Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([NH:16][C:17]([NH:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)=[O:18])=[CH:14][C:13]([C:30](C)([CH3:32])[CH3:31])=[N:12]2)=[CH:7][CH:6]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([NH:16][C:17]([NH:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)=[O:18])=[CH:14][C:13]([CH:30]([CH3:32])[CH3:31])=[N:12]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc3ccccc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.9 %

Procedure:
To a stirred solution of Example 195 (500 mg, 0.83 mmol) in THF (10 mL) was added LiAlH4 powder (65 mg, 1.66 mmol) in portion at 0° C. under N2. The mixture was stirred for 2 h at RT, excess LiAlH4 was destroyed by a slow addition of ice, and the reaction mixture was acidified to pH=7 with dilute HCl. After the solvent was removed, the residue was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), and filtered. After concentration in vacuo, the crude product was purified by preparative-TLC to afford 1-[2-(4-hydroxymethyl-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-naphthalen-1-yl-urea (415 mg, 92%). 1H NMR (DMSO-d6): 9.04 (s, 1H), 8.78 (s, 1 H), 7.98 (d, J=8.0 Hz, 1 H), 7.90 (d, J=7.2 Hz, 2H), 7.63 (d, J=8.4 Hz, 1 H), 7.55-7.42 (m, 7 H), 6.39 (s, 1 H), 5.30 (t, J=5.6 Hz, 1 H), 4.56 (d, J=5.6 Hz, 2 H), 1.27 (s, 9 H); MS (ESI) m/z: 415 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10](=[O:12])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[H-].[Na+].[CH3:20][C:21]1[C:25]([S:26](Cl)(=[O:28])=[O:27])=[C:24]([CH3:30])[O:23][N:22]=1>O>[CH3:20][C:21]1[C:25]([S:26]([N:11]2[C:10](=[O:12])[O:9][N:8]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:28])=[O:27])=[C:24]([CH3:30])[O:23][N:22]=1
Reactant: O=c1[nH]c(-c2ccccc2)no1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(C)c1S(=O)(=O)n1c(-c2ccccc2)noc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.3 %

Procedure:
At room temperature, a mixture of 2.0 g (15 mmol) of 3-phenyl-4H-[1,2,4]oxadiazol-5-one and 30 ml absolute tetrahydrofuran is admixed with stirring with 0.40 g (10 mmol) of a suspension of sodium hydride (60% strength) and then stirred at room temperature for 10 minutes. 1.9 g (10 mmol) of 3,5-dimethylisoxazol-4-sulphonyl chloride are subsequently added, and the mixture is stirred at room temperature for another 20 hours. For work-up, the reaction mixture is poured into 150 ml of water. The resulting mixture is extracted twice with 80 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue that remains is chromatographed over silica gel using methylene chloride as mobile phase. In this manner, 0.3 g (9% of theory) of 4-(3,5-dimethylisoxazole-4-sulphonyl)-3-phenyl-4H-[1,2,4]oxadiazol-5-one is obtained in the form of a colourless solid of melting point 90 to 95 C.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:27]#[N:28])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: N#CCC(=O)O
Agent: Cl
Product: N#CCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (50 mg, 51%), MS (ISP) m/z=394.3 [(M+H)+], mp 186° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-cyano-acetic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[OH:24])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:28][C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=3)=[CH:19][C:18]=2[O:24][CH2:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(O)cc2O)CC1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(OCc3ccc(C#N)cc3)cc2OCc2ccc(C#N)cc2)CC1
Yield: 70.5 %

Procedure:
{2-[1-(2,4-Dihydroxy benzoyl)piperidin-4-yl]ethyl}carbamic acid tert-butyl ester (1.13 g, 3.1 mmol) and 4-bromomethyl-benzonitrile (2.43 g, 12.4 mmol) and other reagents as described in Example 75(a) were used to afford 1.3 g of the required product. 1H NMR (DMSO-d6): δ 1.35 (8H, s), 2.1 (4H, s), 2.9 (3H, m), 4.55 (4H, d), 5.25 (3H, s), 5.5 (2H, t), 6.8 (1H, m), 7.3 (1H, d), 7.4 (1H, d), 7.5 (4H, d), 7.66 (1H, d), 7.8 (3H, m), 7.86 (2H, m).
Reaction SMILES: [C:1]1([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:16]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][N:17]=1>>[C:1]1([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][C:16]2[N:21]=[C:20]([NH:14][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:19]([F:23])=[CH:18][N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: NC(c1ccccc1)c1ccccc1
Product: Fc1cnc(NC(c2ccccc2)c2ccccc2)nc1NC(c1ccccc1)c1ccccc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 1,1-diphenyl methylamine and 2,4-dichloro-5-fluoropyrimidine were reacted to produce N2,N4-bis(diphenylmethyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.91 (d, 1H, J=2.3 Hz), 7.39-7.25 (m, 20H), 6.51 (d, 1H, J=8.2 Hz), 5.77 (d, 1H, J=7.0 Hz); LCMS: ret. time: 33.46 min.; purity: 92%; MS (m/e): 461 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F.C([O-])(O)=O.[Na+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:17][C:24]2[CH:23]=[CH:22][C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:19]=2[F:18])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2
Reactant: Oc1cc2cn(C3CCCCO3)nc2cc1Br
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc3cn(C4CCCCO4)nc3cc2Br)c(F)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of 6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-5-ol (1.475 kg, 4.96 mol) in DMF (5.3 L) is added 3,4-difluoronitrobenzene (1.18 kg, 7.45 mol) and NaHCO3 (625.5 g, 7.45 mol) at RT. The reaction mixture is heated at 70° C. for 10 hours and then cooled to less than 20° C. Deionized (DI) water (7.9 L) is slowly added to the solution and the resulting slurry is stirred at 15° C. for one hour. The solid is collected by vacuum filtration, and the solid cake is washed with water (8 L). It is then air dried under vacuum on filter and is triturated with methyl MTBE (18.6 L) at reflux conditions for two hours. The slurry is then cooled to RT and the solid is collected by vacuum filtration. The solid cake is washed with MTBE (4 L×2) and dried in a vacuum oven at 35° C. to give the desired product (1.405 kg, 64.9% yield). MS (m/z): 436.0 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:17]3[N:18]=[CH:19][N:20]([C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)=[O:16])[CH:11]=2)[CH:6]=1)=[O:4].Cl.[C:42]([O:45][CH2:46]C)(=[O:44])[CH3:43]>C1COCC1>[OH:16][C@@:15]([C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:6]=2)[CH:11]=1)([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:21]=1)[CH2:43][C:42]([O:45][CH3:46])=[O:44]
Reactant: CCOC(C)=O
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 0.69 g (1.32 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 6.9 mL of THF was added dropwise at −35˜−40° C. The mixture was stirred at −40˜−35° C. for 1 hour. 2.5 mL (1.32 mmol) of the solution of methyl bromozincacetate in tetrahydrofuran obtained in Example 55 was added dropwise at −40° C., and the mixture was stirred at −40˜−35° C. for 1 hour. 20 mL of 1N hydrochloric acid was added dropwise at 0° C. or lower, followed by dilution with 30 mL of ethyl acetate. The layers were separated. The organic layer was washed successively with 5 mL of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, 5 mL of water, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing and concentration under reduced pressure, 4 mL of IPE was added, crystals were loosened, filtered, and washed with 1 mL (×2) of IPE. After washing, vacuum drying (40° C.) to a constant weight afforded 0.72 g of methyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 92%, enantiomer excess 93.6% ee).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([Cl:24])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([Cl:24])[S:22][CH:23]=2)[CH3:15])=[CH:11][CH:12]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(Cl)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1ccc(OCC(=O)O)cc1)NCC(O)c1csc(Cl)n1

Procedure:
Prepared by analogy to Example 97 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanamine with 1N sodium hydroxide solution in methanol
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[N:11][CH:12]=1.[H-].[Na+].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1F)[CH:21]=[O:22]>O>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][N:11]=1)[CH:21]=[O:22]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: OCc1ccc(F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccc(F)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.2 %

Procedure:
To an N,N-dimethylformamide (20.0 mL) solution of (5-fluoro-pyridin-2-yl)-methanol (760 mg, 5.98 mmol) described in Manufacturing Example 41-1-1 was added sodium hydride (239 mg, 5.98 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 10 minutes at room temperature. 3,4-Difluorobenzaldehyde (935 mg, 6.58 mmol) was then added at room temperature, and stirred for 30 minutes at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane=1:3) to obtain the title compound (629 mg, 42.2%).
Reaction SMILES: C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C(O)=CC4C[CH2:22][O:23]C=4C=3)C2=O)C=CC=CC=1.[F:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:43]=1[N:42]([CH2:44][C:45]1[O:46][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:48][CH:49]=1)[C:41](=[O:54])[CH:40]2[C:55]1[C:63]([OH:64])=[CH:62][C:58]2[O:59][CH2:60][O:61][C:57]=2[CH:56]=1>>[F:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:43]=1[N:42]([CH2:44][C:45]1[O:46][C:47]([C:50]([F:53])([F:51])[F:52])=[CH:48][CH:49]=1)[C:41](=[O:54])[C:40]2([C:55]1[C:63]([OH:64])=[CH:62][C:58]2[O:59][CH2:60][O:61][C:57]=2[CH:56]=1)[CH2:22][OH:23]
Reactant: O=C1C(c2cc3c(cc2O)OCO3)c2cccc(F)c2N1Cc1ccc(C(F)(F)F)o1
Reactant: O=C1C(c2cc3c(cc2O)CCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2c(F)cccc2C1(CO)c1cc2c(cc1O)OCO2

Procedure:
Following the procedure as described in PREPARATION 26C, and making non-critical variations to replace 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one with 7-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one, the title compound was obtained (67%): MS (ES+) m/z 488.4 (M+23).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH3:12])=[C:4]([CH3:21])[N:3]=1.P(Cl)(Cl)([Cl:24])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:24])[C:5]([CH2:9][CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH3:12])=[C:4]([CH3:21])[N:3]=1
Reactant: CC(=CCc1c(C)nc(N)nc1O)c1cc(Cl)ccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CC(=CCc1c(C)nc(N)nc1Cl)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 2.0 grams (0.006 mole) of 2-amino-4-hydroxy-6-methyl-5-[3-(2,5-dichlorophenyl)-2-butenyl]pyrimidine, 16.5 grams (0.107 mole) of phosphorus oxychloride, and 1.5 grams (0.007 mole) of phosphorus pentachloride is heated at reflux for about 18 hours. After this time the reaction mixture is slowly pipetted into wet ice during a 20 minute period. The mixture is then stirred until the ice melted, and the resultant solid is collected by filtration. The solid is dissolved in methylene chloride, and the solution is dried with magnesium sulfate. The mixture is filtered and the filtrate is concentrated under reduced pressure, yielding 2.0 grams of 2-amino-4-chloro-6-methyl-5-[3-(2,5-dichlorophenyl)-2-butenyl]pyrimidine; mp 97°-100° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: C([O:5][CH2:6][C:7]([O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=[O:21]>C(Cl)Cl>[C:6]([CH2:7][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)([OH:5])=[O:21]
Reactant: COC(=O)c1ccc(OC(=O)COC(C)(C)C)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC(=O)O)cc1
Reaction time: 2 h

Procedure:
Ester 24-1 was dissolved in 15 mL CH2Cl2, then 15 mL TFA was added. After 2 h, the mixture was concentrated providing 24-2 as a white solid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[NH2:12][NH:13][C:14]([NH2:16])=[S:15].C(O)(=O)C>[OH-].[K+]>[NH2:1][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:4]1[C:2](=[O:3])[NH:16][C:14](=[S:15])[NH:13][N:12]=1
Reactant: NNC(N)=S
Reactant: O=C1Nc2ccccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccccc1-c1n[nH]c(=S)[nH]c1=O
Temperature: 115 °C
Yield: 86.2 %

Procedure:
This was prepared by a modified literature procedure (Doleschall, G.; Lempert, K. Tetrahedron 1973, 29, 639-649). Isatin (10 g, 67.96 mmol) was dissolved in ca. 10% aqueous KOH (9.9 g in 100 mL of water) and then treated with thiosemicarbazide (6.28 g; 68.90 mmol). After 1 hour of heating at 115° C. (bath temperature), the reaction mixture was poured over ice and treated with glacial acetic acid drop-wise, till the pH was ca. 5. The yellow fluffy precipitate was filtered, washed copiously with water (8×50 mL) and dried first in air and then under high vacuum to afford 12.9 g of yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][CH2:29]O)=[CH:27][C:22]=2[O:21][CH2:20]1>>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][CH2:29][O:16][C:13]3[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=3)=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: OCCc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCc2ccc3c(c2)OCO3)cc1
Yield: 87 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (300 mg, 1.19 mmol) prepared in Example 1 (1a) and 2-(1,3-benzodioxol-5-yl)ethanol (which is the compound disclosed in Tetrahedron, (2003), 59, 3369-3378, 239 mg, 1.44 mmol) to give 356 mg of the title compound (pale red powder, yield: 87%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:2]1.[C:19]([C:21]1[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>O1CCCC1>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]4[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:2]1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccsc2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccsc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.9 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-(thiophen-3-ylmethoxy)-phenyl)-acetohydroximoyl chloride (150 mg, 0.532 mmol) described in Manufacturing Example 77-1-4 and 3-ethynyl-pyridin-2,6-diamine (45.2 mg, 0.339 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (185 μL, 1.33 mmol). This reaction mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (73 mg, 36%).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][C@@H:8]([C:27]1[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[N:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[NH:18][C:19]2[NH:20][CH2:21][CH2:22][CH2:23][N:24]=2)[C:10]1=[O:26])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:34][O:33][C:30]1[N:29]=[CH:28][C:27]([C@@H:8]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[NH:18][C:19]3[NH:20][CH2:21][CH2:22][CH2:23][N:24]=3)[C:10]2=[O:26])[CH2:7][C:6]([OH:35])=[O:5])=[CH:32][CH:31]=1
Reactant: COc1ccc([C@H](CC(=O)OC(C)(C)C)N2CCN(CCCC(=O)NC3=NCCCN3)C2=O)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc([C@H](CC(=O)O)N2CCN(CCCC(=O)NC3=NCCCN3)C2=O)cn1

Procedure:
A solution of the ester 1-9(110 mg) in dichloromethane (10 mL) and trifluoroacetic acid (10 mL) were stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, dissolved in water, frozen and lyophilized to give 1-10as a powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH2:17][CH2:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[N:23][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1>[Ni].CO>[NH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:10]([CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])[CH:22]=[N:23][CH:24]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(C#N)ccc2NC(=O)OC(C)(C)C)c1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(CN)ccc2NC(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Into a pressure bottle were added tert-butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-cyanophenyl}ethyl)pyridin-3-yl]carbamate (0.80 g, 1.8 mmol), tetrahydrofuran (3 mL), methanol (10 mL), and Raney nickel (0.30 g, 5 mmol). The reaction mixture was hydrogenated at 45 psi for 2 hours. After filtration to remove the catalyst, the mixture was concentrated under vacuum to give the desired product as an off-white powder (0.30 g, 99%). LCMS for C24H35N4O4 (M+H)+: m/z=443.2.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19](=[O:21])[CH3:20])[CH2:14][CH2:13]1>[OH-].[Na+]>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[CH:20][C:19](=[O:21])[CH2:18][N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)=[CH:5][C:4]=2[O:9]1
Reactant: CC(=O)CN1CCOCC1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Product: O=C(C=Cc1ccc2c(c1)OCO2)CN1CCOCC1
Reaction time: 4 h

Procedure:
15 g of piperonal (0.1 mole), and 14.3 g of 3-morpholinoacetone (0.1 mole) are mixed in an aqueous-alcoholic sodium hydroxide solution (300 cm3 of 10% NaOH and 30 cm3 of ethanol). The mixture is stirred for 4 hours and the product obtained is then filtered. The product is rinsed with water and recrystallised from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16](=S)[CH2:17][C:18](=O)[CH3:19])[C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:12]1)(=[O:10])=[O:9].FC(F)(F)C(O)=O.[S:33]1[CH2:38][CH2:37][CH:36]([NH:39][NH2:40])[CH2:35][CH2:34]1>>[CH3:25][O:24][C:22]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH2:15][N:14]1[C:16]1[N:39]([CH:36]2[CH2:37][CH2:38][S:33][CH2:34][CH2:35]2)[N:40]=[C:18]([CH3:19])[CH:17]=1)=[O:23]
Reactant: NNC1CCSCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1C1CCSCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 253c) was reacted with (tetrahydro-2H-thiopyran-4-yl)hydrazine 2,2,2-trifluoroacetate (CAS Reg. No. 693287-87-5) to give the title compound as yellow foam. MS (ESI): m/z=484.1 [M+H]+.
Reaction SMILES: [IH:1].[O:2]=[C:3]1[N:8]([CH2:9][C:10]#[CH:11])[N:7]=[N:6][C:5]2=[C:12]([C:15](SC)=[NH:16])[N:13]=[CH:14][N:4]12.Cl.[NH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>>[IH:1].[O:2]=[C:3]1[N:8]([CH2:9][C:10]#[CH:11])[N:7]=[N:6][C:5]2=[C:12]([C:15](=[NH:16])[NH:20][CH2:21][C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:13]=[CH:14][N:4]12
Reactant: C#CCn1nnc2c(C(=N)SC)ncn2c1=O
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Agent: I
Product: C#CCn1nnc2c(C(=N)NCC(=O)c3ccccc3)ncn2c1=O
Yield: 29 %

Procedure:
Using the general procedure, the title compound was synthesized from methyl 4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbimidothioate hydroiodide and aminoacetophenone hydrochloride, using a reaction time of 5 hours and 30 minutes for the amidine formation. Yield 29%. δH (DMSO-d6): 9.74 (2H, m), 9.54 (1H, bs), 9.25 (1H, s), 8.07-8.05 (2H, m), 7.78-7.73 (1H, m), 7.65-7.61 (2H, m), 5.27-5.24 (4H, m), 3.62 (1H, t, J=2.5).