Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:6]([CH2:8][C:9]#[N:10])=O.O.[NH2:17][NH2:18]>C(O)C>[NH2:10][C:9]1[CH:8]=[C:6]([C:5]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:18][N:17]=1
Reactant: NN
Reactant: COc1ccc(C(=O)CC#N)cc1OC
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(N)n[nH]2)cc1OC

Procedure:
3,4-Dimethoxybenzoylacetonitrile (3.6 g) was dissolved in ethanol (20 ml) to which was subsequently added hydrazine monohydrate (0.87 ml) under cooling with ice. The mixture was heated under reflux for 7 hours and allowed to cool. Then, the solvent was distilled away under a reduced pressure. The resultant residue was recrystallized from ethyl acetate to obtain the title compound (2.92 g) as colorless crystals (melting point: 124-125° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[NH2:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[C:20]([Cl:25])[N:19]=1>C1COCC1>[Cl:25][C:20]1[CH:21]=[C:22]([O:14][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[C:10]([F:11])([F:12])[F:13])[N:23]=[C:18]([NH2:17])[N:19]=1
Reactant: OC(c1ccc(F)c(F)c1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OC(c2ccc(F)c(F)c2)C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 6 h
Yield: 87.5 %

Procedure:
1-(3,4-Difluorophenyl)-2,2,2-trifluoroethanol (0.1 g, 0.471 mmol) was treated with NaH (60% in mineral oil, 38 mg, 0.943 mmol) in dry THF (3 ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (77 mg, 0.471 mmol) was added and the mixture was stirred at 50° C. for 6 hours. The mixture was quenched with water and extracted with methylenechloride (2×). The organics were combined, washed with water, then brine, dried over MgSO4, and concentrated to give 0.14 g of 4-chloro-6-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethoxy)-pyrimidin-2-amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Cl[CH2:11][CH:12]1[CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:11][CH:12]1[CH2:14][O:13]1
Reactant: ClCC1CO1
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(OCC2CO2)cc1F
Reaction time: 48 h
Yield: 53.9 %

Procedure:
A mixture of 117.1 g of 3,4-difluorophenol, 185.5 g of chloromethyloxirane, 125 g of potassium carbonate and 500 ml of 2-propanone was stirred for 48 hours at reflux temperature. The reaction mixture was evaporated and the residue was taken up in dichloromethane. The whole was washed successively with water, NaOH (aq.) (2×) and water, and was then dried, filtered and evaporated. The residue was distilled (13.3 Pa, 58° C.), yielding 90.4 g (54.0%) of [(3,4-difluorophenoxy)methyl]oxirane (interm. 2).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH2:6][C:5]1([CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[N+:14]([O-])[C:15]3[C:20]([C:21]=1[N+:22]([O-:24])=[O:23])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:4][CH2:3][CH2:2]2.P(Cl)(Cl)Cl>>[N:1]12[CH2:8][CH2:7][CH2:6][C:5]1([CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[N:14][C:15]3[C:20]([C:21]=1[N+:22]([O-:24])=[O:23])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:4][CH2:3][CH2:2]2
Reactant: O=[N+]([O-])c1c(NCCC23CCCN2CCC3)c[n+]([O-])c2ccccc12
Solvent: ClP(Cl)Cl
Product: O=[N+]([O-])c1c(NCCC23CCCN2CCC3)cnc2ccccc12
Yield: 66.3 %

Procedure:
3-[2-(1-Azabicyclo[3.3.0]octan-5-yl)ethyl]amino- 4-nitroquinoline 1-oxide and phosphorus trichloride were reacted in the same manner as in Example 6 to obtain the titled compound in a yield of 66.3%.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:1]1([N:6]2[C:10]3=[N:11][C:30]([C:29]4[CH:32]=[CH:33][C:26]([O:25][CH2:24][CH2:23][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[CH:27][CH:28]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(OCCN4CCOCC4)cc3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.19 g, 9.86 mmol), 4-[2-(4-morpholinyl)ethoxy]benzaldehyde (3.5 g) and xylenes (10 ml) was heated at 160° C. overnight. p-Toluenesulfonic acid (0.2 g) was added and the mixture was heated at 160° C. overnight. The reaction mixture was cooled to room temperature, and the precipitate which formed was slurried with methanol, collected by filtration and washed with methanol, and then ether. The product was recrystallized from acetonitrile to afford 1-cyclopentyl-3-ethyl-6-[4-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:13][N:12]([C:14]2[O:15][CH2:16][CH:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C>C1(C)C=CC=CC=1.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([O:9][CH:10]1[CH2:13][N:12]([C:14]2[O:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1COC(N2CC(OC(=O)c3ccccc3)C2)=N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1coc(N2CC(OC(=O)c3ccccc3)C2)n1
Yield: 57.8 %

Procedure:
To a solution of 3-benzoyloxy-1-(4-methoxycarbonyl-1,3-oxazolin-2-yl)azetidine (9.12 g, 30.0 mmol) (obtained as described in Reference Example 70(5)) in a mixture of toluene (450 ml) and methylene chloride (180 ml) was added manganese dioxide (63.8 g) and the mixture was heated under reflux for 5 hours. After checking the completion of the reaction, the mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile=1:1 as the eluant to afford 3-benzoyloxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (5.24 g, yield 58%) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[CH2:12][CH2:11]1
Reactant: O=Cc1ccccc1F
Reactant: NC1CC1
Product: Fc1ccccc1CNC1CC1

Procedure:
Synthesized according to typical procedure J from 2-fluorobenzaldehyde and cyclopropylamine.
Reaction SMILES: C[N:2]1[C:11](CCC2C=CC(OCC3OC3)=C(OC)C=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:27][CH3:28])=[CH:7][CH:8]=2)[C:3]1=[O:29].COC1C=CC=CC=1NCC>>[CH3:28][O:27][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][NH:2][C:3]2=[O:29])=[CH:8][CH:7]=1
Reactant: COc1ccc2cc(CCc3ccc(OCC4CO4)c(OC)c3)n(C)c(=O)c2c1
Agent: CCNc1ccccc1OC
Product: COc1ccc2cc[nH]c(=O)c2c1
Yield: 74 %

Procedure:
2-Methyl-3-[3-methoxy-4-(3-(2-o-methoxy-phenyl-ethyl-amino)-2-hydroxy)-propoxy)-phenethyl]-7-methoxy-isoquinolin-1(2H)-one was prepared analogous to Example 2 from 2-methyl-3-[3-methoxy-4-(2,3-epoxypropoxy)-phenethyl]-7-methoxy-isoquinolin-1(2H)-one and 2-methoxyphenyl-ethylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([N:23]1[CH:27]=[C:26]([CH2:28][NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH:25]=[N:24]1)[CH3:22]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([N:29]([CH2:28][C:26]1[CH:25]=[N:24][N:23]([CH2:21][CH3:22])[CH:27]=1)[C:30]1[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[CH:32][CH:31]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCc2c(OCc3ccccc3)cccc21
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 79.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 4-benzyloxyindan-1-carboxylic acid (0.54 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) as starting materials, 4-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)indan-1-carboxamide (0.79 g) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][OH:8].O[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][O:8][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCc1cnccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCc2cnccn2)cc1
Yield: 38.7 %

Procedure:
To a stirred and cooled (≤5° C.) solution of 8.3 parts of 2-pyrazinemethanol, 13.3 parts of ethyl 4-hydroxybenzoate and 20.2 parts of triphenylphosphine in 178 parts of tetrahydrofuran was added dropwise a solution of 13.93 parts of diethyl azodicarboxylate in 45 parts of tetrahydrofuran. Upon completion, the reaction mixture was stirred over weekend. After evaporation, the residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The precipitate was filtered off and the filtrate was evaporated. The residue was crystallized from 2-propanol, yielding 7.5 parts (38.7%) of ethyl 4-(2-pyrazinylmethoxy)benzoate; mp. 76.1° C. (interm. 9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[ClH:34].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(CCN3C=CN=C3)N=2)C=CC=1OC>>[ClH:34].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NN(CCCCCCBr)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Reactant: c1c[nH]cn1
Agent: COc1ccc(C2=NN(CCn3ccnc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(CCCCCCn3ccnc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 117 and imidazole as described for compound 113. Purified by chromatography and crystallized as the hydrochloride from tetrahydrofurane. M.p. 183° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=[C:10]([C:11]#[N:12])[C:3]=12.[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26](B(O)O)[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.O.[Cl-].[Na+].O>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:31][CH3:32])=[C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=[C:10]([C:11]#[N:12])[C:3]=23)[CH:23]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)ccnc21
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)cc1-c1ccnc2c1c(C#N)cn2COCC[Si](C)(C)C
Temperature: 60 °C

Procedure:
A mixture of Example 248A (3.0 g, 9.78 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (2.5 g, 14.6 mmol), phenylallylchloro(1,3-bis(diisopropylphenyl)-2-imidazol-2-yliden)palladium(II) (0.19 g, 0.29 mmol) and potassium phosphate (4.1 g, 19.6 mmol) in tetrahydrofuran (60 mL) and water (18 mL) was purged with nitrogen and heated at 60° C. for 3 hours. The mixture was treated with brine, extracted with ethyl acetate (three times) and the organic layer was dried over sodium sulfate. Filtration, concentration and purification by flash chromatography (Combi Flash Rf) (silica gel, 30% ethyl acetate in hexane) afforded the title compound. MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8]/[C:9](=[CH:19]\[C:15]3[S:14][CH:18]=[CH:17][CH:16]=3)/[C:10](=[O:11])/[C:12](=[CH:19]/[C:15]3[S:14][CH:18]=[CH:17][CH:16]=3)/[O:13][C:4]=2[CH:3]=1
Reactant: O=Cc1cccs1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Product: Cc1ccc2c(c1)O/C(=C\c1cccs1)C(=O)/C(=C/c1cccs1)O2

Procedure:
Calone is reacted with thiophene-2-carbaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-2,4-bis[1-thiophen-2-yl-meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.O[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:24][C:23]2=[O:36]>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[O:26][CH:25]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:24][C:23]3=[O:36])=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C1CC(c2ccccc2)Oc2ccc(O)cc21
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)C(=O)CC(c2ccccc2)O3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 6-hydroxyflavanone and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]2=[C:11]([NH2:13])[CH:12]=1.[C:14](Cl)(=[O:16])[CH3:15].C(OC(C)C)(C)C.C(O)C>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[C:6]2[CH2:7][CH:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Reactant: CC(=O)Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: COc1cc(NC(C)=O)c2c(c1)OC(C)C2

Procedure:
This compound is prepared according to the procedures of example 10 by reacting 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine with acetyl chloride. M.p. 104° C. (from isopropyl ether/ethyl alcohol).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]2[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:8]([CH2:10][CH:11]3C[CH:13](C=O)[CH2:12]3)=[N:9][C:5]=2[CH:4]=1.[CH3:29][C:30]1([CH3:53])[O:34][C@@H:33]2[C@@H:35]([CH2:48][NH:49][CH:50]([CH3:52])[CH3:51])[CH2:36][C@@H:37]([N:38]3[C:42]4[N:43]=[CH:44][N:45]=[C:46]([NH2:47])[C:41]=4[CH:40]=[CH:39]3)[C@@H:32]2[O:31]1.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>ClCCCl.[Cl-].[Na+].O>[CH3:29][C:30]1([CH3:53])[O:34][C@@H:33]2[C@@H:35]([CH2:48][N:49]([CH:50]([CH3:51])[CH3:52])[CH2:13][CH2:12][CH2:11][CH2:10][C:8]3[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:24])[CH3:22])[C:6]4[CH:25]=[CH:26][C:3]([C:2]([F:27])([F:1])[F:28])=[CH:4][C:5]=4[N:9]=3)[CH2:36][C@@H:37]([N:38]3[C:42]4[N:43]=[CH:44][N:45]=[C:46]([NH2:47])[C:41]=4[CH:40]=[CH:39]3)[C@@H:32]2[O:31]1
Reactant: CC(C)NC[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reactant: C[Si](C)(C)CCOCn1c(CC2CC(C=O)C2)nc2cc(C(F)(F)F)ccc21
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: CC(C)N(CCCCc1nc2cc(C(F)(F)F)ccc2n1COCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
A solution of 3-{[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutane-1-carbaldehyde (243 mg, 0.59 mmol), 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-[(propan-2-ylamino)methyl]-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (170 mg, 0.49 mmol) and MgSO4 (710 mg, 5.90 mmol) in DCE (10 ml) was stirred for 15 min. STAB (175 mg, 0.83 mmol) was then added to the reaction mixture and stirred for 1 h at RT. The reaction was monitored by LCMS, no amine was seen after 1 h. Sat. NaHCO3 (20 ml) was added to the reaction mixture and stirred for 5 mins. Brine (10 ml) was then added to the reaction mixture. The product was extracted with DCM (2×30 ml), dried over Na2SO4, filtered and evaporated. Purification by silica gel column chromatography, eluting with 7N NH3 in MeOH:DCM (1:99-4:96) gave the desired product (170 mg, 47%) as an oil; MS (ESI+) for C38H54F3N7O3Si m/z 742.40 [M+H]+; HPLC purity 100% (ret. time, 1.78 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm −0.25-0.11 (9 H, m), 0.66-1.04 (8 H, m), 1.17-1.48 (5 H, m), 1.49-1.61 (3 H, m), 1.77-2.04 (2 H, m), 2.19-2.37 (5 H, m), 2.37-2.51 (2 H, m), 2.52-2.80 (2 H, m), 2.81-2.91 (1 H, m), 2.91-3.22 (2 H, m), 3.34-3.79 (2 H, m), 4.29-4.52 (1 H, m), 4.78-5.12 (2 H, m), 5.28-5.70 (4 H, m), 6.34 (1 H, d, J=3.63 Hz), 6.80-7.16 (1 H, m), 7.29-7.71 (2 H, m), 7.71-8.11 (1 H, m), 8.11-8.46 (1 H, m)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:18]([NH2:22])[CH:19]([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:22][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: CC(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)CNC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.2 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and isobutylamine (37 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile] to give an anti-form compound (8 mg) and a syn-form compound (6 mg).
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH3:24][CH:25]([C:31]([CH3:33])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O>[OH:32][CH:31]([CH3:33])[CH:25]([CH3:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C(C)C(C)=O
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: CCOC(=O)C(C)C(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a 6 L Erlenmeyer flask containing Baker's yeast (100 g) and sucrose (150 g) was added tap water (1000 mL) and the reaction mixture was mechanically stirred at room temperature for 0.5 h. Ethyl 2-methylacetoacetate (10 g, 0.0694 mol) was added to the reaction mixture and stirring continued for 24 h. Sucrose (50 g) was added and stirring continued for another 24 h. Hyflo super cel (50 g) was added to the reaction mixture and filtered through a sintered glass funnel. The aqueous solution was then extracted with ether (1.5 L), dried over sodium sulfate, and filtered. The solvent ether was removed via simple distillation to obtain ethyl 3-hydroxy-2-methylbutyrate (10 g, 100%) as a mixture of two isomers: 1H NMR (CDCl3) δ1.18-1.30 (18H, m), 2.47-2.52 (2H, m), 3.85-3.91 (1H, m), 4.05-4.10 (1H, m), 4.13-4.21 (4H, m).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.Cl[CH2:33][C:34]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]=1[O:46][CH3:47]>>[CH3:47][O:46][C:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]([O:44][CH3:45])=[CH:43][C:34]=1[CH2:33][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccccc3)cc2)C(O)C1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOc3ccccc3)cc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(3-phenoxy-propoxy)-phenyl]-piperidine-1-carboxylate [Example 123 (j)] with 2-chloromethyl-1,4-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-[4-(3-phenoxy-propoxy)-phenyl]-piperidine-1-carboxylate as a viscous, yellow oil; MS: 628 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([CH:21]=[O:22])=[C:19]([Cl:23])[N:18]=[C:17]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=1)(=[O:8])=[O:7])=[O:4].[CH3:28][C:29]([CH3:45])([CH3:44])[C:30]([O:32][NH:33][C:34]([CH:36]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:37](O)=[O:38])=[O:35])=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:24]([C:17]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([S:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:37](=[O:38])[CH:36]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:34]([NH:33][O:32][C:30](=[O:31])[C:29]([CH3:44])([CH3:45])[CH3:28])=[O:35])(=[O:7])=[O:8])=[CH:10][CH:11]=2)[C:20]([CH:21]=[O:22])=[C:19]([Cl:23])[N:18]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)CC(C(=O)O)C(=O)NOC(=O)C(C)(C)C
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CNC(=O)C(CC(C)C)C(=O)NOC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(2-Aminoacetyl)-4-(2-butyl-4-chloro-5-formyl-imidazol-1-ylmethyl)benzenesulfonamide (770 mg, 1.2 mmol, 1.0 eq) and 2-(2,2-Dimethylpropionyloxycarbamoyl)-4-methylpentanoic acid (360 mg, 1.2 mmol, 1.0 eq) were dissolved in 13 mL DMF. HATU (460 mg, 1.2 mmol, 1.0 eq) was then added followed by DIPEA (630 μL, 3.6 mmol, 3.0 eq) and the mixture was stirred at room temperature. After 3 hours, the mixture was diluted with 30 mL EtOAc, washed with 20 mL 10% aq. LiCl solution, water, saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to yield crude intermediate 3a. MS m/z: [M+H+] calcd for C29H40ClN5O8S, 654.2. found 654.4.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:17][C:18](Cl)=[O:19]>>[C:1]([C:5]1[C:6]([NH:14][C:18](=[O:19])[CH2:17][C:16]([CH3:15])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: CC(C)(CC(=O)Cl)c1ccccc1
Product: CC(C)(C)c1c(NC(=O)CC(C)(C)c2ccccc2)nn2cccnc12

Procedure:
The product from Example 105B and the product from Example 117A were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 1.45 (s, 6H), 2.65 (s, 2H), 6.97 (dd, J=7.1, 4.1 Hz, 1H), 7.15-7.19 (m, 1H), 7.28-7.33 (m, 2H), 7.42-7.44 (m, 2H), 8.46 (dd, J=4.1, 1.7 Hz, 1H), 8.91 (dd, J=7.0, 1.9 Hz, 1H), 9.59 (s, 1H); MS (DCI) m/z 351 (M+H)+.