Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[NH:25][N:24]=[N:23]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26](=[O:27])[N:25]([C@H:12]([CH3:13])[C@:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[O:10][CH2:11]3)[N:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]nnn1-c1ccc(Cl)cc1
Product: C[C@@H](n1nnn(-c2ccc(Cl)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 60.5 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.38 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.09 g of 1-(4-chlorophenyl)-5(1H,4H)-tetrazolone, 1.27 g of 1-(4-chlorophenyl)-4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-5(1H,4H)-tetrazolone was obtained as a cololess oil.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C:18]([C:20]3[CH:42]=[CH:41][C:23]([C:24]([N:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[N:38]=4)[CH3:27])=[O:25])=[CH:22][C:21]=3[O:43][CH3:44])=[O:19])[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C:18]([C:20]3[CH:42]=[CH:41][C:23]([C:24]([N:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[N:38]=4)[CH3:27])=[O:25])=[CH:22][C:21]=3[O:43][CH3:44])=[O:19])[C:11]=2[N:10]=[CH:9]1
Reactant: COc1cc(C(=O)N(C)c2ccccc2C2=NC(C)(C)CO2)ccc1C(=O)Nc1cccc2c1ncn2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccccc2C2=NC(C)(C)CO2)ccc1C(=O)Nc1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 4-[N-[1-[(tert-butyl)oxycarbonyl]benzimidazol-4-yl]carbamoyl]-N-[2-[4,4-dimethyl(2,5-oxazolinyl)]phenyl]-3-methoxy-N-methylbenzamide (400 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (4 ml). The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with a mixture of chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography (chloroform:methanol=100:3) to give 4-[N-(1H-benzimidazol-4-yl)carbamoyl]-N-[2-[4,4-dimethyl(2,5-oxazolinyl)]phenyl]-3-methoxy-N-methylbenzamide (290 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[C:29]([Cl:31])[CH:30]=1>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:35]2[CH2:34][CH2:33][N:32]([C:27]3[CH:26]=[C:25]([Cl:24])[CH:30]=[C:29]([Cl:31])[CH:28]=3)[CH2:37][CH2:36]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 81.3 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1.[NH:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:34][CH2:35]2)=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1nccc2c(-c3cc(C=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nccc2c(-c3cc(CN4CCC(NC(=O)OC(C)(C)C)CC4)ccc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 426.9 %

Procedure:
A solution of Example 105B (125 mg, 0.317 mmol), tert-butyl piperidin-4-ylcarbamate (190 mg, 0.951 mmol) and acetic acid (0.181 mL, 3.17 mmol) in dichloromethane (3 mL) was heated at 50° C. for 1 hour. The reaction mixture was cooled in an ice bath and the sodium triacetoxyborohydride (134 mg, 0.634 mmol) was added portionwise over a few minutes. The reaction mixture was stirred 2 hours while warming to ambient temperature. The reaction mixture was quenched with 1 M sodium hydroxide (2 mL) and partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (783 mg, 100% yield).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:14])[C:5]2[CH:10]=[CH:9][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:6]=2[N:7]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(Cl)Cl.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>[CH:11]1([N:8]2[C:6]3[N:7]=[C:2]([C:20]4[CH:21]=[CH:22][C:17]([C:16]([F:27])([F:26])[F:15])=[CH:18][CH:19]=4)[NH:3][C:4](=[O:14])[C:5]=3[CH:10]=[CH:9]2)[CH2:13][CH2:12]1
Reactant: O=c1[nH]c(Cl)nc2c1ccn2C1CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)nc2c1ccn2C1CC1
Temperature: 150 °C
Yield: 55.8 %

Procedure:
A microwave reaction vial was charged with 2-chloro-7-cyclopropyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (57 mg, 272 μmol), 4-(trifluoromethyl)phenylboronic acid (62.0 mg, 326 μmol), a 2M aqueous sodium carbonate solution (408 μL, 816 μmol), and tetrakis(triphenylphosphine)palladium(0) (15.7 mg, 13.6 μmol) in ethanol (1.09 mL). The reaction mixture was heated in a microwave at 150° C. for 8 min. At this time, the reaction was diluted with methylene chloride and was filtered through a pad of Celite®, washing with a 10% methanol/methylene chloride solution. The filtrate was dried over sodium sulfate, filtered, and concentrated in vacuo onto Celite®. Flash chromatography (12 g silica gel column, 25-50% ethyl acetate/hexanes) afforded 7-cyclopropyl-2-(4-trifluoromethyl-phenyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a white solid (48.5 mg, 55.9%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.71-1.29 (m, 4H) 3.65 (d, J=4.90 Hz, 1H) 6.49 (d, J=3.58 Hz, 1H) 7.15 (d, J=3.39 Hz, 1H) 7.91 (d, J=8.67 Hz, 2H) 8.35 (d, J=7.91 Hz, 2H) 12.35 (br. s., 1H). LC-MS calcd. for C16H13F3N3O [(M+H)+] 320, obsd. 320.0.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:15]([N:17]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([CH2:26][NH2:27])=[CH:23]2)=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([CH2:26][NH:27][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:23]2)=[N:18]1)[CH3:16]
Reactant: CCn1cc2cc(CN)ccc2n1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CCn1cc2cc(CNS(=O)(=O)c3ccc(C(=O)OC)cc3)ccc2n1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (2-ethyl-2H-indazol-5-yl)methanamine (step-4 of Example 13).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[N:9]=1)[C:5](=O)[CH3:6].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:37][C:38]([NH2:40])=[NH:39])[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:37][C:38]2[N:40]=[C:5]([CH3:6])[C:4]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[N:9]=3)=[CH:3][N:39]=2)[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1
Reactant: CC(=O)C(=CN(C)C)c1nc(C)no1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc(-c3nc(C)no3)c(C)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 4-dimethylamino-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-but-3-en-2-one (313 mg, 1.6 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (297 mg, 0.8 mmol) using in analogous manner the procedure described in example 39b). Obtained as a pale-yellow solid (142 mg, 47%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.O.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>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COCOc1ccc(Cl)nc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(-c2cccc(F)c2)nc1
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
200 mg (1.0 eq) of the obtained 2-chloro-5-(methoxymethoxy)pyridine was dissolved in N,N-dimethylformamide/H2O=5:1 (16 mL), 193 mg (1.2 eq) of (3-fluorophenyl)boronic acid, 48 mg (3 mol %) of Pd(PPh3)4 and 586 mg (4.0 eq) of Na2CO3 were added. After reacting with microwave reactor at 120° C. for 30 minutes, N,N-dimethylformamide was removed by concentrating under reduced pressure. After extracting with ethyl acetate, the extract was treated with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent, hexane:ethyl acetate=9:1) to obtain 220 mg of 2-(3-fluorophenyl)-5-(methoxymethoxy)pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C(N(CC)CC)C>CC(C)=O>[CH3:14][O:13][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([NH:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: COc1cc(N)c2nccc(C)c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1cc(NCCCCCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1
Reaction time: 0.5 h

Procedure:
A stirred mixture of 20.9 g (0.111 mole) of 8-amino-6-methoxy-4-methylquinoline and 34.5 g (0.111 mole) of N-(6-bromohexyl)phthalimide was heated in an oil bath (130° ) while 11.2 g (15.4 ml; 0.111 mole) of triethylamine was added dropwise over a period of 45 minutes. The temperature of the bath was kept at 130° for 60 minutes, at 150° for 60 minutes, between 150° and 190° for 30 minutes, and at 190° for 30 minutes. The mixture was cooled then diluted with acetone (100 ml). The precipitate as collected on a filter, washed with acetone (2×50 ml), dried, then discarded. The filtrate was concentrated in vacuo to a dark oil; yield 53 g. The oil was dissolved in 100 ml of dischloromethane, and the solution was chromatographed on a column (40 cm× 8 cm dia) of silica gel (1000 g; activity III) using dichloromethane (1.5 l) as the eluent. Fractions containing the product were combined then concentrated in vacuo; yield 35.5 g (83.7%). That material was satisfactory for conversion to the target compound, however a 93% recovery of analytically pure material (mp 84°-85° ) could be obtained by crystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:41])[C:7]([CH2:18][NH:19][C:20](=[O:40])[NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30]C4C=CC([N+]([O-])=O)=CC=4)=O)[CH2:24][CH2:23]3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:51][S:52]([CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1)(=[O:54])=[O:53]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:41])[C:7]([CH2:18][NH:19][C:20]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([N:58]4[CH2:59][CH2:60][CH:55]([S:52]([CH3:51])(=[O:54])=[O:53])[CH2:56][CH2:57]4)=[O:30])[CH2:24][CH2:23]3)=[O:40])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CS(=O)(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)C1CCN(C(=O)N2CCC(NC(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)CC2)CC1
Temperature: 100 °C

Procedure:
In a 20 mL round-bottomed flask, 4-nitrophenyl 4-(3-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)ureido)piperidine-1-carboxylate (0.100 g, 0.174 mmol), N,N-diisopropylethylamine (112 mg, 152 μL, 0.868 mmol) and 4-(methylsulfonyl)-piperidine (28.3 mg, 0.174 mmol) were combined with DMF (5 mL). The reaction mixture was stirred at 100° C. over the weekend. The reaction mixture was concentrated. The crude product was purified by preparative reverse-phase HPLC, giving the product 1-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-[1-(4-methanesulfonyl-piperidine-1-carbonyl)-piperidin-4-yl]-urea. MS calcd. for C29H35ClN5O5S [(M+H)+] 600.2, obsd. 600.0.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.Br[CH2:10][CH2:11][O:12][CH2:13][CH2:14]Br.C(N(CC)CC)C>C(#N)C>[O:12]1[CH2:13][CH2:14][N:1]([C@H:2]2[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]2)[CH2:10][CH2:11]1
Reactant: BrCCOCCBr
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 60 °C

Procedure:
Trans-4-Aminocyclohexanol (0.5 g), 1-bromo-2-(2-bromoethoxy)ethane (1.07 g) and triethylamine (2.42 mL) were dissolved in anhydrous acetonitrile (20 mL). The reaction mixture was heated at 60° C. overnight. The organic solvent was removed under vacuum. The residue was purified with flash column chromatography on silica gel eluting with 7%-10% methanol in dichloromethane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](O)[CH3:13]>OS(O)(=O)=O>[CH2:12]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[N:10]=[C:2]([Cl:1])[CH:3]=1)[CH3:13]
Reactant: CCO
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C)nc(Cl)c1

Procedure:
A solution of 2-chloro-6-methyl-isonicotinic acid (15.5 g, 90.3 mmol) in ethanol (200 mL) and H2SO4 (0.5 mL) is stirred at 75° C. for 24 h. The solvent is evaporated and the residue is dissolved in EA (200 mL). The solution is washed with sat. aq. NaHCO3-solution (70 mL) and water (70 mL), dried over MgSO4, filtered, concentrated and dried under HV to give 2-chloro-6-methyl-isonicotinic acid ethyl ester (16.3 g) as a pink powder; LC-MS: tR=0.92 min; [M+1]+=200.17.
Reaction SMILES: [CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][N:4]1[C:12]2[N:11]=[C:10]([CH2:13][CH3:14])[NH:9][C:8]=2[C:7](=O)[NH:6][C:5]1=[O:16].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].[OH-].[Na+]>N1C=CC=CC=1>[CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][N:4]1[C:12]2[N:11]=[C:10]([CH2:13][CH3:14])[NH:9][C:8]=2[C:7](=[S:20])[NH:6][C:5]1=[O:16]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCc1nc2c([nH]1)c(=O)[nH]c(=O)n2CC(C)CC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCc1nc2c([nH]1)c(=S)[nH]c(=O)n2CC(C)CC
Temperature: 10 °C
Reaction time: 4.5 h

Procedure:
3-(2-Methylbutyl)-8-ethylxanthine (13.33 gm) and phosphorus pentasulphide (14.23 gm) were refluxed in pyridine (190 ml) at a bath temperature of 140° C. After 4.5 hr, the brown solution was cooled to 10° C. and 2N sodium hydroxide (70 ml) was added. The pyridine was removed in vacuo from the suspension.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[CH2:5]([O:12][CH2:13][C@@H:14]1[CH2:16][O:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH2:5]([O:12][CH2:13][C@H:14]1[O:15][C:2]([NH2:3])=[N:1][CH2:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: N#CN
Agent: [Na]
Solvent: CO
Product: NC1=NC[C@@H](COCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a vigorously stirred solution of sodium hydrogen cyanamide (1.95 g, 30.4 mmol) in methanol (30.5 mL) was added dropwise (S)-2-benzyloxymethyl-oxirane (5 g, 30.4 mmol) in methanol. The reaction mixture was stirred at room temperature overnight after which the reaction mixture was concentrated to remove methanol. Ethyl acetate was added (150 mL) along with 50 ml of water. The contents were transferred to a separatory funnel, the organic layer was removed, dried over Na2SO4 and concentrated under vacuum to give 6.01 g (96%) of the title compound.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[CH2:20][C@@H:21]1[CH2:26][CH2:25][NH:24][C:23](=[S:27])[NH:22]1>>[F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([O:10][CH2:20][C@@H:21]2[CH2:26][CH2:25][NH:24][C:23](=[S:27])[NH:22]2)=[O:9])[CH2:3]1
Reactant: OC[C@@H]1CCNC(=S)N1
Reactant: O=C(O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Product: O=C(OC[C@@H]1CCNC(=S)N1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylacetic acid and (4S)-4-(hydroxymethyl)tetrahydropyrimidine-2(1H)-thione, the title compound was prepared by a method similar to Step 2 of Referential Example 12.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:25](C1C=CN=C(CN)C=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:23]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:18][NH:17][C:11]2[N:10]=[C:9]([NH:8][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=2)[CH:24]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1ccnc(CN)c1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2cc(C(C)(C)C)ccn2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(4-tert-butylpyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02-1.10 (m, 3H), 1.24 (d, J=11.01 Hz, 11H), 1.42 (d, J=10.48 Hz, 2H), 1.55 (d, J=9.94 Hz, 3H), 1.90 (s, 3H) 2.29 (s, 3H), 3.43 (s, 1H), 4.71 (d, J=5.10 Hz, 2H), 7.52 (s, 2H) 7.59 (d, J=7.52 Hz, 1H), 8.21 (s, 1H), 8.53 (d, J=6.72 Hz, 1H), 12.48 (s, 1H); MS (ESI) m/z 368.1 (M+1)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([CH2:2][N:27]3[C:26]([CH3:25])=[CH:30][C:29]([CH3:31])=[N:28]3)=[CH:4][CH:5]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Product: Cc1cc(C)n(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)n1

Procedure:
70 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to 50 mg of 3,5-dimethyl-1H-pyrazole via Procedure P. The reaction was evaporated to dryness and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide. MS (Q1) 417.3 (M)+.
Reaction SMILES: [ClH:1].Br[C:3]12[CH2:12][C:7]3([CH3:13])[CH2:8][CH:9]([CH2:11][C:5]([CH3:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH:15]([NH:18][C:19](NC(C)C)=O)([CH3:17])[CH3:16]>O>[ClH:1].[CH3:19][N:18]([C:3]12[CH2:12][C:7]3([CH3:13])[CH2:8][CH:9]([CH2:11][C:5]([CH3:14])([CH2:6]3)[CH2:4]1)[CH2:10]2)[CH:15]([CH3:17])[CH3:16]
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Reactant: CC(C)NC(=O)NC(C)C
Agent: Cl
Solvent: O
Product: CC(C)N(C)C12CC3CC(C)(CC(C)(C3)C1)C2
Reaction time: 0.17 h
Yield: 44 %

Procedure:
2.43 grams of 1-bromo-3,5-dimethyl-adamantane hydrochloride were heated in a closed vessel for 40 minutes at 180° C., with 2.8 grams of N,N'-di-isopropylurea. After cooling, the reaction product was suspended in 50 ml. of water, acidified, and extracted with two 10-ml. portions of ether. Next, the water phase was brought to a pH of between 12 and 13 with sodium hydroxide, stirred for 10 minutes, and extracted with four 10-ml. portions of benzene. The benzene extracts were combined, the benzene stripped off, and the residue refluxed for 10 hours with 4 ml. of a 32% formaldehyde solution and 4 ml. of concentrated formic acid. After cooling, the solution was worked up as in Example 6. It yielded 1.04 grams of 1-(N-methyl,N-isopropylamino)-3,5-dimethyl-adamantane hydrochloride. Yield: 38% of theoretical yield.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH:11]([CH2:14][NH2:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH2:29]([O:28][C:26](=[O:27])[NH:15][CH2:14][CH:11]1[CH2:10][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:13]=2[O:12]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)c1cccc2c1OC(CN)C2
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 96.1 %

Procedure:
Treatment of (±)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (3.25 g, 13.4 mmol) with diisopropylethylamine (4.34 g, 33.6 mmol) and benzyl chloroformate (2.64 g, 15.5 mmol) generally according to the procedure described for Intermediate 12 gave 4.37 g (96%) of (±)-benzyl(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a white solid. mp 73-76° C.; Anal. Calcd. for C21H25NO3 C, 74.31; H, 7.42; N, 4.13. Found C, 74.95; H, 7.51; N, 4.18. Chiral HPLC separation of (±)-benzyl(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol) provided two fractions. Fraction 1 (Rt=9.100 min, Chiralcel OJ, ethanol); Fraction 2 (Rt=14.428 min, Chiralcel OJ, ethanol).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:21](OC)=[O:22])[C:17]([O:19][CH3:20])=[O:18]>CC(O)C>[OH:22][C:21]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(Cl)C(=O)OC
Reactant: Cc1nn2ccccc2c1C(N)=S
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1O
Temperature: 90 °C
Reaction time: 7 h
Yield: 82.4 %

Procedure:
A suspension of 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (3.0 g, 13 mmol) produced in Example 11-B (v) and dimethyl chloromalonate (6.6 g, 40 mmol) in 2-propanol (40 mL) was stirred at 90° C. for 7 hr. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration, washed with ethyl acetate and diisopropyl ether and dried to give the title compound (3.1 g, 82%) as a yellow solid.