Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].Br[CH2:24][C:25]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)=[O:26]>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH:20]4[CH2:22][CH2:21]4)[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)[S:6][C:24]=1[C:25]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)=[O:26]
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Reactant: N#CN
Reactant: S=C=Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Product: Nc1nc(Nc2ccc(N3CCN(CC4CC4)CC3)cc2)sc1C(=O)c1ccc2c(c1)OCCO2

Procedure:
This compound was prepared from cyanamide, 1-(4-isothiocyanato-phenyl)-4-cyclopropylmethylpiperazine (of Example 14G) and 2-bromo-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)ethanone (Maybridge Chemical Company Ltd.) following the procedure used in Example 24. Mass spectrum (ES) MH+=492.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:12])([O-:11])[O-:10])=[C:5]([CH2:13]CBr)[C:4]=1CC)C.Cl[C:19]1C=CC=C[C:20]=1Cl>>[CH2:19]([O:10][P:9]1(=[O:12])[C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=2[CH2:13][O:11]1)[CH3:20]
Reactant: Clc1ccccc1Cl
Reactant: CCc1ccc(P(=O)([O-])[O-])c(CCBr)c1CC
Product: CCOP1(=O)OCc2ccccc21
Yield: 75 %

Procedure:
A mixture of diethyl-2-bromoethylphenylphosphonate (2.2 g, 0.00717 mol) in 25 ml. of 1,2-dichlorobenzene was refluxed for 10 hours. The resulting mixture was vacuum distilled. Fractions containing the benzoxaphosphole were collected and then taken up in a hot mixture of benzene-petroleum ether. The mixture was cooled while adding sufficient benzene to prevent oiling out. The cooled mixture yielded 1-ethoxy-1,3-dihydro-2,1-benzoxaphosphole-1-oxide (1.06 g, 75% yield) as colorless crystals having a melting point of 60° C. and the following analysis:
Reaction SMILES: [ClH:1].[NH:2]1[C:10]23[CH2:11][CH2:12][CH2:13][CH2:14][C:5]2([CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=23)[CH2:4][CH2:3]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:1].[C:20]1([CH2:19][N:2]2[C:10]34[CH2:11][CH2:12][CH2:13][CH2:14][C:5]3([CH2:6][CH2:7][C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=34)[CH2:4][CH2:3]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: c1ccc2c(c1)CCC13CCCCC21NCC3
Agent: Cl
Product: c1ccc(CN2CCC34CCCCC23c2ccccc2CC4)cc1
Yield: 42 %

Procedure:
In a manner similar to that described in Example 32, the product from Example 23 (0.34 g, 1.50 mmol) and benzaldehyde are reacted. Workup, followed crystallization from ether and HCl gave the title compound (0 22 g, 42%) as a white solid mp 235-237° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[C@@H:32]([CH3:35])[CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>>[CH3:34][N:33]1[C:26]2[N:27]([C:28](=[O:30])[N:29]=[C:24]([O:22][CH2:21][C:19]3[CH:18]=[CH:17][C:3]([O:4][C:5]4[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:14])[F:15])[CH:6]=4)=[C:2]([F:1])[CH:20]=3)[CH:25]=2)[CH2:31][C@@H:32]1[CH3:35]
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2F)cc1C(F)(F)F
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(C#N)c(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 4-(2-fluoro-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][N:10]=[CH:9][C:8]=2[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[C:12]2[S:11][N:10]=[CH:9][C:8]=2[C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c2cnsc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c2cnsc12
Yield: 68.5 %

Procedure:
200 g of 7-nitro-4-hydroxy-1,2-benzisothiazole, 260 g of benzyl bromide and 210 g of potassium carbonate in 2.5 l of acetone are refluxed for 12 hours. The entire mixture is then concentrated to one liter under reduced pressure, the residue is poured into a threefold amount of water and the batch is repeatedly extracted with methylene chloride. The combined organic phases are dried over magnesium sulfate and freed from solvent under reduced pressure. The crude product is recrystallized from a mixture of methanol and tetrahydrofuran. 200 g (70% of theory) of 7-nitro-4-benzyloxy-1,2-benzisothiazole of melting point 158°-160° C. are obtained.
Reaction SMILES: [H][H].[C:3](#[N:12])[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1>[Ni]>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([CH2:3][NH2:12])=[CH:5][CH:6]=1)#[N:9]
Reactant: [H][H]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Ni]
Product: N#Cc1ccc(CN)cc1

Procedure:
20 kg of p-cyanobenzylamine crude product (p-cyanobenzylamine 92% by weight, p-xylylenediamine 8% by weight) obtained by hydrogen reduction of terephthalonitrile in the presence of sponge metal nickel catalyst was mixed with 90 kg of water while stirring at 40° C. or less and the mixture was stirred for 3 hours. The crystals which precipitated were separated by centrifugation while washing with water to obtain 20 kg of p-cyanobenzylamine hydrate (water content: 22% by weight). 20 kg of the p-cyanobenzylamine hydrate, 17.6 kg of hexamethylenetetramine, and 83 kg of acetic acid were mixed and the internal temperature was elevated to 80° C. while stirring. An aqueous sulfuric acid solution of 12.6 kg of 98% by weight sulfuric acid and 9.3kg of water was added dropwise thereto over 20 minutes. Further, the reaction mixture was stirred at 100° C. for 1 hour. After the internal temperature was decreased to 50° C., 12.6 kg of 98% by weight sulfuric acid was added. The reaction mixture was concentrated under reduced pressure to recover 75 kg of acetic acid solution. Totheresidue inthereaction vesselwas added 60 kg of water and 70 kg of toluene and stirred vigorously and thereafter left to stand. After removing the water layer, 20 kg of water was added, followed by vigorous stirring and left to stand to remove water (this operation being performed twice). The toluene was concentrated under reduced pressure to recover 48 kg of toluene. After reverting to atmospheric pressure, 54 kg of water was added and the mixture was concentrated until the distillation temperature reached a constant value (distillation of toluene was completed) to recover 21 kg of toluene and 6 kg of water. The mixture was cooled to room temperature while stirring (the mixture became an aqueous solution from which p-cyanobenzaldehyde had precipitated). 12.0 kg of acetonitrile and 8.0 kg of sodium hydrogen carbonate were mixed therewith and 125 kg of an aqueous 13.5% by weight sodium hypochlorite solution was added dropwise over 2 hours while maintaining the internal temperature of the reaction system at around 40° C. (±5° C.), and the mixture was stirred for additional 1 hour. Then, 2.1 kg of urea was added and stirred for 20 minutes and further 7.5 kg of 98% by weight sulfuric acid and 190 kg of water were added. The precipitated crystals were collected by centrifugation while washing with water, and dried to obtain 16.5 kg (yield: 94%) of p-cyanobenzoic acid. The purity was 99% or more.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[CH2:9][N:8]([C:22](=[O:30])[NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])[CH3:32]>>[C:31]([O:34][CH2:35][C:36]([N:12]1[CH2:13][CH2:14][C@@:10]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:8]([C:22](=[O:30])[NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)[CH2:9]2)[CH2:11]1)=[O:37])(=[O:33])[CH3:32]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@]2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Product: CC(=O)OCC(=O)N1CC[C@@]2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 2 and 3, with the exceptions that (S)-t-butyl 5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of t-butyl 5-bromo-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate, and that acetoxyacetyl chloride was used instead of acetyl chloride.
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:20]=[CH:19][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>C(OCC)(=O)C.O>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH2:11][C:10]1[CH:19]=[CH:20][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=1
Reactant: Brc1ccc(COc2ccccn2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(COc2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran solution (120 mL) of 2-(4-bromo-benzyloxy)pyridine (34 g, 128 mmol) described in Manufacturing Example 1-2-1 was added n-butyl lithium (50 mL, 2.6 M, hexane solution, 134 mL) dropwise at −78° C. After stirring for 30 minutes, N,N-dimethylformamide (10 mL, 134 mmol) was added dropwise at −78° C. to the reaction solution, which was stirred at room temperature. Water and ethyl acetate were added to separate the reaction solution. The ethyl acetate layer was washed with water (twice) and saline (once). This was combined with the aqueous layer and extracted with ethyl acetate. The ethyl acetate layer thus obtained was washed with water (twice) and saline (once). The previously obtained ethyl acetate layer and the ethyl acetate layer obtained this time were combined, dried over anhydrous magnesium sulfate, and filtered. This filtrate was concentrated under a reduced pressure, so as to obtain a crude product of the titled compound (26.8 g).
Reaction SMILES: [C:1](=[O:10])([O:6][CH:7]([CH3:9])[CH3:8])[O:2][CH:3](Cl)[CH3:4].[Cl:11][C:12]1[C:13]([F:52])=[C:14]([C@@H:18]2[C@:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:21]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[NH:20][C@H:19]2[C:38]([NH:40][C:41]2[CH:49]=[CH:48][C:44]([C:45]([OH:47])=[O:46])=[CH:43][C:42]=2[O:50][CH3:51])=[O:39])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Cl:11][C:12]1[C:13]([F:52])=[C:14]([C@@H:18]2[C@:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:21]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[NH:20][C@H:19]2[C:38]([NH:40][C:41]2[CH:49]=[CH:48][C:44]([C:45]([O:47][CH:3]([O:2][C:1]([O:6][CH:7]([CH3:9])[CH3:8])=[O:10])[CH3:4])=[O:46])=[CH:43][C:42]=2[O:50][CH3:51])=[O:39])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)OC(=O)OC(C)Cl
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OC(C)OC(=O)OC(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 73.8 %

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood Products, 1.99 g, 1.5 mL, 13.9 mmol) was reacted with 2-propanol (785 mg, 1 mL, 13.0 mmol) and pyridine (1.27 g, 1.3 mL, 16.1 mmol) in methylene chloride (11 mL) at room temperature for 4 h to give 1-chloroethyl isopropyl carbonate. A portion of 1-chloroethyl isopropyl carbonate (221.6 mg, 1.33 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150.3 mg, 244 μmol) in the presence of cesium carbonate (478 mg, 1.47 mmol) in dimethylformamide (5 mL) overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 1-(isopropoxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (134.4 mg, 73% yield). MS (ES+) m/z calcd. for C37H40Cl2F2N3O7: [(M+H)+]: 746, found: 746
Reaction SMILES: BrC1C2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=O)C=2C(NC)=CC=1.Cl[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[NH:24][C:25](=O)[CH3:26].[C:31](=O)([O-])[O-:32].[K+].[K+]>ClC1C=CC=CC=1Cl.[Cu]>[C:31]1(=[O:32])[C:22]2[C:21]3[C:30]([CH:29]=[CH:28][C:23]=2[N:24]=[CH:25][CH2:26]1)=[CH:7][C:8]1[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:14]=3
Reactant: CC(=O)Nc1cccc(Cl)c1
Reactant: CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: O=C1CC=Nc2ccc3cc4ccccc4cc3c21
Yield: 70 %

Procedure:
A mixture of 1-bromo-4-methylaminoanthraquinone (16 parts) of the following formula: ##STR10## and m-chloroacetoanilide (12.7 parts) of the following formula: ##STR11## was heated at 135°-145° C. for 25 hours in o-dichlorobenzene in the presence of metallic copper (powder, 0.3 part) and potassium carbonate (17.3 parts). After cooling, the resulting precipitate was filtrated, washed with methanol and then water and dried to obtain a cake (13.5 parts, yield 70%) of anthrapyridone compound of the following formula: This compound showed a single red spot when thin-layer-chromatographed and λ max (in N,N-dimethylformamide) of 547 nm and had a melting point of 281°-284° C. (uncorrected).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24].[OH-].[Na+].[NH2:29]O.Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:22][NH:29][C:17](=[O:18])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(F)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)cc1F
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
Cis-methyl 2-(2,4-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (870 mg, 2.36 mmol) was dissolved in MeOH (9 mL) and cooled to −45° C. under nitrogen. Sodium hydroxide (0.693 mL, 2.36 mmol) was added during 10 min and the yellow solution continued to stir at −45° C. for 20 min. Hydroxylamine (50% by weight in water, 0.144 mL, 2.36 mmol) was added during 8 min. The resulting solution was stirred at −45° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (12.13 mL, 72.78 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (397 mg, 49%) was isolated. MS m/z 339 (M+H)+
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:53][C:54]1[CH:66]=[CH:65][CH:64]=[CH:63][C:55]=1[O:56][CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>CN(C=O)C.O>[Cl:53][C:54]1[CH:66]=[CH:65][CH:64]=[CH:63][C:55]=1[O:56][CH:57]1[CH2:62][CH2:61][N:60]([C:18](=[O:20])[CH2:17][NH:16][C:14](=[O:15])[C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:13][CH:12]=2)[CH2:59][CH2:58]1
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1ccc(Nc2ccccc2)nc1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirred solution of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid (0.035 g, 0.00013 mol) in DMF (1 mL) was added DIPEA (0.05 g, 0.00039 mol), HOBt (0.0209 g, 0.00015 mol) and EDCI.HCl (0.029 g, 0.0001549 mol) at ambient temperature. After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.0382 g, 0.00015 mol) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (70% ethyl acetate in hexane) to afford 0.037 g (62%) of N-{2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-6-phenylamino-nicotinamide. LCMS: 465.16 (M+1)+, 96.6%, 1H NMR (DMSO-d6): δ 9.4 (s, 1H), 8.8 (s, 1H), 8.4 (t, 1H), 8.0 (dd, 1H), 7.7 (d, 2H), 7.45 (d, 1H), 7.4 (m, 4H), 7.0 (d, 2H), 6.8 (d, 1H), 4.7 (m, 1H), 4.25 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 1.7 (q, 2H).
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@@H:5]1[OH:11])(C)=[CH2:2].[O:12]=[O+][O-].O=O>C(Cl)Cl.CO>[OH:11][C@H:5]1[CH2:6][C@H:7]([CH3:10])[CH2:8][CH2:9][C@H:4]1[C:1](=[O:12])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=C(C)[C@H]1CC[C@@H](C)C[C@@H]1O
Agent: O=O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)[C@@H]1CC[C@@H](C)C[C@@H]1O
Temperature: 25 °C
Yield: 67 %

Procedure:
To the (1S, 2R, 5R)-2-Isopropenyl-5-methyl-cyclohexanol (2.07 g, 13.42 mmol) in DCM (67 mL) and MeOH (1.6 mL) at −78° C. was bubbled ozone/oxygen gas until the reaction mixture was turned blue and the excess ozone was flushed off with oxygen, Dimethyl sulfide (4.9 mL) was added at the same temperature, slowly warmed up to room temperature, stirred for over night, concentrated, purified on column chromatography using 10-20% EtOAc/hexane to give (1R, 2S, 4R)-1-(2-Hydroxy-4-methyl-cyclohexyl)-ethanone (1.40 g, 67%) as an oil. NMR 1H (CDCl3, 400 MHz): 4.29-4.27 ppm (m, 1H); 2.40-2.35 ppm (m, 1H); 2.19 ppm (s, 3H); 1.91-1.73 ppm (m, 5H); 1.05-0.91 ppm (m, 2H); 0.88 ppm (d, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:27][NH2:28]>C1COCC1.ClCCl>[CH3:27][NH:28][C:24](=[O:25])[C@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17]
Reactant: CN
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
A solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine, acid chloride (3.5 g, 10 mmol) in 50 mL of THF was charged with solution of methylamine (0.62 g, 20 mmol) in 50 mL of dichloromethane, at room temperature. The reaction mixture was stirred for 30 min. The solvents were removed and the residue was dissolved in 100 mL of ethyl acetate. The solution was washed with aqueous solution of 10% potassium carbonate, water, brine, dried over magnesium sulfate and evaporated. Recrystallization of the product from ethyl acetate/hexane mixture afforded 1.67g (46.6%) of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine methylamide, mp 173°-174° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>O1CCCC1>[CH3:1][N:2]([CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:28][C:27]1[CH:30]=[CH:31][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=1
Reactant: CNCc1cccc2ccccc12
Reactant: CC(C)c1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(CN(C)Cc2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
1.71 g (0.01 mole) of N-methyl-1-naphthylmethylamine was dissolved in 30 ml of tetrahydrofuran, and 1.2 g (0.012 mole) of triethylamine was added. With stirring at room temperature, 1.85 g (0.011 mole) of p-isopropylbenzyl chloride was added, and the mixture was reacted at room temperature for 6 hours. The reaction mixture was filtered, and the solvent was removed under reduced pressure. The residue was distributed between ether and a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was collected. The organic layer was washed with water, dried over sodium sulfate and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column and eluted with 4% ethyl acetate/n-hexane. The eluate was concentrated to give 2.82 g (yield 93%) of an oily substance.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][C:8]#[C:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH:22]=[CH:23][C:24]2[C:32]3[C:27](=[CH:28][C:29]([NH:33][C:34]4[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=4[C:36](O)=[O:37])=[CH:30][CH:31]=3)[N:26]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[N:25]=2)[CH:16]=1>O>[C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][C:8]#[C:9][CH2:10][NH:11][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=1[NH:33][C:29]1[CH:28]=[C:27]2[C:32]([C:24]([CH:23]=[CH:22][C:17]3[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[N:18]=3)=[N:25][N:26]2[CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)=[CH:31][CH:30]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC#CCN
Reactant: Cc1cc(C)nc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Solvent: O
Product: Cc1cc(C)nc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)NCC#CCO[Si](C)(C)C(C)(C)C)ccc23)c1

Procedure:
Prepared in a similar manner to that described for Example 33(a) step (v), in U.S. Pat. No. 6,531,491, issued Mar. 11, 2003, herein incorporated by reference in its entirety for all purposes, except using 4-(tert-Butyl-dimethyl-silanyloxy)-but-2-ynylamine and 2-[3-[2-(4,6-Dimethyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid. 1H NMR (DMSO-d6) δ 9.56 (1H, s), 9.01 (1H, t, J=5.7 Hz), 8.06 (1H, d, J=8.7 Hz), 7.81 (1H, d, J=16.4 Hz), 7.66 (1H, d, J=7.5 Hz), 7.41 (4H, m), 7.32 (1H, s), 7.09 (1H, dd, J=1.8, 8.7 Hz), 6.98 (1H, s), 6.89 (1H, t, J=8.0 Hz), 5.79 (1H, dd, J=2.4, 9.2 Hz), 4.28 (2H, s), 4.09 (2H, m), 3.86(1H,m), 3.72 (1H, m), 2.46 (3H, s), 2.42 (1H, m), 2.30 (3H, s), 2.08 (2H, m), 1.74 (1H, m), 1.57 (2H, m), 0.80 (9H, s), 0.03 (6H, s). Anal. Calcd for C38H47N5O3Si. 0.7 H2O: C, 68.89; H, 7.36; N, 10.57. Found: C, 68.99; H, 7.36; N, 10.21.