Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@H:11]([CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[I-:25].[Na+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@H:11]([CH2:13][I:25])[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@H](c3ccc(F)cc3)C2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Fc1ccc([C@H]2C[C@H](CI)CO2)cc1

Procedure:
A mixture of 9.2 g of trans-2-(4-fluorophenyl)-4-(tosyloxymethyl)tetrahydrofuran and 12.6 g of sodium iodide in 130 ml of acetone is heated under reflux for 6 hours. The solvent is then distilled off under reduced pressure, and the residue is extracted with ether. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off to give a quantitative yield of trans-2-(4-fluorophenyl)-4-(iodomethyl)tetrahydrofuran as colorless oil, nD27 1.5675.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13].O>C(O)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:13][CH3:12])[CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Solvent: O
Solvent: CCO
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 2,4-dibromo-1-nitro-benzene (2.0 g, 7.14 mmol) in ethanol (50 mL) was added a 40% aqueous solution of methylamine (50 mL). The reaction mixture was stirred at 80° C. in a closed vessel for 3 h, then cooled to 0° C. Water was added and the precipitate was filtered, washed with water, and dried in vacuo to give 1.26 g of (5-bromo-2-nitro-phenyl)-methyl-amine as an orange solid (76% yield): 1H NMR (CDCl3) δ 3.04 (s, 3H), 6.79 (dd, 1H), 7.03 (d, 1H), 8.05 (d, 1H), 8.0-8.1 (broad s, 1H); MS (m/z) 231, 233 [M+H+]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1>C(N)(C)C>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([NH:4][CH:3]([CH3:12])[CH3:2])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1F
Solvent: CC(C)N
Product: CC(C)Nc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]

Procedure:
44.0 g of 3-chloro-2-(4-fluoro-3-nitrophenyl)-5-trifluoromethylpyridine in 250 ml of isopropylamine were stirred at 23° C. for six hours. The reaction mixture was then concentrated. The residue was stirred with 100 ml of water, after which the residual solid portion was separated off, washed with water and dried in a vacuum drying oven. Yield: 48.2 g (98%) of colorless crystals; m.p.: 107-109° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=2[O:2]1.[H-].[Na+].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]I)[CH3:17]>CN(C)C=O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][CH:10]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[C:11](=[O:13])[CH3:12])[CH3:17]
Reactant: CCOC(CI)OCC
Reactant: CC(=O)Cc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CC(C(C)=O)c1ccc2c(c1)OCO2)OCC
Yield: 94.7 %

Procedure:
To 11.7 g of 3,4-methylenedioxyphenylacetone in 100 ml of dimethylformamide, 2.76 g of 60% oily sodium hydride was added under cooling with ice with stirring, and after stirring at the same temperature for 30 minutes, 20.9 g of iodoacetaldehyde diethyl acetal in 20 ml of dimethylformamide was added. The reaction solution was stirred at room temperature for 2 hours and partitioned between water and ethyl ether. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=15/1→10/1] to give 18.3 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:32][N:31]=[N:30][N:24]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 72 h
Yield: 57.9 %

Procedure:
To a solution of ethyl 5-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]pyrazole-3-carboxylate (730 mg) in dimethylformamide (10 ml) were added sodium azide (1.3 g) and ammonium chloride (1.07 g) and the mixture was stirred at 110°-115° C. for 72 hours. Insoluble materials were filtered off, and the filtrate was concentrated to dryness. To the residue were added 0.5 N-hydrochloric acid (40 ml) and ether (100 ml) for partitioning, and the organic layer was washed with water, dried, and concentrated to dryness. The residue was purified by column chromatography on silica gel to give the desired product as a colorless powder (470 mg, 58%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][CH2:38][CH2:39][C:40]([NH:42][NH2:43])=O>CC1C=CC(C)=CC=1>[CH3:36][O:37][CH2:38][CH2:39][C:40]1[N:26]2[C:21]3[CH:20]=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)=[N:28][C:22]=3[O:23][CH2:24][C:25]2=[N:43][N:42]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: COCCC(=O)NN
Solvent: Cc1ccc(C)cc1
Product: COCCc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Temperature: 150 °C
Yield: 29.1 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (100 mg, 0.205 mmol) and 3-methoxypropanehydrazide (48 mg, 0.410 mmol) in p-xylene (2 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in cyclohexane) to give the title compound (33 mg, 30%). LCMS (Method D): RT=1.414 min, M+1=554. 1H NMR (500 MHz, CDCl3) δ 8.16 (1H, s), 7.27-7.36 (7H, m), 7.23-7.18 (2H, m), 5.60 (2H, s), 3.99 (2H, t), 3.43 (3H, s), 3.38 (2H, t), 2.57-2.40 (4H, m), 2.12-2.01 (1H, m), 1.87-1.77 (1H, m), 1.49-1.27 (9H, bs).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:26]4[C:25](=[O:27])[N:24]([CH:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:23][C:22]([CH3:35])([CH3:34])[O:21][C:20]=4[N:19]=[C:18]([N:36]4[CH2:42][CH:41]5[O:43][CH:38]([CH2:39][CH2:40]5)[CH2:37]4)[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH2:51])=[N:47]1.CN(C=O)C>C1COCC1>[CH3:35][C:22]1([CH3:34])[O:21][C:20]2[N:19]=[C:18]([N:36]3[CH2:37][CH:38]4[O:43][CH:41]([CH2:40][CH2:39]4)[CH2:42]3)[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:51][C:48]4[CH:49]=[CH:50][N:46]([CH3:45])[N:47]=4)=[O:7])=[CH:15][CH:14]=3)[C:26]=2[C:25](=[O:27])[N:24]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1
Reactant: CC1(C)CN(C2CCOCC2)C(=O)c2c(nc(N3CC4CCC(C3)O4)nc2-c2ccc(NC(=O)Oc3ccccc3)cc2)O1
Reactant: Cn1ccc(N)n1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)Nc2ccc(-c3nc(N4CC5CCC(C4)O5)nc4c3C(=O)N(C3CCOCC3)CC(C)(C)O4)cc2)n1
Temperature: 100 °C

Procedure:
50 mg (83.4 μmol) of {4-[8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-6-(tetrahydropyran-4-yl)-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]phenyl}carbamic acid phenyl ester are placed in a microwave reactor and 25 mg (26 μmol) of 1-methyl-1H-pyrazol-3-ylamine are added. 1 ml of DMF and 2 ml of THF are added. The reactor is heated in a Biotage microwave machine for 30 minutes at 100° C. 100 mg (100 μmol) of 1-methyl-1H-pyrazol-3-ylamine are added and the mixture is heated for 2 hours at 110° C. The solvents are evaporated off. The residue is chromatographed on silica gel, eluting with an MeOH/DCM mixture from (0/100 v/v) up to (5/95 v/v) to give a solid, which is then washed with water and dried. 23 mg of 1-{4-[8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-6-(tetrahydropyran-4-yl)-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]phenyl}-3-(1-methyl-1H-pyrazol-3-yl)urea are recovered.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.[Br:22][C:23]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:24]=1[CH2:25]Br>>[Br:22][C:23]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:24]=1[CH2:25][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: Clc1cc(Cl)c(Br)c(CBr)c1
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1cc(Cl)cc(Cl)c1Br
Yield: 55 %

Procedure:
Compound 38.2 was prepared as described for example 6.2, by reacting compound 1.1 with 2-bromo-3,5-dichlorobenzyl bromide. 4-[3-(2-Bromo-3,5-dichlorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained in a yield of 55%. 1H NMR: 8.35, d, 1H, 8.25, s, 1H, 8.1, d, 1H, 7.7, s, 1H, 7.65, s, 1H; 4.65, s, 2H, 1.45, s, 6H.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH3:21])[C:10](=[O:22])[CH2:9]1)=O)(C)(C)C.[ClH:23].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:23].[CH3:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:22]
Reactant: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c(C)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCNCC2=O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-oxopiperazine-1-carboxylic acid tert-butyl ester (5 g), 1-bromo-2,4-dimethylbenzene (3.4 mL), potassium carbonate (10.6 g) and copper (I) iodide (952 mg) were added toluene (25 mL) and N,N′-dimethylethylenediamine (1.1 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give 4-(2,4-dimethylphenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester. The obtained 4-(2,4-dimethylphenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester was dissolved in chloroform (10 mL), 4N hydrogen chloride/ethyl acetate (10 mL) was added, and the mixture was stirred at room temperature for 3 hr. The precipitate was collected by filtration to give 1-(2,4-dimethylphenyl)piperazin-2-one hydrochloride (3 g).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8](=O)[NH:7][N:6]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(CC3CC3)n[nH]c(=O)c2c1
Product: COc1ccc2c(CC3CC3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-cyclopropylmethyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])C(O)=O.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)cc(Cl)c1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])cc(Cl)c1OC

Procedure:
from 2-chloro-N-(3-methoxyphenyl)-4-pyrimidineamine (0.50 g, 2.13 mmol) [see Example 92] and 3-chloro-4,5-dimethoxyaniline (0.40 g, 2.13 mmol) to give the title compound (0.55 g) as a white soid m.p. 204-205°. δH (d6DMSO) 11.19 (1H, br s),10.85 (1H, brs), 8.00 (1H, d, J 7.1 Hz), 7.23 (4H, m), 7.12 (1H, d, J 4.4 Hz), 6.75 (1H, m), 6.59 (1H, d, J 7.1 Hz), 3.74 (3H, s), 3.69 (3H, s) and 3.65 (3H, s). MS m/z 387 (M+H)+. The aniline starting material was prepared in a similar manner to the analogous aniline of Example 113, from 1-chloro-2,3-dimethoxy-5-nitrobenzene (1.08 g, 5.82 mmol), to give the desired product (0.85 g) as a white solid m.p. 66-68°. MS m/z 188 (M+H)+. The 1-chloro-2,3-dimethoxy-5-nitrobenzene was prepared by heating a solution of 3-chloro-4,5-dimethoxybenzoic acid (3.50 g, 16.2 mmol) in glacial acetic acid (15 ml) and 70% nitric acid (15 ml) at 600 for 1 h. The reaction was poured onto ice-water and the white precipitate which formed was filtered off, washed with water and dried in vacuo and washed thoroughly with hexane. The hexane washings were evaporated and the residue subjected to column chromatography [silica 20% ethyl acetate-hexane] to give the desired product (1.03 g) as a white solid m.p. 104-105°. MS m/z 217 (M+H)+. The acid used as starting material was prepared according to the method of Y. Ohtani et al. Acta. Chem. Scand., Ser B. B36, 613 (1982).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])/[C:5](/[C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:8]=1)[C:17](=[O:18])[CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1)[CH3:2]
Reactant: CCOC(=O)/C(=C\c1cccc(C(F)(F)F)c1)C(=O)C1CCC(c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc(C(F)(F)F)c1)C(=O)C1CCC(c2ccccc2)CC1
Reaction time: 2 h
Yield: 69.5 %

Procedure:
A mixture of (Z)-2-(4-phenylcyclohexanecarbonyl)-3-(3-trifluoromethylphenyl)-acrylic acid ethyl ester (10) (12.3 g, 28.6 mmol) and 10% Pd on carbon (2.5 g, 20% by weight) in denatured ethanol (250 mL) was stirred under a hydrogen atmosphere for 2 hr. The solids were removed by filtration through celite and washed with ethanol. The filtrate was evaporated under vacuum to yield a clear oil. The residue was purified by column chromatography on silica gel (gradient: 0 to 10% tert-butyl methyl ether in cyclohexane) to afford 8.6 g (70%) of 3-oxo-3-(4-phenylcyclohexyl)-2-(3-trifluoromethylbenzyl)-propionic acid ethyl ester (22). 1H NMR (400 MHz, 192227). LCMS (method A), Rt=4.76 min, (M+H)+=433.2 (94%); Rt=5.22 min, (M+H)+=262.9 (6.5%).
Reaction SMILES: P(Cl)(Cl)(Cl)=[O:2].[CH3:6][N:7]1[C:12]2[C:13]([CH3:16])=[CH:14][NH:15][C:11]=2[C:10](=[O:17])[N:9]([CH3:18])[C:8]1=[O:19]>CN(C)C=O>[CH3:6][N:7]1[C:12]2[C:13]([CH:16]=[O:2])=[CH:14][NH:15][C:11]=2[C:10](=[O:17])[N:9]([CH3:18])[C:8]1=[O:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Solvent: CN(C)C=O
Product: Cn1c(=O)c2[nH]cc(C=O)c2n(C)c1=O
Reaction time: 2 h
Yield: 43.2 %

Procedure:
At a temperature of 5-10° C., phosphorous oxychloride (1.84 ml, 20.087 mmol) was mixed with N,N-dimethylformamide (2 mL). Then a solution of Intermediate 1 (600 mg, 3.348 mmol) in N,N-dimethylformamide (3 mL) was added while stirring. The reaction mixture was held for 2 h at 95° C., cooled and poured onto ice (10 g). The precipitate formed was filtered off and recrystallised from water to give 300 mg of the product as an off-white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.25 (s, 3H), 3.75 (s, 3H), 8.06 (s, 1H), 9.79 (s, 1H), 13.15 (br s, 1H); APCI-MS (m/z) 208.20 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[CH2:19][C:20](OCC)=[O:21]>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([OH:21])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(-c3ccccc3Cl)cc2O)c1
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-(2-chlorophenyl)-3-oxopropanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C15H9ClN4O 297; Found, 297.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:31])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:12]=3)[O:8][C:7](=[O:29])[C:6]=2[CH:30]=1.[CH3:32][NH2:33].C(OCC)C>O1CCCC1>[Cl:1][C:2]1[CH:30]=[C:6]([C:7]([NH:33][CH3:32])=[O:29])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:12]=2)=[O:8])=[C:4]([CH3:31])[CH:3]=1
Reactant: CN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(OCC(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21.8 %

Procedure:
To a suspension of the 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (i.e. precipitate product of Step E) (3.53 g, 7.5 mmol) in tetrahydrofuran (15 mL), methylamine (2.0 M solution in THF, 11 mL, 22 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 45 minutes. Thin layer chromatography then showed the reaction to be complete. Ethyl ether (100 mL) was added, and the reaction mixture was stirred for 2 hours while a precipitate formed. The precipitate was collected by filtration and then recrystallized from acetonitrile to yield a white solid (0.82 g). A second crop of white solid (0.35 g) precipitated from the acetonitrile mother liquor and was collected by filtration. The initial ether/tetrahydrofuran mother liquor was concentrated to dryness, and the residual solid was recrystallized from acetonitrile to yield a third crop of white solid (0.95 g). The three crops were combined, totaling 2.12 g (after drying) of the title compound, isolated as a white solid, melting at 207-208° C.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:10][CH2:9]2)C=CC=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:20][O:19][CH2:18][CH2:17][O:16][C:15](=[O:21])[NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COCCOC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COCCOC(=O)NC1CCNCC1
Reaction time: 6 h
Yield: 97.9 %

Procedure:
2-Methoxyethyl (1-phenylmethyl-4-piperidyl)carbamate (9.6 g), prepared according to Preparation 3, was dissolved in ethyl acetate (100 mL). Palladium hydroxide (10% on carbon, 1 g) was added, and the mixture was stirred under hydrogen (1 bar) for 6 hours. The catalyst was removed by filtration, and the solvent evaporated to give 6.5 g of 2-methoxyethyl-4-piperidylcarbamate as an oil, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:17]=O)[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH:25]1[CH2:28][CH:27]([N:29]2[CH2:34][CH2:33][NH:32][C:31](=[O:35])[CH2:30]2)[CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:17][N:25]3[CH2:26][CH:27]([N:29]4[CH2:34][CH2:33][NH:32][C:31](=[O:35])[CH2:30]4)[CH2:28]3)[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: O=C1CN(C2CNC2)CCN1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C1CN(C2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4n3C3CCCCO3)C2)CCN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
A mixture of 2-chloro-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purine-8-carbaldehyde (1.06 g, 3.01 mmol) and 4-azetidin-3-ylpiperazin-2-one (560 mg, 3.61 mmol) in DCE (60 mL) and DMF (20 mL) was allowed to stir at r.t. for 10 min before the addition of 4 Å powdered molecular sieves (3.0 g) followed by sodium triacetoxyborohydride (1.28 g, 6.04 mmol). The resulting mixture was allowed to stir for 64 h then filtered through Celite® which was washed with DCM. The filtrate was concentrated in vacuo and the resulting residue dissolved in EtOAc and washed with NaHCO3, H2O and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo affording the title compound as a yellow gum (997 mg, 67%). LCMS (method A): RT 2.19 and 2.11 min [M−C5H9O+H]+407.3
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=[O:35])=[O:29])[CH2:24][CH:23]1[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:47].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:47].[F:46][C:42]1[CH:41]=[C:40]([CH:23]2[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]3[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=3)[C:34]([OH:36])=[O:35])=[O:29])[CH2:24]2)[CH:45]=[CH:44][CH:43]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)Oc2cccc(C(=O)O)c2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](NCC1CCN(C(=O)Oc2cccc(C(=O)O)c2)CC1c1cccc(F)c1)c1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a solution of 88 mg of 3-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid in 2.0 mL of ethyl acetate was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 2 hours. The resulting precipitate was collected by filtration, and dried under reduced pressure to obtain 22 mg of 3-({[3-(3-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]carbonyl}oxy)benzoic acid hydrochloride as a white solid.
Reaction SMILES: [I-:1].[Na+].I.Cl[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1>CC(C)=O>[I:1][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: [I-]
Agent: I
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(I)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 27.97 g (186.6 mmol) of sodium iodide cooled to -78° C. was added 121.77 g (71.6 ml, 952.0 mmol) of hydriodic acid (in 57 wt % aqueous solution). The reaction mixture was allowed to warm slightly with stirring for 5 minutes and then 30.00 g (190.4 mmol) of 6-chloronicotinic acid was added. The resulting mixture was allowed to warm to room temperature with stirring and then heated at 120°-125° C. in an oil bath for 42 hours. A dark brown layer formed above the yellow solid material. The reaction mixture was allowed to cool to room temperature and then poured into acetone (chilled to 0° C.). The resultant yellow solid was collected by filtration, washed with 200 ml of 1N aqueous NaHSO3 solution, and dried in vacuum (3 mm Hg) to give the title compound as a pale yellow solid. PMR (DMSO-d6): d 7.90 (1H, dd, J=8.1, 2 Hz), 7.99 (1H, d, J=8.1 Hz), 8.80 (1H, d, J=2 Hz).