Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH:3]=O.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:3])[CH2:5][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)C=O)s1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CN2CCOCC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (41 mg), morpholine (25 mg), acetic acid (0.02 ml) in methylene chloride (1 ml) was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (42 mg) was added. The mixture was stirred at room temperature for at least two days. The mixture was quenched with diluted NaOH and extracted with methylene chloride. The organic layer was separated, concentrated to dryness and the residue was purified by silica gel column chromatography using 35% to 65% ethyl acetate in hexane as eluent to give the title compound. The title compound was prepared as the corresponding HCl salt by adding HCl/doxane, followed by concentration to give a solid. LC_MS retention time 1.7 min M+1=497.0, M−1=495.0.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)[C:4]([NH:6][CH3:7])=[O:5]>CO.[Pd]>[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=1)[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CC#CCOc1ccc(C[C@H](N)C(=O)NC)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCOc1ccc(C[C@H](N)C(=O)NC)cc1
Reaction time: 17 h
Yield: 100 %

Procedure:
(S)-2-Amino-3-(4-but-2-ynyloxy-phenyl)-N-methyl-propionamide hydrochloride (2.00 g, 7.07 mmol) was dissolved in methanol (100 mL), and Pd/C (230 mg) was then added at room temperature. After stirring for 17 hours under a hydrogen atmosphere, insoluble material was filtered off, and washed with methanol (3.0 mL). The filtrate was concentrated under reduced pressure, and then dissolved in ethyl acetate (150 mL). The solution was washed with sodium bicarbonate (100 mL) and a saturated aqueous solution (50 mL) of sodium chloride in this order, then dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain 1.77 g of the title compound (7.07 mmol, quant.).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:21]3[N:22]([CH:25]([C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[CH3:26])[CH:23]=[N:24][C:20]=3[CH:19]=[C:18]([C:34]#[N:35])[N:17]=2)[CH:13]=[N:14][CH:15]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:23]1[N:22]([CH:25]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH3:26])[C:21]2[C:16]([C:12]3[CH:13]=[N:14][CH:15]=[C:10]([Cl:9])[CH:11]=3)=[N:17][C:18]([C:34]#[N:35])=[CH:19][C:20]=2[N:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC([C@H]1CC[C@H](C)CC1)n1cnc2cc(C#N)nc(-c3cncc(Cl)c3)c21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC([C@H]1CC[C@H](C)CC1)n1c(Br)nc2cc(C#N)nc(-c3cncc(Cl)c3)c21
Temperature: 25 °C

Procedure:
N-bromosuccinimide (4.07 g, 22.9 mmol) was added to a room temperature solution of racemic 4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (4.14 g, 7.63 mmol) stirring in degassed chloroform (38 mL). The reaction was heated to reflux for 1.5 hours. The mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated aqueous sodium thiosulfate (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-80% ethyl acetate/hexanes, linear gradient) to afford racemic 2-bromo-4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. The racemic material was then purified by chiral supercritical fluid chromatography (Chiralpak IB, 21×250 mm, 25% methanol in CO2) to afford 2-bromo-4-(5-chloropyridin-3-yl)-3-[(1S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile and 2-bromo-4-(5-chloropyridin-3-yl)-3-[(1R)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. Faster eluting enantiomer 1: MS ESI calc'd. for C21H21BrClN5 [M+H]+ 458. found 458. Slower eluting enantiomer 2: MS ESI calc'd. for C21H21BrClN5 [M+H]+ 458. found 458.
Reaction SMILES: [CH3:1][C:2]1([C:5]2[O:9][N:8]=[C:7]([NH2:10])[CH:6]=2)[CH2:4][CH2:3]1.C(C1C=C(N[C:20](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)ON=1)(C)C>>[CH3:1][C:2]1([C:5]2[O:9][N:8]=[C:7]([NH:10][C:20](=[O:28])[O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:6]=2)[CH2:4][CH2:3]1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: CC1(c2cc(N)no2)CC1
Product: CC1(c2cc(NC(=O)Oc3ccccc3)no2)CC1
Yield: 70 %

Procedure:
Prepared from 5-(1-methylcyclopropyl)isoxazol-3-amine (80 mg, 0.58 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 5-(1-methylcyclopropyl)isoxazol-3-ylcarbamate as a colorless solid (105 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 7.87 (brs, 1H), 7.39-7.44 (m, 2H), 7.18-7.29 (m, 3H), 6.52 (s, 1H), 1.58 (s, 3H), 1.20-1.24 (m, 2H), 0.84-0.87 (m, 2H); LC-MS (ESI) m/z 259 (M+H)+.
Reaction SMILES: [Mg].[CH3:2][O:3][CH:4]([O:12][CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1.[CH3:14][C:15]([CH3:19])=[CH:16][CH2:17]Br.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH3:2][O:3][CH:4]([O:12][CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:17][CH:16]=[C:15]([CH3:19])[CH3:14])[CH:6]=1
Reactant: COC(OC)c1cccc(Br)c1
Reactant: CC(C)=CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(OC)c1cccc(CC=C(C)C)c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
Magnesium metal (1.2 g) was added to 2 ml of tetrahydrofuran. With stirring at room temperature, 20 ml of a solution of 2.0 g of 3-bromobenzaldehyde dimethyl acetal in a 1:1 mixture of tetrahydrofuran and ethyl ether was added dropwise over the course of 1 hour. With stirring under ice cooling, 15 ml of a tetrahydrofuran solution of 2.25 g of 3-methyl-2-butenyl bromide was added to the resulting solution. The temperature of the mixture was returned to room temperature, and then it was stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to terminate the reaction. Ethyl ether was added, and the reaction mixture was treated in a customary manner to give 1.71 g (yield 90%) of 3-(3-methyl-2-butenyl)benzaldehyde dimethyl acetal as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8]C.N.OO.[CH3:14][C:15]1[C:20]([CH3:21])=[C:19]([NH2:22])[CH:18]=[CH:17][C:16]=1[OH:23]>O.CC(C)=O>[NH2:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([OH:23])=[C:15]([CH3:14])[C:20]=2[CH3:21])[C:4](=[O:10])[CH:3]=1
Reactant: COc1ccc(O)cc1N
Reactant: Cc1c(N)ccc(O)c1C
Agent: N
Agent: OO
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(O)ccc(NC2=CC(=O)C(N)=CC2=O)c1C
Reaction time: 3 h

Procedure:
0.01 mole (1.39 g) of 3-amino-4-methoxy phenol is dissolved in 100 cc of water to which have been added 50 cc of acetone and 10 cc of ammonia (22° Be'). To this solution there are added 100 cc of H2O2 (20 volumes) and immediately thereafter, with good agitation, 0.01 mole (1.37 g) of 2,3-dimethyl-4-amino phenol in suspension in 100 cc of water. The resulting reaction mixture is agitated for three hours at which time it is filtered to recover the 2-amino-5-(4'-hydroxy-2',3'-dimethyl anilino)-1,4-benzoquinone which is first washed with water and then with acetone. It is dried for 8 hours under a vacuum with a boiling water bath and is chromatographically pure, melting at 320° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[Cl-].[CH3:37][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:37])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To a suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (200 mg, 0.371 mmol) and tetrakis(triphenylphosphine)palladium (8.6 mg, 7.4 μmol) in THF (5 mL) was added a 2 M solution of methylzinc chloride in THF (0.371 mL, 0.742 mmol). The suspension was stirred for 16 h at 60° C. The reaction mixture was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified via column chromatography, eluting with 0-100% EtOAc/DCM. The desired fractions were combined and concentrated to generate 90 mg (0.174 mmol, 46.8% yield) of the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.47 (d, J=5.3 Hz, 1H), 7.52-7.58 (m, 1H), 7.40-7.50 (m, 4H), 7.29 (t, J=7.8 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 2.58 (s, 3H), 1.42 (s, 9H). MS (ESI): 520.0 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:37]N1C(=O)CCC1=O.ClCCCl>C(Cl)Cl>[Br:37][CH:2]([Cl:1])[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CCl)c3c2)c1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Cl)Br)c3c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A mixture of 3-[3-(chloromethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.00 g, 0.00266 mol), azo-bis-isobutyronitrile (0.100 g), N-bromosuccinimide (0.712 g, 0.00400 mol) and 1,2-dichloroethane is stirred one hour at reflux. Additional azo-bis-isobutyronitrile (0.0500 g) and N-bromosuccinimide (0.100 g) are added and the mixture is stirred two hours at reflux, cooled to room temperature, diluted with methylene chloride, washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to an orange gum. Chromatography of the gum on silica gel with methylene chloride:ether gives the title compound as a white foam (0.950 g, 80.2%, mp 93-96° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C:36]1([O:39]C(=O)C)[CH2:38][CH2:37]1)=[O:35]>>[OH:39][C:36]1([C:34]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=5[O:28][CH2:29][CH:30]5[CH2:31][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:35])[CH2:38][CH2:37]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5(O)CC5)CC4)c[nH]c23)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A153) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[N:3]=1.[Cl:23][CH2:24][CH2:25][N:26]=[C:27]=[O:28].C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:27](=[O:28])[NH:26][CH2:25][CH2:24][Cl:23])=[CH:18][CH:17]=2)[N:3]=1
Reactant: O=C=NCCCl
Reactant: CSc1c(Cl)nc(-c2ccc(O)cc2)nc1N1CCOCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CSc1c(Cl)nc(-c2ccc(OC(=O)NCCCl)cc2)nc1N1CCOCC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenol (80.0 mg, 0.236 mmol), 1-chloro-2-isocyanato-ethane (43.1 mg, 0.354 mmol, eq=1.5), toluene and CH2Cl2 was added to the reaction vessel and flushed with argon. The reaction mixture was stirred at 80° C. for 16 hrs and then dried, and the solvent was evaporated. The reaction mixture was partitioned between EA and water, the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Hexane/EtOAc 2:1) to give a gray solid of 58.9 mg (58.1%)
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][C:6]1([CH3:20])[C:10]([CH3:12])([CH3:11])[O:9][B:8]([C:13]2[CH:14]=[C:15]([CH:18]=O)[S:16][CH:17]=2)[O:7]1.C([BH3-])#N.[Na+].[N-]=C=O>C1COCC1>[CH3:5][C:6]1([CH3:20])[C:10]([CH3:11])([CH3:12])[O:9][B:8]([C:13]2[CH:14]=[C:15]([CH2:18][N:1]3[CH2:4][CH2:3][CH2:2]3)[S:16][CH:17]=2)[O:7]1
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Reactant: C1CNC1
Agent: [BH3-]C#N
Agent: [N-]=C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2csc(CN3CCC3)c2)OC1(C)C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
A solution of azetidine (0.014 g, 0.252 mmol) in THF (1 mL) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (0.05 g, 0.210 mmol) in THF (1 mL) in 1-Dram vial and let stir for 30 minutes. Sodium Cyanoborohydride Resin (0.128 g, 0.583 mol, 2.33 mmol/g)) was then added to the mixture and let stir 3 days. The mixture was then agitated for 3 hrs with MP-Isocyanate Resin (0.135 g, 0.230 mmol, 1.7 mmol/g) and THF (2 mL). The reaction was resubjected to the same amounts of Sodium Cyanoborohydride Resin and amine as above and stirred for 2 days. The resins were then filtered and solvent concentrated to give 0.035 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17])[CH2:3][C:4]([OH:6])=O.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>C(Cl)Cl>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][NH:19][C:4](=[O:6])[CH2:3][C:2]([CH3:1])([CH3:18])[N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17]
Reactant: CC(C)(CC(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: NCc1ccccn1
Solvent: ClCCl
Product: CC(C)(CC(=O)NCc1ccccn1)N1C(=O)c2ccccc2C1=O
Reaction time: 24 h
Yield: 58.3 %

Procedure:
To a solution of β,β-dimethyl-1,3-dioxo-2-isoindolinepropionic acid (5 g, 20.2 mmol) and N,N-dicyclohexylcarbodiimide (4.6 g, 22.24 mmol) in 50 ml of dry methylene chloride is added 2-(aminomethyl)pyridine (2.41 g, 2.3 ml, 22.24 mmol) at ambient temperature. The mixture is stirred for 24 hours. The precipitate of dicyclohexyl urea is filtered off and discarded. The filtrate is evaporated and the residue is purified via flash chromatography on silica gel using a methylene chloride/methylene chloride-ethanolic ammonia gradient (100 to 96:4) to give 3.97 g of N-[(2-pyridinyl)methyl]-1,3-dihydro-β,β-dimethyl-1,3-dioxo-2H-isoindole-2-propanamide (58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]=[CH:7][C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].C(=O)([O-])[O-].[K+].[K+].[N+:29](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([NH2:29])[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: CCOC(=O)c1cnc2cc(-n3cccc3)c(F)cc2c1O
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 24 h
Yield: 23.8 %

Procedure:
A mixture of 6 g (0.02 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-4-hydroxyquinoline-3-carboxylate and 5.6 g (0.04 mol) of potassium carbonate in 80 ml of dimethylformamide is heated for 30 minutes at 60° C. and left to cool, 8.5 g (0.042 mol) of 2,4-dinitrophenylhydroxylamine are added, the mixture is kept for 24 hours at room temperature and poured into 200 ml of a water/ice mixture, and the precipitate formed is filtered off, washed with water, dried in a desiccator and recrystallized from dimethylformamide to give 1.5 g of a solid melting at 276°-279° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:10]([C:11]([CH3:13])=[CH2:12])[CH2:9][CH2:8][C:7]=1[CH3:14])[CH2:3][OH:4]>[Ni].CO>[CH3:1][CH:2]([CH2:5][C:6]1[CH:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][C:7]=1[CH3:14])[CH2:3][OH:4]
Reactant: C=C(C)C1CCC(C)=C1CC(C)CO
Agent: [Ni]
Solvent: CO
Product: CC1=C(CC(C)CO)C(C(C)C)CC1
Yield: 93.9 %

Procedure:
9.7 g of 2-methyl-3-(2-methyl-5-isopropenyl-cyclopent-1-en-1-yl)-propanol were catalytically hydrogenated in the presence of traces of Raney nickel in methanol. 1130 ml of hydrogen were absorbed and the reaction mixture was filtered, whereupon the clear filtrate was evaporated to give 9.2 g of 2-methyl-3-(2-methyl-5-isopropyl-cyclopent-1-en-1-yl)-propanol; nD = 1.4789; d20 = 0.9084;
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1.[OH-:26].[K+]>O>[OH:26][CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1
Reactant: [OH-]
Reactant: COc1ccc(-c2nc(SCCBr)sc2-c2ccc(OC)cc2)cc1
Agent: [K+]
Solvent: O
Product: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of 2-(2-bromoethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole are dissolved in 10 ml of polyethylene glycol, 0.5 ml of water and 0.5 g of potassium hydroxide are added, the mixture is heated at 120° for 30 minutes, cooled to room temperature, diluted with 50 ml of water and left to stand at +5° for 2 hours. The precipitated crystals are filtered off and recrystallised from diethyl ether/hexane. 2-(2-Hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 82°-83° is obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:22]N1C(=O)CCC1=O.CCOC(C)=O>CN(C=O)C>[Cl:22][C:5]1[C:6]([C:18]([F:20])([F:21])[F:19])=[N:7][N:8]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[C:4]=1[CH:1]1[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2C2CC2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Intermediate 13 (1 g, 3.36 mmol) was dissolved in DMF and to this N-Chlorosuccinimide (0.54 g, 4.0 mmol) was added at 0° C. Then reaction was allowed to stir at rt for 2 h. After completion of the reaction, work up (EtOAc) afforded the title compound (0.802 mg). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.39 (d, J 9, 2H), 7.82 (d, J 9, 2H), 1.91-1.80 (m, 1H), 1.10-1.00 (m, 2H), 0.80-0.72 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[CH2:1]([N:8]1[C:12]([NH:13][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cc(N)n(Cc2ccccc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(Cc2ccccc2)n1
Yield: 61.4 %

Procedure:
Following the procedure in Example 118A, 1-benzyl-3-tert-butyl-1H-pyrazol-5-amine (666 mg, 2.64 mmol) and phenyl chloroformate (1.0 mL, 8.0 mmol) to give phenyl 1-benzyl-3-tert-butyl-1H-pyrazol-5-ylcarbamate (565 mg, 1.62 mmol, 61%). 1H NMR (300 MHz, DMSO-d6) δ 10.20 (br s, 1H), 7.43-7.10 (m, 10H), 6.14 (s, 1H), 5.29 (s, 1H), 1.22 (s, 9H); LC-MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])C>C(O)=O>[CH:16]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: O=CO
Product: O=CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold and vigorously stirred solution of dibenzylamine (918 g.) in 98% formic acid (105 ml.) is added dropwise, over 45 minutes, acetic anhydride (35 ml.). The resulting mixture is stirred for one hour at room temperature, then diluted with ice water (40 ml.) and kept overnight at 15° C. The solution is evaporated in vacuo to dryness and the residue extracted with ether. The ethereal solution is washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo to yield N-formyl-dibenzylamine (9.9 g.) as a white solid, m.p. 53°-54.5° C.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:26]=[N:27][C:28]6[C:33]([CH:34]=5)=[CH:32][CH:31]=[CH:30][CH:29]=6)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Brc1cnc2ccccc2c1
Product: OC1(c2cnc3ccccc3c2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 44 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromoquinoline, the title compound was formed in 44% yield as a white solid, mp 205°-207° C. free base: 1H NMR (CDCl3, 300 MHz) 9.06 (d, J=3.6 Hz, 1H), 8.20 (d, J=3.0 Hz, 1H), 8.08 (d, J=8.1Hz, 1H), 7.80 (d, J=8.1Hz, 1H), 7.68 (dd, J=6.0, 5.9 Hz, 1H), 7.54 (dd, J=8.5, 9.0 Hz, 1H), 7.23 (m, 4H), 6.94 (m, 4H), 4.30 (s, 1H), 3.52 (s, 2H), 2.98 (m, 2H), 2.78 (m, 2H), 2.64 (d, J=1.4 Hz, 2H), 2.24 (dt, J=3.9, 11.6 Hz, 2H), 1.99 (s, 1H), 1.83 (m, 2H) MS (CI, CH4) m/z 433 (M+1.17), 415 (4), 211 (12), 89 (100), 79 (45), 73 (13) hydrochloride salt: