Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C@@H:20]([OH:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:23])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)#[N:2].N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>Cl>[C:30]([O:23][C@@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[C@@H:20]([OH:22])[CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[C:1]#[N:2])[CH2:13]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@H](C#N)CC[C@@H]12
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@@H](O)C[C@]2(C)[C@@H](C#N)CC[C@@H]32)C1
Reaction time: 72 h

Procedure:
A solution of 17β-cyano-5α-androstane-3α,11β-diol (20 mg) in acetic anhydride (0.5 ml) containing pyridine (0.5 ml) was kept at room temperature for three days. The mixture was diluted with 2N-hydrochloric acid and extracted with ethyl acetate. Evaporation of the organic extract afforded title compound (21 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:15][C:16]#[N:17])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.C(O[CH:23](N(C)C)[N:24]([CH3:26])[CH3:25])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:15][C:16]#[N:17])[CH2:13][CH2:12][CH2:11][C:10](=[CH:23][N:24]([CH3:26])[CH3:25])[C:9]2=[O:14])=[CH:6][CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: N#CCC1(c2ccc(Cl)cc2)CCCCC1=O
Product: CN(C)C=C1CCCC(CC#N)(c2ccc(Cl)cc2)C1=O

Procedure:
[1-(4-Chlorophenyl)-2-oxo-cyclohexyl]-acetonitrile (101 mg, 0.43 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (149 mg) as a red oil which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1.C(N(CC)CC)C>CC(O)C>[C:29]([O:28][C:27](=[O:33])[NH:26][CH:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:25][CH2:24]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (2.5 g, 9.0 mmol) in 2-propanol (100 mL) was added trans-tert-butyl 4-aminocyclohexylcarbamate (2.2 g, 9.9 mmol) followed by triethylamine (1.0 g, 9.9 mmol). The reaction mixture was stirred and heated at reflux for 15 hours. The solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (200 mL) and washed with water (3×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford {4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 2.5 g, 61.0%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH3:11])[CH:7]=[CH:6][CH:5]=2.Cl[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][N:14]=1)=[C:8]([CH3:11])[CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C)cccc2[nH]1
Reactant: Clc1nsc2ccccc12
Product: Cc1[nH]c2cccc(C)c2c1-c1nsc2ccccc12

Procedure:
The sub-title compound was prepared by the method of Example 16 step a) from 2,4 dimethyl indole and 3-chlorobenzisothiazole.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:15]2=[C:16](Cl)[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:15]2=[C:16]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: C1COCCN1
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(N3CCOCC3)c2CC1
Temperature: 60 °C

Procedure:
To 0.15 g 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester (0.42 mmol), in a sealed tube in 8 mL ethanol, was added 78 μL (0.88 mmol) morpholine, and the reaction was heated at 60° C. for 16 hours. 5 mL of H2O was added and the mixture was extracted with EtOAc (2×10 mL), the organic layers were combined and dried with MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, DCM/MeOH 2%).
Reaction SMILES: [NH3:1].[C:2]([C:4](=[C:7](SCC)[S:8][CH2:9][CH3:10])[C:5]#[N:6])#[N:3]>C(O)C>[NH2:1][C:7]([S:8][CH2:9][CH3:10])=[C:4]([C:5]#[N:6])[C:2]#[N:3]
Reactant: CCSC(SCC)=C(C#N)C#N
Reactant: N
Solvent: CCO
Product: CCSC(N)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into 2.0 liters of ethanol, previously saturated with ammonia, was added 378 g of 2-cyano-3,3-bis(ethylthio)propenenitrile. The mildly exothermic reaction warmed the mixture to 38°. The mixture was stirred at ambient temperature for 0.5 hour, then heated under reflux (ca 55°) for 1.0 hour. The mixture was concentrated by distillation of about one liter of solvent. To the mixture was added 1.5 liters of ice-water and the mixture was cooled in an ice-bath. The yellow solid was isolated and dried to give 223 g of 3-amino-2-cyano-3-(ethylthio)propenenitrile, m.p. 180°-182°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]([OH:15])=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[C:10]2=[O:16])=[C:5]1[C:26]([O:28][CH3:29])=[O:27])[CH:2]=[CH2:3].[C:30](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]([O:15][CH3:30])=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[C:10]2=[O:16])=[C:5]1[C:26]([O:28][CH3:29])=[O:27])[CH:2]=[CH2:3]
Reactant: C=CCn1c(C(=O)OC)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCn1c(C(=O)OC)c2c(c(OC)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 40 °C

Procedure:
A mixture of methyl 2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (6.08 g, 14.92 mmol), cesium carbonate (6.08 g, 18.65 mmol), and iodomethane (2.79 mL, 44.77 mmol) in DMF (20 mL) was heated at 40° C. overnight. The reaction mixture was filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the title compound. (ES MS M+1=435.2)
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][CH2:28][CH2:29][NH2:30].C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:30][CH2:29][CH2:28][NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1
Reactant: NCCNc1ccccn1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(NCCNc2ccccn2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A solution of 5-amino-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg, 1.07 mmol), N-2-pyridyl-1,2-ethanediamine (221 mg, 1.61 mmol) and triethylamine (0.224 mL, 1.61 mmol) in DMSO (5 mL) was stirred at 100° C. for 3 h. After the reaction mixture was cooled to room temperature, 10% aq. NH4Cl was added to neutralize and the suspension was stirred for 30 min. The resulting precipitate was collected by filtration in vacuo, washed with water and hot EtOH, dried to yield 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (385 mg, 91%) as a colorless solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1.O1CCCC1.Br[CH2:33][CH2:34][Cl:35]>>[Cl:35][CH2:34][CH2:33][C:11]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][N:9]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:10]1
Reactant: ClCCBr
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCl)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide (1.8 M in THF, 3.9 mL) was slowly added to a solution of 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (1.50 g, 0.00583 mol) in tetrahydrofuran (20 mL, 0.2 mol) at −78° C. and the mixture was stirred for about 1 hour during which the temperature was allowed to rise to about −50° C. 1-Bromo-2-chloro-ethane (0.75 mL, 0.0082 mol) was slowly added to the mixture and then the resulting mixture was allowed to warm to rt (room temperature). After stirring for 2 h, the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl ether twice. The combined organic layers were dried and concentrated in-vacuo to afford the crude product, which was purified by CombiFlash eluting with hexane/EtOAc (max. EA 20%).
Reaction SMILES: [BH4-].[Na+].C1COCC1.[CH:8]([C:10]1[Se:11][C:12]([C:15]2[Se:16][C:17]([C:20]3[Se:21][C:22]([CH:25]=[O:26])=[CH:23][CH:24]=3)=[CH:18][CH:19]=2)=[CH:13][CH:14]=1)=[O:9]>C(OCC)(=O)C>[OH:26][CH2:25][C:22]1[Se:21][C:20]([C:17]2[Se:16][C:15]([C:12]3[Se:11][C:10]([CH2:8][OH:9])=[CH:14][CH:13]=3)=[CH:19][CH:18]=2)=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(-c2ccc(-c3ccc(C=O)[se]3)[se]2)[se]1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc(-c2ccc(-c3ccc(CO)[se]3)[se]2)[se]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
NaBH4 (10 mg) was added to a THF solution (2 mL) containing 2,5″-diformyl-5,2′:5′,2″-terselenophene (15 mg) and stirred at room temperature for 5 h. The reaction solution was diluted with ethyl acetate (50 mL), washed with 2N HCl (5 mL), and washed with H2O (3×100 mL). The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was chromatographed over silica gel using (1:1) hexanes/ethyl acetate to afford 2,5″-dihydroxymethyl-5,2′:5′,2″-terselenophene in 98% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.Br[CH2:30][CH2:31][C:32]#[N:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:30][CH2:31][C:32]#[N:33])[N:9]=2)[CH:7]=1
Reactant: N#CCCBr
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Temperature: 65 °C
Yield: 56.4 %

Procedure:
A mixture of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (500 mg, 1.24 mmol), 3-bromopropanenitrile (412 mg, 3.08 mmol), Cs2CO3 (1.21 g, 3.70 mol) in N,N-dimethylformamide (15 mL) was purged with a gentle flow of nitrogen gas. The resulting mixture was stirred in a sealed tube at 65° C. for 16 then poured into water (200 mL). The crude product was collected by filtration and then purified by flash chromatography on silica eluting with ethyl acetate/petroleum ether (1:2). Appropriate fractions were collected and evaporated to afford N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-cyanoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid (320 mg, 57%). LCMS (Method 17) [M+H]+=458.1, RT=1.67 min.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:12](Cl)[CH2:13][CH2:14][Si:15]([Cl:18])([Cl:17])[Cl:16]>>[C:1]1([CH:12]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:14][Si:15]([Cl:18])([Cl:17])[Cl:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: ClC(Cl)CC[Si](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)CCC(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 50 %

Procedure:
In the same apparatus and procedures as EXAMPLE 2 above, 36.0 ml (405 mmol) of benzene and 0.53 g (4.0 mmol) of aluminum chloride were alkylated with 10.08 g (41.0 mmol) of (3,3-dichloropropyl)trichlorosilane. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane (50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and benzene were distilled, the reaction products were vacuum distilled to give 6.76 g of (3,3-diphenylpropyl)trichlorosilane (bp; 124-125° C./0.5 torr, yield; 50%).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([N:12]1[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:14]2([CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:16][CH2:15]2)[CH2:13]1)C1C=CC=CC=1.Cl.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[CH3:29][C:27]1([CH3:30])[O:26][C:14]2([CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])[CH2:16][CH2:15]2)[CH2:13][NH:12][CH2:28]1
Reactant: CC1(C)CN(Cc2ccccc2)CC2(CCN(C(=O)C(F)(F)F)CC2)O1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CNCC2(CCN(C(=O)C(F)(F)F)CC2)O1

Procedure:
A mixture of acetic acid (100 μL, 1.76 mmol), Pd(OH)2 (11 mg, 0.02 mmol), 1-(8-benzyl-10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanone (80 mg, 0.22 mmol), HCl (108 μL of 4 M in dioxane, 0.43 mmol) and ethanol (2 mL) was treated to an atmosphere of hydrogen at 85 psi for 3 days. The reaction mixture was filtered and the catalyst was washed with methanol, then concentrated in vacuo to give 1-(10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanone acetic acid salt as a yellow solid. ESI-MS m/z calc. 280.1. found 281.5 (M+1)+; Retention time: 0.91 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:40]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:39])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:38])[C:20]=2[N:21]2[CH2:30][CH2:29][C@@H:28]([NH:31]C(=O)C(F)(F)F)[C:24]3([CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:40][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:38])[C:20]=1[N:21]1[CH2:22][CH2:23][C:24]2([O:25][CH2:26][CH2:27]2)[CH:28]([NH2:31])[CH2:29][CH2:30]1)=[O:39]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CC[C@@H](NC(=O)C(F)(F)F)C2(CCO2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(N)C2(CCO2)CC1
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl N-[2-(2,6-difluorophenyl)-4-[[1-methyl-5-[(10R)-10-[(2,2,2-trifluoroacetyl)amino]-3-oxa-7-azaspiro[3.6]decan-7-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (30 mg, 0.044 mmol) in methanol (2 mL) and water (2 mL) was added potassium carbonate (67 mg, 0.48 mmol). The mixture was heated at 65° C. for 8 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EA 3×. Combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was stirred with DCM (4 mL) and TFA (2 mL) for 20 min and concentrated under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 510. LCMS (ES+) m/z 490 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[C:19]=1[CH3:20].Cl.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[C:19]([CH3:20])[C:7]=3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2cc3c(C)c(OC)ccc3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1c(O)ccc2oc(-c3ccc(O)cc3)cc12
Temperature: 200 °C
Yield: 75 %

Procedure:
The crude 5-Methoxy-2-(4-methoxyphenyl)-4-methylbenzofuran 136 (0.134 g) was taken into a sealed tube along with enough pyridine hydrochloride to fill the tube halfway and heated at 200° C. for 2.5 hours. The reaction was dissolved into a mixture of ethyl acetate and 1 N HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organics was washed with 1 N HCl (1×), water (1×) and then dried over magnesium sulfate, filtered and concentrated. The resulting material was purified by column chromatography on silica gel, using 30% ethyl acetate in hexanes as the eluent to yield the desired product (0.090 g, 23.4% based on starting 4-Bromo-5-methoxy-2-(4-methoxyphenyl)-benzofuran from two runs) as a tan powder: Mp. 221-222° C.; 1H NMR (DMSO-d6) δ 9.81 (s, 1 H), 8.94 (s, 1 H),) 7.70 (d, 2 H, J=8.6 Hz,), 7.16 (d, 1 H, J=8.9 Hz), 7.14 (s, 1 H), 6.86 (d, 2 H, J=8.6 Hz), 6.72 (d, 1 H, J=8.6 Hz), 2.27 (s, 3 H); MS 241 (M+H)+.
Reaction SMILES: [C:1]1([C:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.O1CCOCC1.Cl>[Zn].C1(C)C=CC=CC=1>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:9][C:1]2[CH:2]=[CH:3][C:4]([O:5][CH3:6])=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(CCc2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 60 g of desoxyanisoin, 120 g of amalgamated zinc, 200 ml of dioxane, 100 ml of toluene and 200 ml of concentrated hydrochloric acid was refluxed for 24 hours. Another 50 ml of concentrated hydrochloric acid was added after the first 6 hours. The reaction mixture was cooled to room temperature and the organic layer was separated and mixed with 300 ml of ethyl acetate. It was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 26 g of white waxy solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.N>>[CH2:7]([N:23]1[CH2:22][CH2:21][C@@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:3]5[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=5[Cl:1])=[CH:18][C:17]=4[C@@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1cccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c1Cl
Agent: N
Product: CCCCN1CC[C@H]2[C@@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (23 mg, 62%) from (7aS,11aR)-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol). The title compound was spectroscopically identical to Example 384. MS (CI, NH3): 415.1 (base, M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19]C(=O)C2C=CC=CC=2)=[N:10]1.N12CCCN=C1CCCCC2>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:16])([F:17])[F:18])[O:12][C:11]([NH2:19])=[N:10]1
Reactant: O=C(NC1=N[C@](CF)(c2cccc(F)c2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@](CF)(c2cccc(F)c2F)C[C@@H](C(F)(F)F)O1
Temperature: 60 °C
Yield: 98.3 %

Procedure:
To a solution of N-((4S,6S)-4-(2,3-difluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (2.2 g, 5.28 mmol) in MeOH (25 mL) was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.947 mL, 6.34 mmol) The mixture was heated in a 60° C. oil bath for 22 h. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-40% EtOAc/hexane) to afford (4S,6S)-4-(2,3-difluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.62 g, 5.19 mmol, 98% yield) as light yellow solid. MS m/z=313.1 [M+H]+. Calculated for C12H10F6N20: 312.2
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[C:45](C#N)=[CH:44][S:43][CH:42]=4)=[CH:37][CH:36]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C([NH:51][C:52]1[C:53]2SC=[C:58](C3C=CC(O)=CC=3)[C:54]=2[N:55]=[CH:56][N:57]=1)(C)C>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:36]=[CH:37][C:38]([C:41]4[C:45]5[N:51]=[CH:52][N:57]=[C:56]([NH:55][CH:54]([CH3:58])[CH3:53])[C:44]=5[S:43][CH:42]=4)=[CH:39][CH:40]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)Nc1ncnc2c(-c3ccc(O)cc3)csc12
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Product: CC(C)Nc1ncnc2c(-c3ccc(OCCCc4sc(N5CCc6cccc(C(=O)Nc7nc8ccccc8s7)c6C5)nc4C(=O)O)cc3)csc12

Procedure:
The title compound 69 was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 69B: 1H NMR (DMSO-d6): δ 8.59 (s, 1H), 8.25 (s, 1H), 8.00 (d, J=7.67 Hz, 1H), 7.66-7.79 (m, 4H), 7.32-7.48 (m, 4H), 7.03 (d, J=8.59 Hz, 2H), 4.84 (s, 2H), 4.41-4.47 (m, 1H), 4.05 (t, J=6.14 Hz, 2H), 3.72-3.75 (m, 2H), 3.19-3.22 (m, 2H), 3.03 (t, J=5.98 Hz, 2H), 2.00-2.08 (m, 2H), 1.28 (d, J=6.44 Hz, 6H). ESI (+)/MS: 762 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[C:26]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:30])[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Product: Cc1cc(C(C)NC(=O)c2ccnc(NC(=O)C(C)C)n2)cnc1OCC(F)(F)F

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.06 mmol, Step-1 of Example 223, single enantiomer) and isobutyryl chloride (30 mg, 0.28 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].[H][H]>C(O)C.[Pd]>[C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)N1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N1CCNCC1
Yield: 74 %

Procedure:
34.0 g (0.15 mole) of 1-carbomethoxy-4-benzylpiperazine dissolved in 300 ml of ethanol was treated with hydrogen over a palladium catalyst at 40 psi and room-temperature for 24 hours. The catalyst was removed by filtration and the solvent removed under reduced pressure. The residue was distilled, b.p. 70°-75° C. at 1.5 mmHg to give 16.0 g of 1-carbomethoxypiperazine.