Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[BH4-].[Na+].Cl.[OH-].[Na+]>C(O)C.CO.CCOC(C)=O.O>[C:2]1([CH:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)[OH:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)C1CCN(CCCc2ccccc2)CC1
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: OC(c1ccccc1)C1CCN(CCCc2ccccc2)CC1
Reaction time: 72 h

Procedure:
To a stirred solution of phenyl[1-(3-phenylpropyl)-4-piperidinyl]-methanone hydrochloride (6.8 g, 0.02 mol) in absolute ethanol (120 ml) was added sodium methoxide (1.08 g, 0.04 mol) followed by sodium borohydride (1.51 g, 0.04 mol). The reaction mixture was stirred for 72 h and then concentrated at reduced pressure to a solid residue. This material was stirred with aqueous 10% NaOH for 1 h and then extracted with toluene (2×50 ml). The extracts were washed with water and then saturated NaCl solution. The toluene solution was dried over MgSO4, filtered and concentrated to a colorless oil. This material was dissolved in dry Et2O (50 ml) and treated with a solution of HCl (0.02 mol) in CH3OH/EtOAc (1:4, 12.5 ml). The resultant precipitate was dissolved in water, basified using 10% aqueous NaOH and extracted into toluene. The toluene solution was washed with saturated aqueous NaCl dried over MgSO4, filtered and concentrated to a solid. This material was flash chromatographed on a 2.5×6.0 inch silica gel column, and eluted with CH3OH/CH2Cl2 (1:9). The resultant fractions (7-9) eventually solidified and were recrystallized from acetone to give alpha-phenyl-1-(3-phenylpropyl)-4-piperidinemethanol, mp 87°-88° C.
Reaction SMILES: C(O)(=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+].Br[C:15]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][C:24]2=[O:29]>CC(N(C)C)=O.C([O-])(=O)C(C)(C)C.[Pd+2].C([O-])(=O)C(C)(C)C.FC1C=CC(P(C2C=CC(F)=CC=2)C2C=CC(F)=CC=2)=CC=1>[Cl:34][C:31]1[CH:32]=[CH:33][C:15]2[C:28]3[C:19](=[C:20]4[CH2:21][CH2:22][CH2:23][C:24](=[O:29])[C:25]4=[CH:26][CH:27]=3)[O:18][CH2:17][C:16]=2[CH:30]=1
Reactant: O=C1CCCc2c(OCc3cc(Cl)ccc3Br)cccc21
Agent: [Pd+2]
Agent: CC(C)(C)C(=O)O
Agent: CC(C)(C)C(=O)[O-]
Solvent: CC(=O)N(C)C
Product: O=C1CCCc2c1ccc1c2OCc2cc(Cl)ccc2-1
Temperature: 60 °C
Reaction time: 24 h
Yield: 97.4 %

Procedure:
To a flask containing palladium(II) pivalate (68 mg, 0.22 mmol), tri(4-fluorophenyl)phosphine (70 mg, 0.22 mmol), pivalic acid (135 mg, 1.3 mmol) and potassium carbonate (1.83 g, 13.1 mmol) was added a solution of 5-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (1.61 g, 4.4 mmol) in dimethyacetamide (23 mL). The flask was evacuated and backfilled with argon 5 times and then stirred under argon at 60° C. for 24 hours. The reaction was poured directly onto a silica gcl column and purified by flash column chromatography (hexanes/DCM) to yield 8-chloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-1-one (1.22 g, 97% yield) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]([C:21]3[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=3)=[O:20])[CH:15]=[CH:16][CH:17]=1)[N:5]=2.[C:28](Cl)(=[O:30])[CH3:29]>CN(C)C(=O)C>[C:28]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]([C:21]3[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=3)=[O:20])[CH:15]=[CH:16][CH:17]=1)[N:5]=2)(=[O:30])[CH3:29]
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4n3)c2)n(C)n1
Reactant: CC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cc(C)nn4C)c3)nc2s1
Yield: 56.6 %

Procedure:
In the same manner as in Example 28-2 and using N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (199 mg, 0.523 mmol), N,N-dimethylacetamide (2 mL) and acetyl chloride (89.2 μL, 1.26 mmol) as starting materials, the title compound (125 mg, 57%) was obtained as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15](CC2CC2)[C:16]2[S:20][C:19]([CH3:21])=[N:18][C:17]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]1(OC)[CH:32]=[CH:31][CH:30]=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH:32]1([CH2:27][N:14]([CH2:15][C:16]2[S:20][C:19]([CH3:21])=[N:18][C:17]=2[CH3:22])[CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:30][CH2:31]1
Reactant: COc1ccccc1
Reactant: Cc1nc(C)c(C(CC2CC2)NC2CCN(C(=O)OC(C)(C)C)CC2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C)c(CN(CC2CC2)C2CCNCC2)s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
4-{[Cyclopropylmethyl-(2,4-dimethyl-thiazol-5-ylmethyl)]-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.96 g, 5.18 mmol) is added to a stirred solution of dichloromethane (5 ml) and anisole (9.0 ml, 82.8 mmol). The reaction is cooled to 0° C. Trifluoroacetic acid (6.0 ml, 72.9 mmol) is then added. The reaction is stirred for 20 minutes at 0° C. and then for 5 h at room temperature. The reaction is loaded onto a pre-washed SCX-2 (10 g) column and washed with methanol (200 ml). The product is then eluted off with 2M ammonia in methanol (100 ml) and concentrated on a rotary evaporator to yield (1.25 g, 87%) of N-(cyclopropylmethyl)-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]piperidin-4-amine: mass spectrum (ion spray): m/z=280.2 (M+1); 1H NMR (CDCl3): δ=3.75 (2H, s), 3.19-3.11 (2H, m), 2.81-2.73 (1H, m), 2.65-2.52 (5H, m), 2.42 (2H, d), 2.32 (3H, s), 1.76 (3H, brd), 1.50-1.38 (2H, m), 0.89-0.80 (1H, m), 0.52-0.44 (2H, m), 0.11-0.05 (2H, m).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@H:49]([C:54](O)=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:14]=1)[C:54](=[O:55])[C@H:49]([CH2:50][CH:51]([CH3:52])[CH3:53])[NH:48][C:46]([O:45][CH2:44][CH:42]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:43]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:47])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)[C@H](CC(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)ccn2)cc(OC)c1OC

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amine (1.40 g) and N-(9-fluorenylmethoxycarbonyl)-L-leucine (1.16 g) were treated in the same manner as in Preparation Example 9 to obtain the title compound.
Reaction SMILES: ClC(OCC)=O.[CH3:7][C:8]1[NH:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH:9]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=1.[OH-].[Na+]>C(O)C.C(N(CC)CC)C.O1CCCC1>[CH3:7][C:8]1[NH:12][N:11]=[C:10]([C:13]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)=[O:15])[CH:9]=1
Reactant: CCOC(=O)CCc1ccc(CCN)cc1
Reactant: Cc1cc(C(=O)O)n[nH]1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCc2ccc(CCC(=O)O)cc2)n[nH]1
Reaction time: 0.25 h
Yield: 22 %

Procedure:
1.27 ml. triethylamine and 0.85 ml. ethyl chloroformate are added at -10° C. to a solution of 1.12 g. of 5-methylpyrazole-3-carboxylic acid in 25 ml. anhydrous tetrahydrofuran. After 15 minutes, a further 1.27 ml. triethylamine is added and then 2.57 g. ethyl β-[4-(2-aminoethyl)-phenyl]-propionate hydrochloride. The reaction mixture is stirred for 1 hour at +20° C., filtered with suction and the filtrate is evaporated and the residue taken up in methylene chloride. After extraction with 2N hydrochloric acid, 2N aqueous sodium hydroxide solution and neutralization, the solution is dried and evaporated. The crude ester thus obtained is heated under reflux for 1 hour with 0.6 g. sodium hydroxide in 30 ml. ethanol. After cooling, the precipitated sodium salt is filtered off with suction, dissolved in water and carefully acidified. The precipitate obtained is filtered off and recrystallized from 20% ethanol. There is obtained β-{4-[2-(5-methylpyrazole- 3-carboxamido)-ethyl]-phenyl}-propionic acid in a yield of 22% of theory; m.p. 202°-205° C.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[CH2:25]([Sn](CCCC)(CCCC)C=C)[CH2:26]CC>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.O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:8]2[C:7]3[C:2]([CH:25]=[CH2:26])=[CH:3][C:4]([N+:22]([O-:24])=[O:23])=[CH:5][C:6]=3[O:11][C:10]([CH3:13])([CH3:12])[C:9]2=[O:14])=[CH:16][CH:17]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)Oc2cc([N+](=O)[O-])cc(Br)c2N(c2ccc(F)cc2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cc([N+](=O)[O-])cc2c1N(c1ccc(F)cc1)C(=O)C(C)(C)O2

Procedure:
A mixture of 5-bromo-4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 53(6); 100 mg), tributyl(vinyl)tin (78 μL) and tetrakis(triphenylphosphine)palladium(0) (59 mg) and dioxane was refluxed under argon atmosphere for 6 hours. After cooling, the reaction mixture was concentrated in vacuo, and the resultant residue was diluted with acetonitrile and n-hexane. The n-hexane layer was removed from the mixture, and the acetonitrile layer was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=8/1→4/1) and filtered through NH-silica gel. The filtrate was concentrated in vacuo to give 4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-5-vinyl-2H-1,4-benzoxazin-3(4H)-one (40 mg) as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)O)[C:10]([CH3:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1>>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([CH3:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: Cc1nn(Cc2ccccc2)cc1C(O)C1CCCCC1
Product: Cc1nn(Cc2ccccc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 2.3 %

Procedure:
Using (1-benzyl-3-methyl-1H-pyrazol-4-yl)(cyclohexyl)methanol (1.0 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.62 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (28.6 mg, 4%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([O:32]C)=[O:31])[CH:24]=3)[NH:19]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[C:27]([CH3:28])([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=3)[NH:19]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1ccc(F)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1NS(=O)(=O)c1ccc(F)cc1
Yield: 75.4 %

Procedure:
A mixture of methyl 2-(2-(4-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (66 mg, 0.14 mmol, 1.0 eq.) and 1.4 mL aqueous solution of sodium hydroxide (2 M, 2.8 mmol, 20 eq.) in tetrahydrofuran (4 mL) was stirred at reflux for 3 h. Thin layer chromatography indicated that the starting material was consumed completely. The tetrahydrofuran was removed under reduced pressure and the residue was acidified to pH 5-6 with 1 M hydrochloric acid. Then a lot of white precipitates were formed and collected by filtration to afford 48 mg of 2-(2-(4-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid; yield: 76%. MS (ESI+APCI) M+1=455.
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:11][CH:10]=[C:9]([CH3:30])[N:8]=1)([OH:3])=[O:2].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[CH:11][CH:10]=[C:9]([CH3:30])[N+:8]=1[O-:39])([OH:3])=[O:2]
Reactant: COc1ccc(CCCCCCCCOc2ccc(C)nc2/C=C/CC(=O)O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(CCCCCCCCOc2ccc(C)[n+]([O-])c2/C=C/CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
2-(E-2-Carboxymethyl-ethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridine (17.1 g, 41.5 mmol) was dissolved in dry CH2Cl2 (105 mL) and cooled to 0° C.; 50% m-chlorperbenzoic acid (15.8 g, 45.8 mmol) was added in three portions over 10 minutes. The cooling bath was removed and the reaction was stirred for 15 hours at room temperature. The reaction was poured into aqueous NaHCO3 and the product extracted into CH2Cl2. The organic extract was washed with H2O and brine and dried (MgSO4). The crude product was obtained as a yellow solid and was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([O-:16])=[O:15].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]=1[OH:13])([O-:16])=[O:15]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2ccccc2)c1O
Reaction time: 24 h
Yield: 23.8 %

Procedure:
2-phenylphenol (3.00 g, 17.6 mmol) was dissolved in methylene chloride(40 ml) followed by the addition of sodium nitrate (1.65 g, 19.4 mmol). The addition of sulfuric acid (25 ml/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hrs, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(900 mg, 24%). 1H NMR (CD3COCD3): δ 8.19 (d, 1H), 7.79 (d, 1H), 7.64 (d, 2H), 7.50 (t, 2H), 7.45 (t, 1H), 7.22 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:33]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[N:14]=3)=[CH:11][N:10]([CH3:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: CO
Product: CN1CCN(c2ccc(Nc3nccc(-c4cn(C)nc4-c4ccc(Cl)cc4)n3)cc2)CC1

Procedure:
The title compound is prepared as described in Example 55 starting from {4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (Example 1) and using methanol instead.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=O)C=CC=CC=1.[N+:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([O-])=[O:20].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:23]([C:22]1[CH:9]=[C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:20][N:19]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCC[N+](=O)[O-]
Reactant: C#CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCc1cc(Cc2ccccc2)on1
Reaction time: 1 h

Procedure:
To a room temperature, stirred solution of 3-phenyl-1-propyne (54.86 g, 0.4723 mol) and phenyl isocyanate (104 mL, 0.957 mol) in benzene (800 mL) under nitrogen was added dropwise over 30 minutes a solution of 1-nitrotridecane (109.14 g, 0.47583 mol) and triethylamine (6.7 mL, 0.048 mol) in benzene (400 mL), and the mixture was stirred for 1 hour. The mixture was refluxed for 6 hours, allowed to cool, and chilled. The solids were filtered off and the filtrate rotoevaporated to an oil. The oil was chromatographed on silica gel (1.4 kg, 230-400 mesh) using petroleum ether-ether (25:1, 15×1 L), and product fractions rotoevaporated to give an off-white solid; yield 96.1 g (62%), mp 45°-47° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.C([Li])(C)(C)C.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>>[CH3:12][C:7]1([CH3:13])[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:23]([OH:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[C:20]([F:19])([F:29])[F:30])[CH:3]=2)[O:8]1
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [Li]C(C)(C)C
Product: CC1(C)C=Cc2cc(C(O)c3ccccc3C(F)(F)F)ccc2O1

Procedure:
6-Bromo-2,2-dimethyl-2H-chromene is metallated at -78° C. using 2 equivalents of tert.-butyllithium and subsequently reacted with 2-trifluoromethylbenzaldehyde to give 2,2-dimethyl-6-(2-trifluoromethyl-hydroxybenzyl)-2H-chromene which is produced as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[NH:9][C:10]=1[CH2:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=O)C.C([O:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([NH2:45])[CH:40]=1)C1C=CC=CC=1>>[C:13]12([CH2:12][CH2:11][C:10]3[NH:9][C:8]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])=[N:7][C:6]=3[C:4]([NH:45][C:41]3[CH:40]=[C:39]([CH:44]=[CH:43][CH:42]=3)[C:38]([OH:37])=[O:46])=[O:3])[CH2:14][CH:15]3[CH2:16][CH:17]([CH2:18][CH:19]([CH2:21]3)[CH2:20]1)[CH2:22]2
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Reactant: CCOC(=O)c1nc(-c2ccccc2F)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Product: O=C(O)c1cccc(NC(=O)c2nc(-c3ccccc3F)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-Adamantan-1-yl-2,3-dioxo-pentanoic acid ethyl ester monohydrate (Example 44) was reacted with 2-fluorobenzaldehyde according to the procedure of Example 20, step b to produce 5-(2-adamantan-1-yl-ethyl)-2-(2-fluoro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester. The ester was hydrolyzed according to the procedure of Example 20, step c and the resulting 5-(2-adamantan-1-yl-ethyl)-2-(2-fluoro-phenyl)-1H-imidazole-4-carboxylic acid was reacted with 3-amino-benzoic acid benzyl ester using essentially the same procedure as in Example 20, step d. Deprotection was carried out according to the procedure of Example 20, step e to afford the title compound as a colourless foam.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([F:17])=[C:9]([CH:16]=1)[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14].[H-].[Na+].[CH3:22][O:23][CH2:24]Br.O>CN(C)C=O>[CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([F:17])=[C:9]([CH:16]=1)[CH2:10][N:11]([CH2:22][O:23][CH3:24])[C:12](=[O:15])[O:13][CH3:14]
Reactant: COC(=O)NCc1cc(C#CC(C)(C)C)ccc1F
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCN(Cc1cc(C#CC(C)(C)C)ccc1F)C(=O)OC
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
0.20 g of methyl N-[5-(3,3-dimethyl-1-butynyl)-2-fluorobenzyl]carbamate was dissolved in N,N-dimethylformamide (5 ml). To this solution, 0.10 g of sodium hydride (60 wt %) was added at room temperature, followed by stirring for 30 minutes. Then, 0.14 g of bromomethyl methyl ether was added at room temperature, followed by stirring for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.13 g of methyl N-[5-(3,3-dimethyl-1-butynyl)-2-fluorobenzyl]-N-methoxymethylcarbamate as a colorless viscous liquid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[C:12]1(=[O:29])[N:16]([CH:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[C:15](=[O:24])[C:14]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:13]12>C(O)C>[C:15]1(=[O:24])[N:16]([CH:17]2[CH2:18][C:19]3[C:8]4[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:9]=4)[NH:10][C:20]=3[CH2:21][CH2:22]2)[C:12](=[O:29])[C:13]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:14]12
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)CC3
Yield: 93.5 %

Procedure:
Reaction of 4-methoxyphenyl hydrazine hydrochloride (0.87 g, 5.0 mmol) with 4-phthalimido-cyclohexanone (1.22 g, 5.0 mmol) in ethanol (20 ml) heated under reflux for 2 hr, followed by cooling and removal of the precipitated solid by filtration gave 3-phthalimido-6-methoxy-1,2,3,4-tetrahydrocarbazole (1.62 g).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:6]([C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(N)nc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
To a solution of 3-trimethylsilanylethynyl-pyridin-2,6-diamine (7.0 g, 34.1 mmoL) described in Manufacturing Example 13-1-2 in tetrahydrofuran (100 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 17 mL, 17 mmol) on an ice bath, which was stirred for 10 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate 3 times. The extract was dried over sodium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (3.35 g, 73.8%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[O:45])[CH2:13][N:14]([C:23](=[O:44])[C@@H:24]([CH2:33][CH2:34][CH2:35][NH:36]C(OC(C)(C)C)=O)[NH:25]C(OC(C)(C)C)=O)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[O:45])[CH2:13][N:14]([C:23](=[O:44])[C@@H:24]([CH2:33][CH2:34][CH2:35][NH2:36])[NH2:25])[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCc1ccccc1)CC(=O)Nc1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Product: NCCC[C@@H](N)C(=O)N(CCc1ccccc1)CC(=O)Nc1ccc2ccccc2c1

Procedure:
A solution of Nα,Nδ-bis-Boc-D-ornithyl-N-(phenethyl)glycine 2-naphthylamide (100 mg) and trifluoroacetic acid (10 mL) was maintained at 25° C. for 1 hr, and then concentrated in vacuo. The residue was chromatographed on a reverse-phase column (Amberchrome) with elution with acetonitrile/0.1% aqueous trifluoroacetic acid. The appropriate fractions were lyophilized to afford the titled compound (45 mg):