Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([C:9](OCC)=[O:10])=[CH:7][N:6]=[C:5]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[N:4]=1.[NH4+:27].[OH-].C([O-])(O)=O.[Na+]>C(O)C>[CH2:20]([N:17]1[CH2:16][CH2:15][N:14]([C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:10])[NH:27][CH2:2][C:3]=3[N:4]=2)[CH2:19][CH2:18]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1CCl
Reactant: [NH4+]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1NCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21

Procedure:
Dissolved in 10 ml of ethanol was 2.25 g (6 mmol) of ethyl 4-chloromethyl-2-(4-benzylpiperazino)pyrimidine-5-carboxylate (Referential Example 41), followed by an addition of 10 ml (59 mmol) of a 30% aqueous NH4OH solution at 20° C. The resultant mixture was stirred for 12 hours. The reaction mixture was poured in a 10% aqueous NaHCO3 solution, followed by extraction with CHCl3. The solvent was then distilled off and the residue was recrystallized from toluene.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[N:14][C:13]([N:16]2[CH:20]=[C:19]([CH3:21])[N:18]=[N:17]2)=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.Cl[C:23]([C:25]([O:27][CH3:28])=[O:26])=[O:24]>C(Cl)Cl.C[N+]([O-])=O>[CH3:28][O:27][C:25](=[O:26])[C:23]([C:9]1[C:8]2[C:12](=[C:13]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[N:17]3)[N:14]=[CH:15][C:7]=2[O:6][CH3:5])[NH:11][CH:10]=1)=[O:24]
Reactant: COC(=O)C(=O)Cl
Reactant: COc1cnc(-n2cc(C)nn2)c2[nH]ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1c[nH]c2c(-n3cc(C)nn3)ncc(OC)c12
Temperature: 0 °C
Reaction time: 18 h
Yield: 17.3 %

Procedure:
To a solution of AlCl3 (1.382 g, 10.36 mmol) in CH2Cl2 (4 mL) and MeNO2 (1 mL) was added 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindole (0.155 g, 0.677 mmol) as a solid. After dissolution of the starting material (ca. 5 min), ClCOCO2Me (0.29 mL, 3.15 mmol) was added and the mixture was allowed to stir for 18 h. Another portion of ClCOCO2Me (0.29 mL, 3.15 mmol) was then added and stirring continued for a further 24 h. The mixture was subsequently cooled to 0° C., quenched by the slow addition of 1 M aqueous NH4OAc and then extracted with EtOAc. The aqueous layer was separated and acidified with 6 M HCl and then the resultant precipitate was filtered and dried to give the title acid (0.158 g, 69%): LCMS: m/e 302 (M+H)+. The organic layer was washed (H2O, brine), dried (Na2SO4) and evaporated to give 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid methyl ester (0.037 g, 15%): LCMS: m/e 316 (M+H)+. This material was hydrolyzed by dissolving in MeOH (2 mL) and treating with 1M NaOH (0.3 mL). The mixture was allowed to stir for 4 h, at which point the solvent was removed and the residue diluted with H2O (4 mL). The mixture was then acidified to pH 1 using 6N HCl and the precipitated acid was filtered and dried to give a further 0.021 g of the title compound. Total yield=0.179 g (78%). Preparation of 4-(1-Phenyl-1-(3-hydroxy-1-butyl-1-yl)-methylene)-piperidine-1-carboxylic acid tert-butyl ester:
Reaction SMILES: [CH2:1]1[S:4][CH:2]1[CH3:3].[CH3:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1>>[SH:4][CH:2]([CH3:3])[CH2:1][N:9]1[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]1
Reactant: CC1CS1
Reactant: CN1CCNCC1
Product: CC(S)CN1CCN(C)CC1

Procedure:
The 1-(2-mercaptopropyl)-4-methylpiperazine is prepared by heating a mixture of propylene sulphide (19 cc) and N-methylpiperazine (29 cc) at 100° C. for 16 hours. This gives a colourless oil (32 g) distilling at 105° C. under 1.3 kPa.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(OC)c(OC)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3,4-dimethoxy-phenylboronic acid to give [1-(3,4-dimethoxy-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 377(MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[N:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2,5-dibromopyridine (4.10 g, 17 mmol) in anhydrous toluene (250 mL) at −78° C. was dropwise added n-BuLi (1.6 M, 12 mL). After stirred at −78° C. for 2.5 hours, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (2.73 g, 17 mmol) in methylene chloride (25 mL) was added into the reaction mixture, and the resulting mixture was stirred for additional one hour and allowed to warm up to room temperature slowly. The reaction mixture was poured into aqueous NaHCO3 (200 mL) and then extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over MgSO4, and concentrated in vacuo. The resulting solid was triturated with ether and the solid was collected by filtration. The ether solution was concentrated and the solid was chromatographed on silica gel, eluting with hexane/ethyl acetate (2 to 1) to give a pale yellow solid. Weight of combined solids: 4.26 g. LCMS: 316.10/314.10 (M+H+, 100%). 1HNMR: δ 8.6 (s, 1H), 7.82 (d, 1H), 7.38 (d, 1H), 4.6 (s, 1H), 4.0 (m, 4H), 2.2 (m, 4H), 1.7 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:18][CH2:19][OH:20])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.O>[CH3:24][S:21]([O:1][CH2:2][CH2:3][C:4]1([CH2:18][CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:6][CH2:5]1)(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCCC(CCO)(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(CCOS(C)(=O)=O)(CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TEA (1.1 ml, 8.36 mmol, 3.0 eq.) was added to a cooled solution of tert-butyl 4,4-bis(2-hydroxyethyl)azepane-1-carboxylate (800 mg, 2.78 mmol, 1.0 eq.) in methylene chloride (10 ml) at 0° C. and then mesylchloride (0.47 ml, 6.13 mmol, 2.2 eq.) was added to the reaction mixture and it was stirred at RT for 2 h. After completion (monitored by TLC), the reaction mixture was diluted with water (20 ml) and methylene chloride (100 ml). The organic part was separated and the water layer was extracted with methylene chloride (2×20 ml). The combined organic layers were washed with brine (20 ml), dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21]([O:23]CC)=[O:22])[NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1>CO>[Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21]([OH:23])=[O:22])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)c(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1c(Cl)ccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A mixture of ethyl 6-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.74 g), 4N aqueous sodium hydroxide solution (1.2 ml), tetrahydrofuran (6 ml) and methanol (4 ml) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated, and acidified with 10% aqueous citric acid solution, and the resulting crystals were collected by filtration, washed with water, and dried to give the title compound (0.69 g, quantitative) as colorless crystals. melting point 286-288° C.
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH3:10])[N:5]=1.Cl.[NH2:14][OH:15].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:10][C:6]1[N:5]=[C:4]([CH:3]=[N:14][OH:15])[CH:9]=[CH:8][N:7]=1
Reactant: NO
Reactant: COC(OC)c1ccnc(C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nccc(C=NO)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 4-dimethoxymethyl-2-methyl-pyrimidine (10 g) from I.1.1 in methanol (100 mL) was added 8.2 g of hydroxylamine hydrochloride and 10% HCl and the reaction mixture was heated under reflux for 2 h. After cooling to room temperature, the pH was adjusted to 8 using solid sodium carbonate. The mixture was stirred for 30 minutes. The solid was sucked off, dried at 50° C. under reduced pressure to yield 6.0 g (73%) of the title compound as white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[S:36])=[C:30]([CH:38]([CH3:40])[CH3:39])[CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:2]([NH:1][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[N:15]=[CH:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=4)[N:12]=3)[CH:6]=2)=[O:3])=[S:36])=[C:30]([CH:38]([CH3:40])[CH3:39])[CH:29]=1
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CC(C)c1cc(F)ccc1NC(N)=S
Product: CC(C)c1cc(F)ccc1NC(=S)NC(=O)NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(4-fluoro-2-isopropylphenyl)thiourea and isolated as an off-white solid (0.242 g, 56%).
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.[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[N:24][NH:23][C:22]2=[O:26])=[N:17][CH:16]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:23]1[C:22](=[O:26])[N:21]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][N:17]=2)[CH:25]=[N:24]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ncn1-c1ccncn1
Product: C[C@@H](n1ncn(-c2ccncn2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 30.8 %

Procedure:
In the same manner as in Reference Example 5, starting from 536 mg of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 305 mg of 4-(4-pyrimidinyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1methylpropyl]-4-(4-pyrimidinyl)-3(2H,4H)-1,2,4-triazolone (199 mg) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1([CH3:34])[O:33][CH2:32][CH2:31][O:30]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2([CH3:34])[O:30][CH2:31][CH2:32][O:33]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: CC1(c2ccccc2CBr)OCCO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1C1(C)OCCO1
Yield: 89.5 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.547 g, 2.04 mmol), 2-(2-bromomethyl-phenyl)-2-methyl-[1,3]dioxolane (1.03 g, 3.99 mmol), KI (73 mg, 0.42 mmol), and DIPEA (0.70 mL, 4.02 mmol) in DMF (10 mL) was heated at 60° C. for 24 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.81 g (90%) of 3,3″-dimethyl-1′-[2-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine as a white solid. 1H NMR (CDCl3) δ 1.46 (s, 3H), 1.60-1.83 (m, 3H), 2.15-2.20 (m, 1H), 2.47-2.57 (m, 8H), 3.26-3.31 (m, 2H), 3.82-3.87 (m, 2H), 4.01 (s, 2H), 4.44 (d, 2H, J=10.8 Hz), 6.72-6.82 (m, 4H), 7.05 (dd, 1H, J=7.2, 1.5 Hz), 7.21 (d, 2H, J=7.2 Hz), 7.46 (d, 1H, J=6.9 Hz), 8.19 (d, 2H, J=4.8 Hz); ES-MS m/z 444 (M+H).
Reaction SMILES: [NH:1]1[C:11]2[C:12]3[C:3]([CH2:4][NH:5][C:6](=[O:13])[C:7]=3[CH:8]=[CH:9][CH:10]=2)=[CH:2]1.F[B-](F)(F)F.[CH2:19]([O+](CC)CC)[CH3:20]>C(Cl)Cl>[CH2:19]([O:13][C:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[NH:1][CH:2]=[C:3]([C:12]=23)[CH2:4][N:5]=1)[CH3:20]
Reactant: O=C1NCc2c[nH]c3cccc1c23
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC1=NCc2c[nH]c3cccc1c23
Reaction time: 24 h

Procedure:
3,4-Dihydropyrrolo[4,3,2-de]isoquinolin-5(lH)-one (8.6 g), described in Example 4, is added in one portion to a solution of 12 g of triethyloxonium fluoroborate [H.-L. Pan and T. L. Fletcher, J. Org. Chem., 27, 3639 (1962)] in 500 ml dry methylene chloride. The suspension is stirred for 24 hours. The solid is collected and washed with a little methylene chloride and then ether to give 5-ethoxy-1,3-dihydropyrrolo[4,3,2-de]isoquinoline hydrofluoroborate, mp 233° - 234°C, νmaxnujol 3380, 3280, 1645, 1605, 1594, 1540 and 1512 cm-1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[Si:23]([O:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc2c(c1)CCc1ccccc1N2
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)CCc1ccccc1N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of 1.0 g of Compound 31-2a, 1.5 g of imidazole, 1.5 g of tert-butyldimethylsilyl chloride and 30 ml of DMF was stirred overnight at room temperature, followed by addition of ice chips and further stirring. After the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (10/1)] to give 1.34 g (89%) of the product as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[CH3:17][CH2:18]O>N1CCCCC1>[NH:1]1[CH:2]=[CH:3][CH:4]=[C:18]1[CH:17]=[N:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: CCO
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccnc2)n[nH]c1N=Cc1ccc[nH]1

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (100 mg) was then suspended in EtOH (3 mL) 2-Pyrrolecarbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-(((1H-pyrrol-2-yl)methylene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([NH:12][C:13](=[O:35])[N:14]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(OCC)C.[Ag]=O>[CH2:1]([O:34][C@@H:29]([CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N:14]([CH3:15])[C:13]([NH:12][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:35])[CH:17]=2)=[CH:27][CH:26]=1)[C:30]([O:32][CH3:33])=[O:31])[CH:2]=[CH2:3]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](O)C(=O)OC)cc2)c1
Reactant: C=CCBr
Agent: O=[Ag]
Solvent: CCOCC
Product: C=CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)NCCCCCCC)c2)cc1)C(=O)OC
Temperature: 40 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
58 μl (0.70 mmol) of allyl bromide are added to a mixture of 162 mg (0.70 mmol) of silver oxide and 200 mg (0.47 mmol) of methyl (S)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-hydroxypropanoate in 3 ml of diethyl ether. The reaction mixture is stirred at 40° C. for 24 hours. The mixture is filtered and then the solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 80/20 up to 60/40). 180 mg of methyl (S)-2-allyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate are obtained in the form of an oil. Yield=82%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]2[NH:15][C:16](=[O:24])[C:17]([CH:19]3[CH2:22][C:21](=[O:23])[CH2:20]3)=[CH:18][C:13]2=[N:12][N:11]=1.Cl.Cl[CH2:27][C:28]1[N:32]([CH3:33])[N:31]=[CH:30][N:29]=1>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]2[N:15]=[C:16]([O:24][CH2:27][C:28]3[N:32]([CH3:33])[N:31]=[CH:30][N:29]=3)[C:17]([CH:19]3[CH2:20][C:21](=[O:23])[CH2:22]3)=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: Cn1ncnc1CCl
Reactant: O=C1CC(c2cc3nnc(-c4ccccc4F)n3[nH]c2=O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C1CC(=O)C1
Temperature: 80 °C

Procedure:
Sodium hydride (60% dispersion in oil, 62 mg, 1.54 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-7-(3-oxocyclobutyl)-1,2,4-triazolo[4,3-b]pyridazin-6-one (0.23 g, 0.7 mmol) in anhydrous N,N-dimethylformamide (5 ml), and heated to 80° C. under an atmosphere of nitrogen for 0.5 hours. The solution was allowed to cool before addition of 5-chloromethyl-1-methyl-1H-1,2,4-triazole monohydrochloride (prepared using the conditions described in EP-A-170073) (0.14 g, 0.85 mmol). The reaction was then heated to 80° C., under an atmosphere of nitrogen, for 18 hours. The solution was allowed to cool, concentrated and the residue was purified by chromatography on silica using 0-5% methanol/dichloromethane as eluent to give the required product as a white solid. Data for the title compound: 1H NMR (360 MHz, CDCl3) δ 3.29-3.38 (2H, m), 3.45-3.56 (2H, m), 3.73-3.82 (4H, m), 5.52 (2H, s), 7.26—7.31 (1H, m), 7.35-7.39 (1H, m), 7.56-7.60 (1H, m), 7.81-7.85 (1H, m), 7.88 (1H, s), 7.98 (1H, s); MS (ES+) m/e 394 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[OH:18])=[C:11]([O:19][CH3:20])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:29][CH2:30]/[CH:31]=[CH:32]/[P:33](=[O:42])([O:38][CH:39]([CH3:41])[CH3:40])[O:34][CH:35]([CH3:37])[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:24]([O:23][C:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[O:18][CH2:29][CH2:30]/[CH:31]=[CH:32]/[P:33]([O:38][CH:39]([CH3:40])[CH3:41])([O:34][CH:35]([CH3:36])[CH3:37])=[O:42])=[C:11]([O:19][CH3:20])[N:10]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)OP(=O)(/C=C/CCO)OC(C)C
Reactant: COc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2c1ncn2O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2c1ncn2OCC/C=C/P(=O)(OC(C)C)OC(C)C
Temperature: 0 °C
Yield: 61.9 %

Procedure:
To a mixture of 2-[di-(t-butoxycarbonyl)]amino-9-hydroxy-6-methoxypurine (154 mg, 404 μmol), diisopropyl (E)-4-hydroxybut-1-enylphosphonate (89 mg, 404 μmol) and triphenylphosphine (159 mg, 606 μmol) in dry tetrahydrofuran (4 ml) stirred at 0° C. was added diethyl azodicarboxylate (105 mg, 606 μmol). The mixture was allowed to warm to room temperature and stirred for 2.3 hr. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with ethyl acetate-methanol (20:1) to give (E)-2-[di-(t-butoxycarbonyl)]amino-9-[4-(diisopropoxyphosphoryl)but-3-enyloxy]-6-methoxypurine as a colourless gum (150 mg, 62%); λmax (EtOH) 255 (12,300)nm; υmax (KBr) 3440, 3220, 2975, 1790, 1600, 1370, 1280 and 1100 cm-1 ; δH [(CD3)2SO] 1.22 (12H, dd, J 6 Hz and 7 Hz, CH(CH3)2), 1.40 (18H, S, C(CH3)3), 2.70 (2H, m, CH2), 4.08 (3H, s, CH3O), 4.53 (4H, m, CH2O and CH(CH3)2), 5.98 (1H, dd, J 17 Hz and 19 Hz, PCH=CH), 6.25 (1H, ddt, J 6 Hz, 17 Hz and 22 Hz, PCH=CH), 8.71 (1H, s, 8-H) (Found: M+ 599.2724. C26H42N5O9P requires M+ 599.2720).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:29][C:30](Cl)=[O:31].[OH-].[K+]>ClCCl>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:11]2[CH2:12][O:13][CH2:29][C:30](=[O:31])[N:9]([C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[CH2:10]2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCl
Reactant: C[C@@H](NCC(CO)c1ccc(Br)cc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)COCC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diastereopure 3-((R)-1-phenylethylamino)-2-(4-bromophenyl)propan-1-ol (2.40 g, 7.18 mmol) in dichloromethane (22.0 ml) was added triethylamine (0.799 g, 7.90 mmol) and chloroacetyl chloride (0.892 g, 7.90 mmol) at 0° C. The mixture was stirred at 0° C. for one hour. The reaction mixture was partitioned between 0.5N—HCl and dichloromethane, and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. To the residue dissolved into 2-propanol (48 ml) was added potassium hydroxide (805 mg, 14.4 mmol) at 0° C. The mixture was stirred at 0° C. for 3 hours and partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=7/3) to afford (S)-6-(4-bromophenyl)-4-((R)-1-phenylethyl)-1,4-oxazepan-3-one as white solid (2.42 g, 90 W. An analytical sample for X-ray was obtained by crystallization from dichloromethane-hexane and the absolute configuration of 6-position was found to be the (S)-configuration.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][O:27][CH2:28][C:29](Cl)=[O:30]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:29](=[O:30])[CH2:28][O:27][CH3:26])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COCC(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Methoxyacetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-methoxyacetyloxy-2(1H)-pyrimidinone as the residue.