: NCCC1CCOCC1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC2CCOCC2)ccc1Oc1ccc(C(N)=O)nc1
Reaction time: 8 h

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyridine-2-carboxamide (Ex 391, Part A) (0.600 g, 2.20 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.285 g, 2.20 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (11.0 mL), cap and stir overnight. Add NaBH4 (0.0833 g, 2.20 mmol) and stir until the gasses stop evolving. Filter the reaction mixture, then concentrate it. Purify by chromatography eluting with 5% to 30% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes to give 5-(2-methoxy-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide. (0.6103 g, 71.9%). Dissolve the compound in dichloromethane:methanol (3.2 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to give the title compound (0.775 g): TOF MS ES+ 386.2 (M+H)+, HRMS calcd for C21H28N3O4 386.2080 (M+H)+, found 386.2078, time 0.39 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=9.3 min, 100% purity.
Reaction SMILES: [CH3:1][O:2][S:3]([OH:6])(=[O:5])=[O:4].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[NH:33])SC)[N:25]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8].[NH3:34].CO>>[CH3:1][O:2][S:3]([OH:6])(=[O:5])=[O:4].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[NH:33])[NH2:34])[N:25]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8]
Reactant: N
Reactant: CCOc1ccc(-c2nc(-c3cccc(C(=N)SC)n3)cs2)cc1OCC
Agent: COS(=O)(=O)O
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cccc(C(=N)N)n3)cs2)cc1OCC

Procedure:
0.81 g of 2-(3,4-diethoxyphenyl)-4-[6-(1-imino-1-methylthiomethyl)-2-pyridyl]thiazole monomethylsulfate and a saturated ammonia-methanol solution were refluxed at 100° C. for 3 hours in a sealed tube. The solvent was removed by distillation. The residue was recrystallized from chloroform-diethyl ether to obtain 0.44 g of 2-(3,4-diethoxyphenyl)-4-(6-amidino-2-pyridyl)thiazole monomethylsulfate.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[C:24]=1[F:25])[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cccc(F)c1F
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cccc(F)c3F)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and (2,3-difluorophenyl)boronic acid (0.072 g, 0.46 mmol) in 1,4-dioxane (3 mL) was added a 1 N solution of sodium carbonate in water (0.57 mL, 0.57 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.014 g, 0.019 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated, and purified on silica gel (0-30% ethyl acetate/hexane) to give the desired product (83 mg). LCMS calculated for C15H12F2N5OS (M+H)+: m/z=348.1. Found: 348.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:22].[H-].[Na+].[CH3:25][Si:26]([CH3:33])([CH3:32])[CH2:27][CH2:28][O:29][CH2:30]Cl.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1>CN1CCCC1=O.[Cl-].[Na+].O>[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:13]2[N:12]=[C:11]3[N:10]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:33])([CH3:32])[CH3:25])[C:9](=[O:22])[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH2:17][C:16]3=[CH:15][N:14]=2)[CH2:37][CH2:36]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1ccccc1Cl)C2
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)CCOCN1C(=O)N(c2ccccc2Cl)Cc2cnc(N[C@H]3CC[C@H](N)CC3)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of sulfone 11.1 (3.0 g, 8.87 mmol) in 10 mL of 1-methyl-2-pyrrolidinone was added 60% sodium hydride (390 mg, 9.76 mmol, mineral oil). The reaction was stirred for 15 minutes at room temperature and then 2-(trimethylsilyl)ethoxymethyl chloride (1.57 mL, 8.87 mmol) was added. The reaction was stirred at room temperature for 4 hours. To this solution was then added 5.06 g of trans-1,4-diaminocyclohexane predissolved in 15 mL 1-methyl-2-pyrrolidinone. The reaction was then warmed to 60° C. for 24 hours. The reaction was poured into brine and the product extracted into ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate and water, dried over magnesium sulfate, and concentrated in vacuo to give a light brown oil. Purification by chromatography using 2% methanol/dichloromethane to 5% methanol/dichloromethane as eluant gave 2.8 g of 7-(trans-4-aminocyclohexylamino)-3-(2-chlorophenyl)-1-[2-(trimethylsilyl)ethoxymethyl]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a pale yellow foam. (MH+=502).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][NH:19]2)=[CH:15][CH:14]=1.N1C=CC=CC=1.C(Cl)Cl>CN(C=O)C>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][N:19]2[C:2]2[C:3]3[CH:11]=[CH:10][N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:15][CH:14]=1
Reactant: Clc1ncnc2cnccc12
Reactant: Clc1ccc2c(c1)NCC2
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)N(c1ncnc3cnccc13)CC2
Temperature: 70 °C

Procedure:
4-Chloropyrido[3,4-d]pyrimidine (0.10 g, 0.60 mmol), 6-chloroindoline (0.10 g, 0.66 mmol) and pyridine (0.14 g, 1.81 mmol) were combined in DMF (1 mL) and heated at 70° C. for 3 hours. The reaction was cooled to room temperature and then added to methylene chloride (150 mL). The organic layer was washed with saturated sodium carbonate and water and then dried over sodium sulfate. The solvent was removed by rotary evaporation and the residue purified by column chromatography (silica gel, 9/2/1—CH2Cl2/hexanes/methanol) to give the title product as a pale yellow residue (0.048 g, 28%). MP 194-6° C.; LCMS: 283 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]([NH2:37])[CH3:36])[CH:31]=[CH:32][C:33]=1[F:34].FC1C=C2C(=CC=1)C(N)CC2>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH:35]([C:30]1[CH:31]=[CH:32][C:33]([F:34])=[C:28]([Cl:27])[CH:29]=1)[CH3:36]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(N)c1ccc(F)c(Cl)c1
Agent: NC1CCc2cc(F)ccc21
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccc(F)c(Cl)c1
Yield: 65 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (426 mg, 1.0 mmol) with 1-(3-chloro-4-fluoro-phenyl)-ethylamine Isomer 1 (226 mg, 1.3 mmol). Purify by chromatography on silica gel eluting with EtOAc/hexane (1:7) to give 7-chloro-6-[1-(3-chloro-4-fluoro-phenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (293 mg, 65%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.Cl>CN(P(N(C)C)(N(C)C)=O)C>[F:1][C:2]([F:7])([F:6])[CH:3]([CH3:4])[O:5][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: CC(O)C(F)(F)F
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(Oc1ccc(C#N)cc1)C(F)(F)F
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
Add 1,1,1-trifluoro-2-propanol (3.8 g, 66 mmol) slowly to a slurry of sodium hydride (730 mg, 60% in mineral oil, washed with hexane) in HMPA (5 mL) under nitrogen. Stir the slurry for 15 min and add 4-fluorobenzonitrile (2 g, 16.5 mmol). Heat the slurry in a sealed flask to 90° C. for 16 h. Cool the mixture to ambient temperature and pour the mixture into a flask containing 5% aqueous HCl (20 mL). Extract the mixture with diethyl ether (3×50 mL), and wash with 5% aqueous HCl (25 mL). Dry the organic layer over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate (2.5 g, 70%). GC-MS m/z: 215 (M+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:21]1C(C=O)=CC2OCOC=2[CH:22]=1.NC1C=CC(C(OCC)=O)=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[N:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([O:18][CH2:21][CH3:22])=[O:17])=[CH:14][CH:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1ccc(NCc2ccc3c(c2)OCO3)cc1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: CCOC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(N=Cc2ccc3c(c2)OCO3)cc1

Procedure:
Commercial quantities of 4-(((1,3-benzodioxol-5-yl)methyl)amino)benzoic acid are generally prepared by reacting piperonal with ethyl 4-aminobenzoate in absolute ethanol in the presence of a catalytic amount of 4-toluenesulfonic acid monohydrate to give the intermediate ethyl 4-(((1,3-benzodioxol-5-yl)mehylene)amino)benzoate. The intermediate is isolated and reduced in absolute ethanol using sodium borohydrate. The resulting ethyl 4-(((1,3-benzodioxol-5-yl)methyl)amino)benzoate is not isolated, but immediately hydrolyzed with aqueous sodium hydroxide to give sodium 4-(((1,3-benzodioxol-5-yl)methyl)amino)benzoate. The salt is converted to 4-(((1,3-benzodioxol-5-yl)methyl)amino)benzoic acid with aqueous acetic acid. The above process has been used to give satisfactory yields and was used to produce a batch containing 33 kg of pharmaceutically-acceptable product.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(O)C>[NH2:9][C:7]1[N:6]([C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[N:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:8]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cc(C2CC2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(C2CC2)nn1C(=O)Nc1ccccc1

Procedure:
To 0.4 g (3.2 mmol) of 3-cyclopropyl-5-amino-1H-pyrazole in 10 ml of 95% ethanol containing 0.3 g of sodium hydrogencarbonate 0.35 ml (3 mmol) of phenylisocyanate were added dropwise over several minutes. After 30 min water was added, and the solid was filtered, washed with 10% HCl and then with water. The filtrate was concentrated in vacua. The crude was recrystallized from methanol/water to give white peddles of 5-amino-3-cyclopropyl-N-phenyl-1H-pyrazole-l-carboxamide,
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:10]CC1.[ClH:14].[CH2:15]([N:22]1[CH2:28][CH2:27]CC(=C)C[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.CCOC(C)=O>[Os](=O)(=O)(=O)=O.C1COCC1.O>[ClH:14].[CH2:15]([N:22]1[CH2:28][CH2:27][CH2:3][C:1]([CH2:4][OH:10])([OH:5])[CH2:2][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C1CCCN(Cc2ccccc2)CC1
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCC1(O)CCCN(Cc2ccccc2)CC1

Procedure:
A tert-butanol solution of N-methylmorpholine-N-oxide and osmium tetraoxide was added to a mixture of 1-benzyl-4-methyleneazepane hydrochloride and THF-water, and the resultant solution was stirred at ambient temperature for 24 hours and then treated with 4M HCl-EtOAc solution to yield 1-benzyl-4-(hydroxymethyl)azepan-4-ol hydrochloride. To an EtOH solution of 1-benzyl-4-(hydroxymethyl)azepan-4-ol hydrochloride obtained was added 10% palladium on activated carbon, and the suspension was stirred under hydrogen atmosphere at ambient temperature for 6 hours to yield 4-(hydroxymethyl)azepan-4-ol hydrochloride.