Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:33][C:1]1[N:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:4]2=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1c(Br)ccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To tert-butyl spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (13.2 g, 38.8 mmol) in CH2Cl2 (125 mL) at 0° C. was added NBS (7.25 g, 40.7 mmol) in CH2Cl2 (25 mL) dropwise over 10 min. The mixture was stirred at 0° C. for 5 min before it was diluted with 200 mL of 0.5M Na2S2O3. The aqueous phase was removed and the organic phase was washed with 200 mL of brine. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (0-30% EtOAc/hexanes) to give tert-butyl 1-bromospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate. ESI-MS m/z calc. 418.1. found 419.0 (M+1)+; Retention time: 2.29 minutes (3 min run).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C@@H:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CN(C1C=CC=CN=1)C>C1COCC1.C(N=C=NC(C)C)(C)C>[CH3:22][C@H:23]([O:20][C:19]([CH:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH2:15]1)=[O:21])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C(O)C1CCc2cc(OCc3ccccc3)ccc2C1
Reactant: CCCCCC[C@@H](C)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCCC[C@H](C)OC(=O)C1CCc2cc(OCc3ccccc3)ccc2C1
Reaction time: 24 h
Yield: 53 %

Procedure:
To a solution of 6-benzyloxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (31) (1 equi.), (R)-1-methylheptyl-1-ol (13) (1 equi.), and DMAP (dimethylaminopyridine) (0.1 equi.) in THF (25 mL/mmole), DIC (diisopropyl carbodiimide) (1.2 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (3% EtOAc/hexanes) gave 6-benzyloxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (1S)-1-methylheptyl ester (36) as a colorless oil (53%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:4]=1.I[CH:33]([CH3:35])[CH3:34]>CN(C=O)C.CCOC(C)=O>[CH:33]([N:29]1[CH2:30][CH2:31][CH:26]([N:24]2[CH:25]=[C:21]([C:19]3[CH:20]=[C:15]([C:5]4[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=5)[CH:6]=4)[CH:16]=[N:17][CH:18]=3)[CH:22]=[N:23]2)[CH2:27][CH2:28]1)([CH3:35])[CH3:34]
Reactant: CC(C)I
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1cc(-c2cncc(-c3cnn(C4CCN(C(C)C)CC4)c3)c2)cc(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of Methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) (1 eq, 0.122 mmol, 50 mg) in DMF (3 ml) cooled at 0° C. is added 2-iodopropane (7 eq, 0.854 mmol, 0.084 ml) and the reaction is stirred at room temperature for 5 hours. The reaction mixture is dissolved in EtOAc and washed with water. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by reverse phase column chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 454.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][NH:27][O:28][CH3:29].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=1)[C:8]([N:27]([O:28][CH3:29])[CH3:26])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(OCCCOC2CCCCO2)cc(C(=O)O)c1
Reactant: CNOC
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(OCCCOC2CCCCO2)cc(C(C)(C)C)c1
Reaction time: 2 h
Yield: 99.4 %

Procedure:
3-tert-Butyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]benzoic acid (O4.059; 4.90 g) and N,O-dimethylhydroxylaminehydrochloride (1.42 g) were dissolved in DMF (80 ml) and admixed with Hünig's base (4.81 ml) and TOTU (4.78 g). After stirring for 2 h, the mixture was left to stand overnight. Then the DMF was drawn off, the mixture was partitioned between EA and saturated sodium hydrogencarbonate solution, and the EA phase was removed, dried over magnesium sulfate, filtered and concentrated. 5.49 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.N1C=CC=CC=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=2)[CH:3]=1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc(Cl)n2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a 20 mL scintillation vial was added 7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1.1, 0.207 g, 1.131 mmol) and pyridine (2.84 ml, 35.1 mmol) and the solution was cooled to 0° C. To the yellow solution was added 4-(trifluoromethoxy)benzoyl chloride (0.508 g, 2.262 mmol) to give an orange suspension. The reaction mixture was stirred for one hour, quenched by the addition of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure in the presence of silica gel. The silica-adsorbed material was then purified by silica gel chromatography (25-75% ethyl acetate/hexanes gradient) to afford the desired compound N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(trifluoromethoxy)benzamide 14A as an orange solid (215 mg, 51% yield); ESI-MS: m/z 370.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1)[N:8]=[C:7]([CH3:23])[CH:6]=[CH:5]2.[Se](=O)=[O:25]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])[CH:11]=1)[N:8]=[C:7]([CH:23]=[O:25])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)cc(O[Si](C(C)C)(C(C)C)C(C)C)c2n1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[Si](Oc1cc(F)cc2ccc(C=O)nc12)(C(C)C)C(C)C
Yield: 28 %

Procedure:
6-fluoro-2-methyl-8-(triisopropylsilyloxy)quinoline (1.76 g, 5.29 mmol) was dissolved in dioxane (58 mL) and water (0.49 mL). The reaction was treated with selenium dioxide (0.76 g, 6.8 mmol) and the mixture was heated to reflux for 13 hours. The mixture was cooled and filtered through GF/F paper. The filtered solids were washed with Et2O and all the filtrates were concentrated in vacuo. The crude mixture was chromatographed on SiO2 eluting with a gradient of 1-5% Et2O/hexanes to provide the desired product (0.515 g).
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[C:8]([F:17])=[CH:9][C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=O)(=[O:6])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:32]1([C:37]2[S:41][C:40]([NH2:42])=[N:39][N:38]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O.ClCCl>[CH:32]1([C:37]2[S:41][C:40]([NH:42][C:12](=[O:14])[C:11]3[CH:15]=[C:7]([S:4]([NH:3][CH2:1][CH3:2])(=[O:5])=[O:6])[C:8]([F:17])=[CH:9][C:10]=3[F:16])=[N:39][N:38]=2)[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CCNS(=O)(=O)c1cc(C(=O)O)c(F)cc1F
Reactant: Nc1nnc(C2CCCC2)s1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCNS(=O)(=O)c1cc(C(=O)Nc2nnc(C3CCCC3)s2)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,4-difluorobenzoic acid (200 mg, 0.765 mmol) in chlorosulfonic acid (1.535 ml, 22.92 mmol) was stirred at room temperature for 30 seconds, then microwave 200 degree for 10 mins. The reaction mixture was cooled to room temperature and dumped on ice (10 g) slowly. Ethyl acetate (25 ml) was added and extracted twice with ethyl acetate (10 mL X2). The combined organic phase was dried over MgSO4. Ethylamine (1833 μl, 3.67 mmol) in THF (2.0 M) was added, stirred at room temperature for 10 mins and washed with 1 N HCl (10 ml). The organic phase was dried over MgSO4 and concentrated to give 5-[(ethylamino)sulfonyl]-2,4-difluorobenzoic acid, which was purified by HPLC 5%-60% CH3CN/H2O TFA (0.1%) to give 60 mg. To 5-[(ethylamino)sulfonyl]-2,4-difluorobenzoic acid in N,N-dimethylformamide (3 ml) and dichloromethane (3 ml) was added to EDC (32.5 mg, 0.170 mmol) and HOBt (26.0 mg, 0.170 mmol). After 10 mins, 5-cyclopentyl-1,3,4-thiadiazol-2-amine was added. The reaction mixture was stirred at rt overnight, concentrated and purifed by HPLC. The solvents were removed and purified by HPLC (30-70% with TFA 0.1% CNCH3 and H2O, 18 mins) to give the title compound (5 mg).
Reaction SMILES: [Mg].II.Br[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH3:15].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]>BrCCBr.C(OCC)C.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C.C1C=CC=CC=1>[CH3:15][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: Cc1ccc2ccccc2c1Br
Reactant: Cc1ccccc1Br
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: II
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: BrCCBr
Product: Cc1ccccc1-c1c(C)ccc2ccccc12
Temperature: 25 °C

Procedure:
Magnesium turnings (4.00 gr, 0.165 mol) and anhydrous diethyl ether (30 mL) were placed in a 500-mL three-neck round bottom flask, fitted with a condenser, addition funnel and nitrogen inlet. A crystal of iodine and 3-4 drops of 1,2-dibromoethane were added and the mixture was stirred magnetically. A solution of 1-bromo-2-methylnaphthalene (33.20 gr, 0.150 mol) in a 1:1 mixture of diethyl ether-benzene (120 mL) was added dropwise at a rate such that gentle reflux was maintained. After the addition was complete (about 1.5 hour), the mixture was heated at reflux for an additional hour, then cooled to room temperature. This mixture was then added rapidly under nitrogen to a stirring mixture of 2-bromotoluene (22.90 gr, 0.134 mol) and bis(triphenylphosphine)nickel dichloride (1.0 gr, 1.52 mmol) in diethyl ether (100 mL). The flask which had contained the Grignard reagent was rinsed with additional diethyl ether (60 mL), which was then added to the reaction mixture. The mixture was heated at reflux for 16 hours and then cooled to room temperature. Water (100 mL) was added, followed by the addition of 20 percent hydrochloric acid (100 mL). After stirring about 1 hour, the mixture was transferred to a separatory funnel and the layers were separated. The organic solution was washed twice with water (100 mL each) and then dried (MgSO4). After filtration, the solvent was evaporated from the filtrate and the residue was distilled to give the desired product (I), boiling point 156°-163°/0.5 mm Hg, 23.82 gr (77 percent), as a thick, light yellow liquid.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:34]=[CH:33][N:15]4[C:16](=[O:32])[C:17](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[C:18]([N:20]5[CH2:25][CH2:24]C[CH:22]([OH:26])[CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:4]CC1.C(C1N=C(CCC2C=CN3C(=O)C(/C=C/C(OC(C)(C)C)=O)=C(N4CCOCC4)N=C3C=2)SC=1)C>>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:10][CH2:11][C:12]2[CH:34]=[CH:33][N:15]3[C:16](=[O:32])[C:17](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[C:18]([N:20]4[CH2:21][CH2:22][O:26][CH2:24][CH2:25]4)[N:19]=[C:14]3[CH:13]=2)[S:8][CH:9]=1)[CH3:4]
Reactant: O=C(O)/C=C/c1c(N2CCCC(O)C2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Agent: CCc1csc(CCc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCOCC4)nc3c2)n1
Product: CCc1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)n1
Yield: 73 %

Procedure:
Reactions were performed in the same manner as in Example 1, (L) by using tert-butyl (E)-3-{8-[2-(4-ethyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido-[1,2-a]pyrimidin-3-yl}-2-propenoate (144 mg, 0.290 mmol) to obtain 93 mg (73%) of the title compound as yellow crystals.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]#[N:15].[CH2:16]([NH:18][C:19]1[C:24]([CH:25]=O)=[CH:23][N:22]=[C:21]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:20]=1)[CH3:17].O>C(OCCO)C>[CH2:16]([N:18]1[C:19]2[N:20]=[C:21]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:22]=[CH:23][C:24]=2[CH:25]=[C:13]([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[C:14]1=[NH:15])[CH3:17]
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Reactant: N#CCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCCO
Product: CCn1c(=N)c(-c2ccc3ccccc3c2)cc2cnc(Nc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
To a suspension of NaH (60% in mineral oil, 27 mg) in 5 mL of 2-ethoxyethanol was added 2-naphthyl-acetonitrile (227 mg, 1.36 mmol). After stirring for 5 minutes at room temperature, 4-ethylamino-2-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.24 mmol) was added and the reaction heated at 110° C. for 1 hour, resulting in a dark brown solution. Upon cooling, the solution was poured into 30 mL of water which caused precipitation. The resulting precipitate was removed by filtration and washed with water. The crude product was purified by flash chromatography, eluting with 5% methanol/methylene chloride, followed by 10% methanol/methylene chloride. Concentration of product fractions yielded 400 mg (82%) of yellow solid, (8-ethyl-7-imino-6-naphthalen-2-yl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-phenylamine; mp 236-242° C.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH:7]2[C:5]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)([CH2:6]2)[CH2:4]1)=[O:2].C(=O)([O-])[O-].[CH2:20](I)[CH3:21]>C(O)C>[CH:1]([N:3]1[CH2:8][CH:7]2[C:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:20][CH3:21])=[CH:11][CH:10]=3)([CH2:6]2)[CH2:4]1)=[O:2]
Reactant: CCI
Reactant: O=CN1CC2CC2(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOc1ccc(C23CC2CN(C=O)C3)cc1
Yield: 27.2 %

Procedure:
To a stirred mixture of 1.0 g of 3-formyl-1-(p-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane and 0.7 g of potassim carbonate in 25 ml of absolute ethanol is added a solution of 3.2 g of ethyl iodide in 10 ml of absolute ethanol. The mixture is refluxed for 2 hours and then is filtered and evaporated. The residual mixture of crystals and liquid is combined with water and this is extracted with chloroform and the extract is dried over magnesium sulfate and evaporated to give 1.0 g of a colorless, viscous liquid, which crystallizes on standing. Recrystallization from hexane gives 0.31 g of 3-formyl-1 -(p-ethoxyphenyl)-3-azabicyclo[3.1.0]hexane as colorless crystals, m.p. 48°-51° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=1>>[CH3:15][O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[C:12](=[O:14])[CH3:13])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: CC(=O)c1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 1-(2-bromo-5-trifluoromethyl-phenyl)-ethanone and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[S:16])[N:14]([C:17]3[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[C:13](=[O:29])[C:9]32[CH2:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:15](=[S:16])[N:14]([C:17]4[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=4)[C:13](=[O:29])[C:9]43[CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=2)[CH2:33][CH2:32]1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)cc3)C2=S)cc1C(F)(F)F
Reactant: CN1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc(N3C(=S)N(c4cnc(C#N)c(C(F)(F)F)c4)C(=O)C34CCC4)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
To a solution of 5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 63, 150 mg, 0.36 mmol), 1-methylpiperidin-4-ol (50 μL, 0.39 mmol), and triphenylphosphine (125 mg, 0.47 mmol) in anhydrous THF (2 mL) was added diisopropyl azodicarboxylate (0.1 mL, 0.47 mmol) and the reaction mixture was stirred at room temperature overnight. Additional 1-methylpiperidin-4-ol (50 μL, 0.39 mmol), triphenylphosphine (125 mg, 0.47 mmol) and diisopropyl azodicarboxylate (0.1 mL, 0.47 mmol) was added and the reaction was allowed to stir an additional 16 h. The mixture was partitioned between EtOAc and water and the aqueous layer was extracted with EtOAc (2×). The combined organics were washed with water and brine, then dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (0 to 80% EtOAc/hexanes, then 0 to 5% MeOH/dichloromethane) gave impure product which was further purified by preparative HPLC (40 to 75% acetonitrile/water, 0.1% TFA) to afford 45 mg of 5-(5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.22 (d, 1H), 8.76 (d, 1H), 7.30 (d, 2H), 7.15 (d, 2H), 4.52-4.39 (m, 1H), 2.72-2.56 (m, 4H), 2.49-2.38 (m, 2H), 2.25-2.14 (m, 5H), 2.03-1.90 (m, 3H), 1.77-1.49 (m, 3H). LCMS [M+1]+ 516.0.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[NH2:17][C@H:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]2[CH:32]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:34]([CH3:36])=[CH:35][C:19]1=2.[BH4-].[Na+]>CO>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]2[CH:32]=[C:33]([C:37]([F:40])([F:38])[F:39])[C:34]([CH3:36])=[CH:35][C:19]1=2
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
Add 3,5-bistrifluoromethylbenzaldehyde (909 mg, 3.75 mmol) to a solution of (S)-tert-butyl 5-amino-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (1.29 g, 3.75 mmol) in methanol (20 mL) at room temperature under nitrogen and stir for 2 h. Add sodium borohydride (283 mg, 7.5 mmol) and stir the mixture for 2 h. Remove the solvents under reduced pressure and dilute the residue with dichloromethane (50 mL) and water (50 mL). Collect the organic layer and extract the aqueous layer with dichloromethane (3×30 mL). Wash the combined organic extracts with water (20 mL) and brine (20 mL) and dry over anhydrous sodium sulfate. Filter and remove the solvents under reduced pressure to provide the title compound as an amber oil (2.09 g, 98%), which is used in the next step without purification. APCI MS m/z 570 (M+H)+.
Reaction SMILES: C[N:2](CCO)C.CCO.[C:10]([C:12]1[CH:13]=[C:14]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])C=1)[C:20]1[CH2:19][CH2:18][C@@H:17]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])[CH2:16][C:15]2=1)#[N:11]>>[C:10]([C:12]1[CH:13]=[C:14]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:2]=1)[C:20]1[CH2:19][CH2:18][CH:17]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])[CH2:16][C:15]2=1)#[N:11]
Reactant: CN(C)CCO
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C2CC2)C1
Solvent: CCO
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)n2)CCC(NC(=O)C2CC2)C1

Procedure:
Prepare the title compound from cyclopropanecarboxylic acid(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)amide (Preparation 69) (10.0 g, 35.8 mmol) and 2-bromomethyl-6-fluoro-pyridine (Preparation 44) (7.49 g, 39.4 mmol) by essentially following procedures as described in Preparation 45 to obtain 4.30 g (31%) of a salmon colored solid. Resolve the enantiomers using chiral chromatography essentially as described for Example 194, but using 0.2% DMEA/EtOH eluent. (R)-Isomer is first to elute. Slurry the solid in EtOAc and filter to give the title compound. m.p.=243-245° C.; MS (ES): m/z 389 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[C:29]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](Cl)=[O:40])(=[O:31])[CH3:30]>>[C:29]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([N:23]1[CH2:24][CH2:25][CH:20]([N:18]2[C:17](=[O:26])[C:16]([CH3:28])([CH3:27])[C:15]([C:7]3[C:8]4[CH2:9][C:10]([CH3:14])([CH3:13])[O:11][C:12]=4[C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)=[N:19]2)[CH2:21][CH2:22]1)=[O:40])(=[O:31])[CH3:30]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OC(C)=O)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and 2-(chlorocarbonyl)phenyl acetate as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.