Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)[C:6]=1[C:7]([O:9]C)=O.[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:25].Cl.C(O)(=O)C>C(OCC)C>[CH3:23][O:22][C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][N:5]2[C:6]3[C:7](=[O:9])[NH:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:1][C:2]=3[CH:3]=[N:4]2)=[CH:15][CH:16]=1)=[O:21]
Reactant: CCOC(=O)C#N
Reactant: COC(=O)c1ccc(OCCn2ncc(N)c2C(=O)OC)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2cnn(CCOc3ccc(C(=O)OC)cc3)c2c(=O)[nH]1
Temperature: 90 °C
Yield: 67.8 %

Procedure:
Methyl 4-amino-1-[2-({4-[(methyloxy)carbonyl]phenyl}oxy)ethyl]-1H-pyrazole-5-carboxylate (2.18 g, 6.83 mmol) and ethyl cyanoformate (811 mg, 8.18 mmol) were added to 1N hydrogen chloride-acetic acid (40 mL), and the mixture was stirred under heating at 90° C. for 4 hr. After the mixture was allowed to cool, diethyl ether was added, and the precipitated crude crystals were collected by filtration, and washed with diethyl ether to give the title compound (1.79 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][CH:14]=[C:13]([C:16](=[N:18][NH:19][C:20]([NH:22][C:23]3[S:27][C:26]([C:28]([O:30]C)=[O:29])=[CH:25][CH:24]=3)=[S:21])[CH3:17])[C:12]=2[OH:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][CH:14]=[C:13]([C:16](=[N:18][NH:19][C:20]([NH:22][C:23]3[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=3)=[S:21])[CH3:17])[C:12]=2[OH:32])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=S)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)s1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
Methyl 5-{[(2-{1-[5-(4-t-butylphenyl)-4-hydroxy-3-thienyl]ethylidene}hydrazino)carbonothioyl]amino}-2-thiophenecarboxylate (85 mg, 0.18 mmol) synthesized in Synthetic Example 98 was dissolved in isopropyl alcohol (1.8 ml), and 0.2 M sodium hydroxide aqueous solution (1.95 ml, 0.39 mmol) was added thereto, following by stirring overnight at room temperature. Then 0.2 M sodium hydroxide aqueous solution (0.96 ml, 0.19 mmol) was added thereto, following by stirring overnight at 45° C. After completion of the stirring, 1 M hydrochloric acid (0.58 ml, 0.58 mmol) was added. The precipitated solid was filtered to obtain 2.7 mg of the desired product as a pale yellow solid (yield 3%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:42]1[CH2:45][CH:44]([O:46][C:47](=[O:68])[C@@:48]([CH2:66][OH:67])([CH3:65])[CH2:49][C@H:50]([NH2:64])[CH2:51][C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)[CH2:43]1>CN(C=O)C>[O:42]1[CH2:45][CH:44]([O:46][C:47](=[O:68])[C@@:48]([CH2:66][OH:67])([CH3:65])[CH2:49][C@H:50]([NH:64][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:51][C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[CH:54][CH:53]=2)[CH2:43]1
Reactant: O=C(O)c1c[nH]nn1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OC1COC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OC1COC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.1 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 μL, 969 μmol) and HATU (92 mg, 242 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid oxetan-3-yl ester (89.5 mg, 242 μmol), predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (17 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H28N4O5, 465.21. found 465.4.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:12])([F:11])[C@@H:4]([CH3:10])[C@H:5]([NH:8]N)[CH2:6][OH:7]>CO.Cl.O=[Pt]=O>[ClH:1].[NH2:8][C@@H:5]([C@H:4]([CH3:10])[C:3]([F:12])([F:11])[F:2])[CH2:6][OH:7]
Reactant: C[C@@H]([C@@H](CO)NN)C(F)(F)F
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: C[C@@H]([C@H](N)CO)C(F)(F)F
Reaction time: 1 h

Procedure:
(2S,3S)-4,4,4-Trifluoro-2-hydrazino-3-methyl-butan-1-ol HCl (130 g, 0.623 mole) was dissolved in 1.4 L MeOH with 60 mL concentrated HCl. The solution was hydrogenated with 10 g PtO2 at 50 psig for 12 hours. The mixture was filtered and the filter washed with 1 L MeOH. The MeOH was removed to dryness under vacuum at 30-40° C. The solid was chased with two portions of 1 L MeOH. The solid was stirred with 0.5 L MeOH for 1 hour and the NH4Cl was removed by filtration. To remove more NH4Cl, the filtrate can be concentrated to 2/3 volume and crystallized NH4Cl removed by filtration. The filtrate was concentrated to dryness and dried at 35° C. at <10 mm Hg. The hydrochloride can be purified by stirring with 20% v/v CH3CN:EtOAc removing a green coloring and removing essentially all the Pt to the 10 ppm level.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14].O>C1C=CC=CC=1>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:13](=[O:14])[CH2:12][Cl:11])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(NC(=O)CCl)n[nH]1
Yield: 71.9 %

Procedure:
28 g (0.2 mole) of 3-amino-5-t-butylpyrazole prepared in Example 1 as dissolved in 200 ml of benzene, and 23 g of monochloroacetyl chloride was added dropwise thereto at 30° to 40° C. while cooling with water. After completion of the dropwise addition, the mixture was further allowed to react under reflux conditions for 5 hours. Thereafter, the resulting product was cooled and stirred whereby crystals were precipitated. The crystals were collected by filtration and washed with water and benzene to obtain 31 g of 5-t-butyl-3-monochloroacetylaminopyrazole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]#[N:35])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:41]>Cl.O1CCOCC1>[ClH:41].[ClH:41].[CH2:36]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:23]([CH:22]=1)[C:34]#[N:35])[CH2:37][CH2:38][CH3:39]
Reactant: ClCCl
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(C#N)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(C#N)c1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-[6-butyl-5-(3-cyano-4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.025 g, 0.046 mmol) in DCM (2.0 mL), 4.0 M HCl in dioxane (2.0 mL) was added and stirring continued for 30 min. Solvent evaporated, resulting solid was washed with ether, dried to get 5-[3-Butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzonitrile dihydrochloride (22 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:16]([O:18][C:19]2[CH:32]=[CH:31][C:22]([CH:23]=[C:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=2)[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1>O1CCOCC1.[Pd]>[CH3:1][C:2]1[C:3]([CH:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:31][CH:32]=2)[CH3:17])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1C(C)Oc1ccc(C=C3SC(=O)NC3=O)cc1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1cc2c(cc1C(C)Oc1ccc(CC3SC(=O)NC3=O)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C

Procedure:
5-(4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphtalen-2-yl)-ethoxy)-benzylidene)-thiazolidine-2,4-dione (200 mg; 0.44 mmol) was first attempted hydrogenated with Pd/C 5% (235 mg) in dioxane (50 ml) at 100° C. for 10 hours. Filtration and extraction of the mixture showed a mixture of starting material and product (185 mg). The mixture was then dissolved in MeOH (25 ml) and magnesium (100 mg) was added. The reaction mixture was stirred over the week end at room temperature and then evaporated. The residue was dissolved in water and ethyl acetate and the pH was adjusted to 7 with 1 N HCl. The mixture was stirred for 5 minutes after which the organic phase was separated. The organic phase was dried and evaporated, and the residue was purified on column chromatography using methylene chloride: methanol (15:1) as eluent to give the title compound in 76 mg (38%) yield. Compound 1.
Reaction SMILES: C(S([C:8]1[N:13]=[C:12]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([C:23]([NH2:25])=[O:24])=[CH:15]2)[CH:11]=[CH:10][N:9]=1)(=O)=O)CCC.[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)=[O:30])[CH3:27]>O1CCOCC1>[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:8]2[N:13]=[C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([C:23](=[O:24])[NH2:25])=[CH:15]3)[CH:11]=[CH:10][N:9]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CCCCS(=O)(=O)c1nccc(-n2cc(C(N)=O)c3ccccc32)n1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(Nc2nccc(-n3cc(C(N)=O)c4ccccc43)n2)CC1
Yield: 83.3 %

Procedure:
1-(2-Butylsulfonyl-pyrimidin-4-yl)-1H-indole-3-carboxylic acid amide (1.5568 g, 4.349 mmol) was dissolved in dry dioxane (150 mL), and 4-amino-cyclohexanecarboxylic acid ethyl ester (1.86 g, 10.87 mmol) was added. The mixture was heated at reflux overnight, then evaporated to dryness, poured into water, extracted into EtOAc, and dried under vacuum. The product was recrystallized from EtOH-free CHCl3 to provide 4-[4-(3-carbamoyl-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (1.477 g, 83% yield) as a white solid (Compound 322).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[O:20]([CH2:27][CH:28]1[NH:33][CH2:32][CH2:31][NH:30][CH2:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:30]4[CH2:31][CH2:32][NH:33][CH:28]([CH2:27][O:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:29]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: c1ccc(OCC2CNCCN2)cc1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(COc4ccccc4)C3)c(F)cc2c1=O

Procedure:
A 0.6 g portion of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.23 g of 3-(phenoxymethyl)piperazine and 5 ml of pyridine were reacted as described in Example 81, giving 235 mg of the desired product, mp 112°-115° C.
Reaction SMILES: [OH:1][C:2]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[C:30]([CH3:38])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=O.Cl(O)(=O)(=O)=O>C(O)(=O)C.[Pd]>[OH:1][C:2]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[C:30]([CH3:38])[C:3]=1[CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)c1c(C)cc(OC)c(OC)c1O
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCCc1c(C)cc(OC)c(OC)c1O

Procedure:
To a solution of methyl 21-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)heneicosanoate in acetic acid is added perchloric acid and catalytic reduction is carried out with 5% palladium-on-carbon. The reaction mixture is worked up as in the corresponding step of Reference Example 2 and the resultant product is recrystallized from ethanol. The above procedure yields methyl 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoate as colorless needles, m.p. 71° C.-72.5° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC[CH2:12][CH2:13][NH2:14])=C.C=O>>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:12]=[CH:13][NH:14]1
Reactant: Oc1ccccc1
Reactant: C=COCCCN
Agent: C=O
Product: C1=Cc2ccccc2ON1
Yield: 76 %

Procedure:
This compound was made according to the method outlined in Example 3, by combining phenol (28 g, 300 mmole), 3-amino-1-propanol vinyl ether (30 g, 300 mmole), and paraformaldehyde (19.5 g, (650 mmole) in a 500 ml flask. The water condensate was removed using toluene as the azeotrope solvent. The product was worked-up to obtain 50 g (76% yield) of a light yellow, low viscosity liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[C:24](=O)[CH:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[S:16][C:21]3[CH2:20][CH2:19][CH2:24][CH:23]([C:26]4[CH:27]=[CH:28][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=4)[C:22]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: O=C1C(Br)CCCC1c1ccc(OC(F)(F)F)cc1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2F)cn1
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccc(OC(F)(F)F)cc3)cc2F)cn1

Procedure:
The title compound was prepared from [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (45 mg, 0.18 mmol) and crude 6-bromo-2-(4-trifluoromethoxy-phenyl)-cyclohexanone (170 mg, ca. 0.5 mmol) using in analogous manner the procedure described in example 1b). Obtained as a light-brown solid (57 mg, 65%). MS ISP (m/e): 489.0 [(M+H)+]. mp 148-151° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19](C(CC(C)(C)C)(C)C)=[CH:18][CH:17]=2)=[O:14])=[C:7]([CH3:30])[C:6]=1[OH:31])([CH3:4])([CH3:3])[CH3:2].C1(O)C=CC=CC=1>>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:14])=[C:7]([CH3:30])[C:6]=1[OH:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(=O)Oc1ccc(C(C)(C)CC(C)(C)C)cc1
Solvent: Oc1ccccc1
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(=O)Oc1ccccc1

Procedure:
p-tert.-Octylphenyl 4-tert.-butyl-2,6-dimethyl-3-hydroxyphenylacetate is made in analogous manner by substituting p-tert.-octylphenol for phenol in the above procedure.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: OCCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCCC(F)(F)F)cc1
Temperature: 100 °C
Yield: 27.3 %

Procedure:
To a solution of a 3,3,3-trifluoro-propan-1-ol (6.22 g) in acetonitrile (200 ml) kept at RT under an argon atmosphere were added 1-fluoro-4-nitro-benzene (10.1 g) and Cs2CO3 (28.7 g) and the mixture was heated to 100° C. for 18 h. The reaction mixture was cooled to RT and partitioned between AcOEt and ice water. The layers were separated, dried, over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (silica gel; eluent: AcOEt/heptane:gradient 3 to 5%) to afford 1-nitro-4-(3,3,3-trifluoro-propoxy)-benzene as light yellow liquid (3.5 g). MS (EI, m/e): 235.0 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=3)[CH2:36][CH2:35]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: COc1cc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1cc2ccccc2cc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 78.5 %

Procedure:
Phenyl N-(2-methoxynaphth-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 86 to obtain the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:40]=[CH:39][C:30]([CH2:31][N:32]2[CH2:36][CH:35]([CH3:37])[NH:34][C:33]2=[O:38])=[CH:29][CH:28]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH:35]([CH3:37])[CH2:36][N:32]([CH2:31][C:30]5[CH:39]=[CH:40][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:33]4=[O:38])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: COc1ccc(CN2CC(C)NC2=O)cc1
Product: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(C)c3)C2=O)cc1
Yield: 42.7 %

Procedure:
Using (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (155 mg) described in Preparation Example 118 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (132 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 1, 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (90 mg) was obtained. Using the obtained 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 421, the title compound (53 mg) was obtained.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[O:9][CH:10]=[C:11]([OH:15])[C:12](=[O:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>CN(C=O)C>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:15][C:11]1[C:12](=[O:14])[CH:13]=[C:8]([C:7]([CH3:17])([CH3:16])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][CH:10]=1
Reactant: BrCCCCCBr
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(=O)c(O)co1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(=O)c(OCCCCCBr)co1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
2-(tert-Butyl-dimethyl-silanyloxymethyl)-5-hydroxy-4H-pyran-4-one 6 (1.50 g, 5.85 mmol) was charged in a 100 mL round-bottomed flask equipped with a magnetic stirrer and under inert atmosphere. Anhydrous DMF (25 mL) and Cs2CO3 (2.10 g, 6.44 mmol) were successively added. After 5 min, 1,5-dibromopentane (2.39 mL, 17.55 mmol) was added via syringe at room temperature. The reaction mixture Novas heated at 50° C. for 3 h. After cooling and filtration DMF was removed in vacuo. The crude oil was purified by chromatography on silica using as eluent EtOAc:cyclohexane=20:80 then 30:70. After evaporation, 5-5-bromo-pentyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-4H-pyran-4-one 7 was obtained (1.25 g, 53% yield) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[CH:5][CH:4]=1>N>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:9][C:10]3[C:11](=[CH:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:12](=[O:14])[C:7]=2[CH:8]=1
Reactant: CSc1ccc(Sc2cc(F)ccc2C(=O)O)cc1
Agent: N
Product: CSc1ccc2sc3cc(F)ccc3c(=O)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
375 Grams of 2-(p-methylthiophenylthio)-4-fluoro-benzoic acid (Collec.Czech.Chem.Commun. 40, pg. 3523 (1975)) were heated with 2.7 kilograms of polyphosphoric acid while stirring for 3 hours at 140 degrees Centigrade. The mixture was cooled to 110 degrees Centigrade and poured into ice-water. The precipitate was sucked off, suspended in aqueous ammonia and sucked off again. After recrystallization from pyridine 200 grams of 2-methylthio-6-fluoro-9-thioxanthone was obtained as a yellow crystalline substance which melted at 135-138 degrees Centigrade.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([C@H:7]2[CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
4-Phenylcyclohexanone (4 g) is dissolved under argon in MeOH (25 mL), cooled to 0° C. and treated portionwise with NaBH4 (900 mg). The mixture is stirred for 12 hours while warming to room temperature. The mixture is concentrated and then treated dropwise with water (10 mL). Then concentrated hydrochloric acid (8 mL) is added dropwise. The mixture is extracted with ethylacetate and the organic phase is washed with brine and dried (Na2SO4). The solvents are evaporated and the residue is crystallized from cyclohexane to give the title compound. TLC: rf=0.52 (silicagel, dichloromethane/ethanol 19:1).
Reaction SMILES: [OH-:1].[K+].OO.[C:5]([N:9]1[C:13]([NH2:14])=[C:12]([C:15]#[N:16])[C:11]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)([CH3:8])([CH3:7])[CH3:6]>O.C(O)C>[C:5]([N:9]1[C:13]([NH2:14])=[C:12]([C:15]([NH2:16])=[O:1])[C:11]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[N:10]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: [OH-]
Reactant: CC(C)(C)n1nc(CC2CCCCC2)c(C#N)c1N
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)n1nc(CC2CCCCC2)c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 12.2 %

Procedure:
To potassium hydroxide (4.95 g, 0.09 mol) in 50% water/ethanol (83 ml) was added 30% hydrogen peroxide (6.7 ml, 0.06 mol) followed by 1-tert-butyl-3-(cyclohexylmethyl)-5-amino-1H-pyrazole-4-carbonitrile (2.8 g, 0.01 mol). The reaction mixture was stirred at room temperature for 24 hours, then was heated on a steam bath for 4 hours. More 30% hydrogen peroxide was added (6.5 ml, 0.057 mol) and the reaction mixture was heated for an additional 2 hours. The solvent was removed in vacuo, water was added and the residue was extracted with ethyl acetate (2×). The organic layer was washed with brine, dried over anhydrous MgSO4 and the solvent was removed in vacuo. The residue was purified by preparative thin layer chromatography on silica eluting with ethyl acetate (100%) to afford 0.34 g (11%) of 1-tert-butyl-3-(cyclohexylmethyl)-5-amino-1H-pyrazole-4-carboxamide as an amber oil.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:14][C:15]1[CH:19]=[C:18]([C:20](OCC)=[O:21])[N:17]([CH2:25][CH2:26][CH2:27][NH2:28])[N:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH2:7]([O:14][C:15]1[CH:19]=[C:18]2[C:20](=[O:21])[NH:28][CH2:27][CH2:26][CH2:25][N:17]2[N:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)nn1CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1NCCCn2nc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
Na2CO3 (25 g, 235.85 mmol) was added to a solution of ethyl 3-(benzyloxy)-1-[3-amino-propyl]-1H-pyrazole-5-carboxylate (5.5 g, 16.2 mmol) in water (150 mL). The mixture was stirred at room temperature for 18 hours and then extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in petroleum ether 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-(benzyloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one (4 g, 73% yield). C14H15N3O2.