Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[C:4](=[O:20])[C:5]2[C:10]([CH:11]=O)=[CH:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[BH4-].[Na+].Cl>CO>[NH2:1][C:2]1[N:3]([CH2:21][O:22][CH:23]([CH3:24])[CH3:25])[C:4](=[O:20])[C:5]2[C:10]([CH2:11][NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1
Reactant: Nc1ccccc1
Reactant: CC(C)OCn1c(N)nc2c(c(C=O)cn2Cc2ccccc2)c1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)OCn1c(N)nc2c(c(CNc3ccccc3)cn2Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
In 10 ml of dry methanol is dissolved 340 mg of 2-amino-7-benzyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one-5-carbaldehyde and 93 mg of aniline and the mixture is allowed to stand under stirring at room temperature for 60 min. The mixture is then cooled to 0° C. and treated with 38 mg of sodium borohydride for 2 hrs. The excess reagent is decomposed with HCl, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography to give 285 mg of 2-amino-7-benzyl-5-phenylaminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one. The whole amount of the above product is dissolved in 28.5 ml of liquid ammonia-dimethoxyethane (1:1) and an excess of sodium metal shavings are added until a permanent blue color is observed for more than 5 min. To this mixture is added ammonium chloride to terminate the reaction and the whole system is allowed to stand at room temperature until the liquid ammonia is removed. The dimethoxyethane is then distilled off under reduced pressure and the residue is purified by silica gel column chromatography to give 128 mg of 2-amino-5-phenylaminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one. This product is further dissolved in 50 ml of 2 N--HCl and after nitrogen purging, hydrolyzed by heating at 70° C. for 5 hrs. The solvent is then evaporated to dryness under reduced pressure to give 120 mg of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I>CN(C=O)C>[CH3:15][O:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: CI
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1C=O
Temperature: 60 °C
Reaction time: 8.5 h
Yield: 87.4 %

Procedure:
To a solution of 5-nitrosalicylaldehyde (1.00 g, 6.0 mmol) in DMF (20 ml) was added NaH (246 mg) and methyl iodide (2.56 g, 18 mmol) at 0° C. The mixture was stirred for 8.5 hr at 60° C. After the reaction mixture was extracted with ether, the extract was washed with aqueous NaHCO3, brine and 5%-HCl/aq.NaCl, dried over MgSO4 and concentrated in vacuo to afford 2-methoxy-5-nitrobenzaldehyde (0.95 g, 87.8%) as a yellow needle.
Reaction SMILES: [N:1](=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[Cl:9])[OH:2].C1C=CC=CC=1.[Br:16][CH2:17][C:18](Br)=[O:19]>C(N(CC)CC)C>[Br:16][CH2:17][C:18]([OH:19])=[O:2].[Cl:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:3]1=[N:1][OH:2]
Reactant: O=C(Br)CBr
Agent: ON=C1CCCCC1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(O)CBr
Reaction time: 0.5 h

Procedure:
Approximately 5.9 grams (0.04M) of 1-oximino-2-chlorocyclohexane is dissolved in 90 ml. of benzene and the solution is cooled to 10° C. About 8.1 gm. (0.04M) bromoacetyl bromide, diluted with 10 ml. of benzene, and 4.9 grams (6.7 ml.) of triethylamine are added dropwise simultaneously to the solution. Stirring is continued for 30 minutes and the mixture is allowed to come to room temperature. The mixture is then washed twice with water, twice with a mild NaHCO3 solution, and again with water. The mixture is then dried over MgSO4, and the solvent is evaporated to give the product 2-chlorocyclohexanone oxime bromoacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[CH:3]=1.Br[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[C:4]([F:11])[CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1F
Reactant: Brc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1cc(Br)ccc1-c1ncccn1
Reaction time: 8 h

Procedure:
4-Bromo-2-fluorophenyl boronic acid (2AB) (3.0 g, 13.71 mmol, 1 equiv), 2-bromopyrimidine (1AB) (6.54 g, 41.13 mmol, 3 equiv), and 2M sodium carbonate (34 mL) were added in a pressure vessel (350 mL) and a (1v:1v) mixture of toluene and ethanol (45 mL: 45 mL) was added. The mixture was then bubbled with nitrogen gas for about 10 minutes. Tetrakistriphenylphosphine palladium (0) (793 mg, 0.686 mmol, 0.05 equiv) was added to the mixture. The reaction vessel was tightly capped, placed in an oil bath at 90° C. and stirred overnight.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH:29]([O:32][C:33]1[NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[N:34]=1)([CH3:31])[CH3:30]>>[CH:29]([O:32][C:33]1[N:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)([CH3:31])[CH3:30]
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)Oc1nc2ccccc2[nH]1
Product: CC(C)Oc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-isopropoxy-1H-benzo[d]imidazole were reacted to give 338. LCMS: M+H+=549.3
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.[CH3:15]O.S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH2:5]2
Reactant: O=C(O)C1CCc2cc(O)ccc2C1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCc2cc(O)ccc2C1
Yield: 88.9 %

Procedure:
To a solution of 6-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (0.5 g, 3 mmol) in methanol (6 mL, 200 mmol) was added sulfuric acid (0.05 g, 0.5 mmol) and stirred over weekend. After concentration, the residue was dissolved in EtOAc and washed with water, brine and dried over Na2SO4 to give the pure product as a white solid (0.55 g, 100%). LCMS: Rt=1.17 min, m/z=207.00 [M+], 100%.
Reaction SMILES: C(N)C.FCCN.[CH:8]1([NH:11][C:12](=O)[CH2:13][O:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[CH:19]=2)[CH2:10][CH2:9]1.C(NCCOCCOC1C=CC=C(C2C=CSC=2)C=1)C.FCCNCCOCCOC1C=CC=C(C2C=CSC=2)C=1>>[CH:8]1([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[CH:19]=2)[CH2:10][CH2:9]1
Reactant: O=C(COCCOc1cccc(-c2ccsc2)c1)NC1CC1
Agent: CCN
Agent: CCNCCOCCOc1cccc(-c2ccsc2)c1
Agent: FCCNCCOCCOc1cccc(-c2ccsc2)c1
Product: c1cc(OCCOCCNC2CC2)cc(-c2ccsc2)c1

Procedure:
When the same reactions as in Referential Example 34 are carried out using ethylamine or 2-fluoroethylamine instead of the starting cyclopropylamine, N-ethyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine and N-(2-fluoroethyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18][N:19](C)[CH3:20])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.C(O)(=O)C.C(N)=[NH:30].C(N)=O>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:30]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Reactant: N=CN
Solvent: CC(=O)O
Solvent: NC=O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cncnc1-2

Procedure:
A mixture of 90.5 g (0.25 mol) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepine-5-one, 100 g (0.96 mol) of formamidine acetate and 1.0 L of formamide was heated on a steam bath for 16 hr. The mixture was cooled to 0° and the resulting precipitate collected by filtration. The precipitate was washed with water and dried to constant weight to give off-white crystals, mp 120°-121° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:37])[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:20]2[C:15](=[CH:16][C:17]([O:33][CH2:34][CH2:35][OH:36])=[CH:18][CH:19]=2)[O:14]1>N1C=CC=CC=1>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([OH:14])(=[O:9])=[O:8].[CH3:12][C:13]1([CH3:37])[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=2)[C:20]2[C:15](=[CH:16][C:17]([O:33][CH2:34][CH2:35][OH:36])=[CH:18][CH:19]=2)[O:14]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC1(C)CC(c2ccc(C(F)(F)F)cc2)c2ccc(OCCO)cc2O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 2 h

Procedure:
p-Toluene-sulphonyl chloride (0.42 g) was added portionwise to a solution of 2,2-dimethyl-7-(2-hydroxyethyloxy)-4-(4-trifluoromethylphenyl) chroman (0.7 g) in pyridine (20 ml.) and the solution left at room temperature for 2 hours and then at 0° C. for 12 hours. The reaction mixture was poured onto ice, extracted with ether (2×100 ml.) and the ether extract dried (sodium sulphate). Removal of the solvent under reduced pressure gave an oil (0.65 g.) which had spectroscopic properties consistent within the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH2:18][CH2:17][CH2:16]3)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH2:18][CH2:17][CH2:16]3)[C:5]([C:23]([O:25][CH3:26])=[O:24])=[C:4]([CH3:27])[N:3]=1
Reactant: CCOC(=O)C1=C(N)NC(C)=C(C(=O)OC)C1c1ccc2c(c1)CCCO2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(N)nc(C)c(C(=O)OC)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 64.9 %

Procedure:
A mixture of methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate (8.27 g, 31.8 mmol), ethyl 3,3-diaminoacrylate, hydrochloride (5.29 g, 31.8 mmol) and 4-methylmorpholine (3.49 mL, 31.8 mmol) in Isopropanol (76.0 mL) was heated to 90° C. overnight. The mixture was concentrated, dissolved in ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated to provide crude 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.00-6.87 (m, 3 H), 6.64-6.58 (m, 1 H), 6.20 (br. s., 2 H), 4.83-4.77 (m, 1 H), 4.15-4.05 (m, 4 H), 3.71-3.63 (m, 3 H), 2.71 (t, J=6.3 Hz, 2 H), 2.27-2.16 (m, 3 H), 1.99-1.93 (m, 2 H), 1.27-1.22 (m, 3 H); LC/MS (m/z) ES+=373.3 (M+1). A solution of crude 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate in dichloromethane (DCM) (216 mL) was treated with DDQ (7.22 g, 31.8 mmol) and then stirred at ambient temperature (mixture turned dark within one minute). The mixture was filtered over Celite™. The filtrate was diluted with saturated sodium bicarbonate and the layers were separated. The aqueous phase was extracted with DCM. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-100% hexane/EA) to afford 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methylpyridine-3,5-dicarboxylate (7.64 g, 20.63 mmol, 64.9% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.86 (d, 1 H), 6.81 (s, 1 H), 6.73 (d, J=8.4 Hz, 1 H), 6.23-6.02 (m, 2 H), 4.17 (t, J=4.7 Hz, 2 H), 3.99-3.77 (m, 2 H), 3.52-3.43 (m, 3 H), 2.73 (br. s., 2H), 2.45-2.35 (m, 3 H), 1.98 (br. s., 2 H), 0.83-0.67 (m, 3 H); LC/MS (m/z) ES+=371.3 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][C:23]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)([O:26][CH3:27])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:34].[ClH:35].[ClH:34].[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:23]2([O:26][CH3:27])[CH2:24][CH2:25][N:20]([C:17]3[CH:16]=[CH:15][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:19][CH:18]=3)[CH2:21][CH2:22]2)=[CH:29][CH:30]=1
Reactant: COC1(c2ccc(Cl)cc2)CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC1(c2ccc(Cl)cc2)CCN(c2ccc(N3CCNCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 33 h

Procedure:
To a solution of 4-[4-[4-(4-chlorophenyl)-4-methoxypiperidin-1-yl]phenyl]piperazine-1-carboxylic acid tert-butyl ester (1.56 g) in ethyl acetate (62 ml) was added dropwise 4N-HCl/ethyl acetate (40 ml) at ambient temperature. The reaction mixture was stirred for 33 hours at ambient temperature. The precipitate was collected by filtration, and dried under reduced pressure to give 4-[4-[4-(4-chlorophenyl)-4-methoxypiperidin-1-yl]phenyl]piperazine trihydrochloride salt (1.52 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[Br-].[O:14]1CCO[CH:15]1[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>ClCCl.C([O-])([O-])=O.[K+].[K+]>[N:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[CH:19]/[CH:15]=[O:14])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2nccnc2c1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: O=C/C=C/c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A mixture of 6-quinoxalinecarboxaldehyde (0.62 g, 3.92 mmol, prepared as described in Photochem. Photobiol. 1991, 54, 7), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (2.50 g, 5.82 mmol), and TDA-1 (1.20 mL, 3.75 mmol) in dichloromethane (20 mL) and sat. aq. K2CO3 (20 mL) was heated to reflux for 4 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na2SO4), and concentrated. THF (10 mL) and 10% HCl (10 mL) were added and the mixture was stirred for 1 h at rt. The mixture was cooled to 0° C., the precipitated solids were removed by filtration, washed with water and dried in vacuo to give 0.47 g (65%) of the title compound as a tan solid. MS 185 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@@H:11]2[CH2:15][C@@H:14]([C:16](O)=[O:17])[C@H:13]([C:19]([N:21]3[CH2:24][C:23]([F:26])([F:25])[CH2:22]3)=[O:20])[CH2:12]2)(=[O:10])=[O:9])=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:53]2[N:54]=C[CH:56]=[CH:57][C:52]=2[N:51]=N1.F[P-](F)(F)(F)(F)F.C1C(N)(C#N)C1.Cl>C(#N)C>[C:53]([C:52]1([NH:51][C:16]([C@@H:14]2[CH2:15][C@@H:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[C:27]([F:29])([F:30])[F:28])(=[O:10])=[O:9])[CH2:12][C@H:13]2[C:19]([N:21]2[CH2:22][C:23]([F:25])([F:26])[CH2:24]2)=[O:20])=[O:17])[CH2:56][CH2:57]1)#[N:54]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@H]1C(=O)N1CC(F)(F)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a mixture of (1R,2R,4S)-4-(4-Bromo-2-trifluoromethyl-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (150 mg, 0.29 mmol), N,N-diisopropylethylamine (0.15 mL, 0.87 mmol), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (221 mg, 0.58 mmol) in acetonitrile was added 1-amino-cyclopropyl cyanic hydrochloride (41 mg, 0.34 mmol). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo and partitioned between ethyl acetate and an aqueous solution of sodium carbonate (5% w/w). The aqueous layer was extracted with ethyl acetate then the combined organic layers were washed with aqueous hydrochloric acid (1N) and brine then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of dichloromethane/methanol (98:2 v/v) as eluant to afford the title compound (144 mg, 85%) as a brown solid. MS (EI): 584.0 (M−H)−.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Cl[CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>>[CH2:22]([N:23]([CH2:26][CH3:27])[CH2:24][CH2:25][O:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21]
Reactant: O=C1c2ccccc2C(O)N1c1ccccc1
Reactant: CCN(CC)CCCl
Agent: [H-]
Agent: [Na+]
Product: CCN(CC)CCOC1c2ccccc2C(=O)N1c1ccccc1
Yield: 105.3 %

Procedure:
Following the procedure of Example 6 but starting with 3-hydroxy-2-phenyl-isoindolin-1-one (22.5 g.), sodium hydride (50% dispersion in mineral oil) (5.3 g.) and 1-chloro-2-diethylaminoethane (13.5 g.), 3-(2-diethylaminoethoxy)-2-phenyl-isoindolin-1-one (34 g.) is obtained in the form of an 85% pure oil. On treating this oil (28 g.) with fumaric acid (8.5 g.) in ethanol, 3-(2-diethylaminoethoxy)-2-phenyl-isoindolin-1-one hydrogen fumarate (27.6 g.), which melts at 146°-147° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18]Cl.CN(C)C=O>O>[Cl:16][CH2:17][CH2:18][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(CCCl)C1=O

Procedure:
A mixture of 1,664 g of 5,5-dimethyl-hydantoin (13.0 mols), 897 g of anhydrous potassium carbonate (6.5 mols), 5,148 g of 1,2-dichloroethane (52 mols) and 1,485 ml of dimethylformamide is reacted for 18 hours and 20 minutes at 90°C to 100°C internal temperature (external temperature 155°C), the water of reaction produced being removed continuously by azeotropic circulatory distillation. Water of reaction split off: 110 g (94.0% of theory). Thereafter, the reaction mixture, whilst still hot, is separated by filtration from the potassium chloride produced, the filtrate is concentrated on a rotary evaporator at 100°C in a water pump vacuum and the residue is dried to constant weight at 100°C and 10-1 mm Hg.
Reaction SMILES: [CH:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[C:41]([O:40][C:38]([N:37]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][N:11]2[CH:12]=[N:13][C:9]([C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)([OH:8])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:10]2)[CH2:16][CH2:17]1)[C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCBr)C(=O)OC(C)(C)C
Reactant: OC(c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Product: CC(C)(C)OC(=O)N(CCCCCCCCCN1CCC(Cn2cnc(C(O)(c3ccccc3)C3CCCCC3)n2)CC1)C(=O)OC(C)(C)C
Yield: 61 %

Procedure:
The title compound was prepared from cyclohexyl(phenyl)[1-(piperidin-4-ylmethyl)-1H-1,2,4-triazol-3-yl]methanol (Preparation 20, 300 mg, 0.846 mmol) and di-tert-butyl (9-bromononyl)imidodicarbonate (U.S. Pat. No. 4,167,167, 357 mg, 0.846 mmol) using the same method as described in preparation 5, to give a white foam, in 61% yield, 360 mg.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]>C(O)(=O)C.[Fe]>[F:1][C:2]1[C:7]([CH3:8])=[C:6]([NH2:9])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1ccc([N+](=O)[O-])c(C)c1F
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(N)c(C)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iron powder (14.25 g) was added portion wise to a solution of 2-fluoro-1-methoxy-3-methyl-4-nitro-benzene (10.5 g, 90% purity) in acetic acid (350 ml) at room temperature. The resulting brown suspension was stirred during 2 hours at room temperature. The reaction mixture was quenched with concentrated aq NaOH solution and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure to obtain 3-fluoro-4-methoxy-2-methyl-phenylamine as orange oil (8.50 g, 90% purity) which was used in Step 4 without any further purification. 1H NMR (CDCl3) δ ppm: 6.66 (1H, dd); 6.38 (1H, dd); 3.80 (3H, s); 3.34 (2H, br s); 2.08 (3H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1.C(N(CC)CC)C.CO>C(Cl)Cl.CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)c1cccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1cccnc1
Yield: 68.4 %

Procedure:
Preparation of example 22 from the title compound of Example 7 (hydrochloride) (21 mg, 0.076 mmol), nicotinic acid (7 mg, 0.076 mmol), triethylamine (0.014 mL, 0.10 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,′,N′-tetramethyluronium hexafluorophosphate (32 mg, 0.084 mmol) in CH2Cl2 (0.3 mL) and N,N-dimethylformamide (0.3 mL) was carried out analogously to Example 11. Silica gel chromatography (9:1 CH2Cl2:methanol), also in an analogous manner, afforded the title compound (20 mg, 0.052 mmol) as a yellow powder in 69% yield.