Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][C@H:8]1[C:9]([OH:11])=[O:10])=[O:6])[CH3:3].[F-].[K+].[C:25]([O:31][CH2:32]Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.O>[CH3:3][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][C@H:8]1[C:9]([O:11][CH2:32][O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:10])=[O:6])[CH3:1]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)OCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 107 %

Procedure:
To a solution of (cis)-1-[(1,1-dimethylethoxy)carbonyl]-4-(phenylmethyl)-L-proline (3.4 g) in dry dimethylformamide (3.0 ml) is added solid potassium fluoride (1.5 g), followed by chloromethyl pivalate (2.0 g). After stirring for 16 hours at ambient temperature the mixture is diluted with water (100 ml) and extracted with ethyl acetate. The ethyl acetate solution is washed with 5% sodium bicarbonate, water, brine, and dried (MgSO4). The solvent is removed in vacuo to give an oil residue (5 g). The oil is chromatographed on silica gel (120 g) eluting with ether/hexane (1:3) to give the product (4.4 g) as an oil that solidifies on standing, melting point 60°-62° C.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=1.[N:27]1C=CC=CC=1>CN(C)C=O>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][C:6]1[C:5]2[C:9](=[CH:10][CH:2]=[C:3]([NH:27][C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:4]=2)[NH:8][CH:7]=1
Reactant: CN(C)CCc1c[nH]c2cc(N)ccc12
Reactant: c1ccncc1
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: CN(C)C=O
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncccc3C(F)(F)F)cc12
Temperature: 153 °C
Yield: 10 %

Procedure:
6-Amino-3-(2-dimethylaminoethyl)indole and 2-chloro-3-trifiuoromethylpyridine were used. Pyridine was used as base, N,N-dimethylformamide was used as solvent, and the reaction was heated at reflux (153° C.) for 18 hours. Chromatography afforded the title compound (10%) as a clear, pale brown oil: 13C NMR (CD3OD) δ155.4, 152.3, 136.9, 136.1, 131.7, 129.0, 124.0, 120.9, 115.7, 113.9, 113.5, 112.5, 110.5, 61.4, 45.4, 24.3; LRMS (m/z, relative intensity) 348 (100, M+), 303 (16), 290 (28), 268 (11), 250 (20); HRMS calculated for C18H19F3N4 348.1564, found 348.1532.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([NH:15][C:16]1([CH2:20][C:21](OCC)=[O:22])[CH2:19][CH2:18][CH2:17]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1.O.C(OCC)(=O)C>[CH2:7]([NH:15][C:16]1([CH2:20][CH2:21][OH:22])[CH2:19][CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CC1(NC(=O)c2ccccc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCCC1(NCc2ccccc2)CCC1
Reaction time: 1 h
Yield: 60.7 %

Procedure:
LiAlH4 (3.88 g, 0.102 mol) was added to a solution of ethyl 1-(benzoylamino)-cyclobutylacetate (5.30 g, 20.3 mmol) in THF (100 mL) at room temperature. The mixture was stirred for 1 hour, then refluxed for one additional hour. The mixture was cooled in an ice-water bath, a few drops of water were added, and the mixture was allowed to stand overnight. The mixture was diluted with ethyl acetate, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Distillation of the residue gave the title compound as a colorless oil (2.53 g, 61%). 1H-NMR (400 MHz, CDCl3) δ 1.69-1.86 (2H, m), 1.88 (2H, t, J=5.5 Hz), 1.92-2.09 (4H, m), 3.73 (2H, s), 3.87 (2H, t, J=5.5 Hz), 7.22-7.35 (5H, m).
Reaction SMILES: [CH2:1]([N:8]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[CH:13]=[C:12]([CH:23]=O)[CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>C1(C)C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[CH2:1]([N:8]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[CH:13]=[C:12]([CH:23]=[C:29]3[S:25][C:26](=[O:31])[NH:27][C:28]3=[O:30])[CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2c(c1)c1ccccc1c(=O)n2Cc1ccccc1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)c2ccccc2c(=O)n3Cc2ccccc2)S1
Yield: 79.7 %

Procedure:
592 mg of 5-benzyl-6-oxo-5,6-dihydrophenanthridine-2-carboxaldehyde and 221 mg of 2,4-thiazolidinedione were suspended in 10 ml of toluene. Two drops of acetic acid and two drops of piperidine were added to the suspension, followed by heating and refluxing overnight. The reaction liquid was cooled, and the solid thus obtained was collected by filtration. The collected solid was washed with toluene-diethyl ether, and dried, giving 620 mg (80% yield) of 5-[1-(5-benzyl-6-oxo-5,6-dihydrophenanthridin-2-yl)methylidene]thiazolidine-2,4-dione as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[CH:13]=[N:12]2)=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[CH:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl
Product: O=C(Cl)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl

Procedure:
A mixture of 2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzoic acid (50 mg) in thionyl chloride (1 ml) was stirred at reflux for 1 hour. The mixture was concentrated under vacuum to provide 50 mg of the title intermediate as an amorphous amber solid that was used immediately in the next step.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].CCN(CC)CC.Br[C:16]1[C:17]([CH:34]([CH3:36])[CH3:35])=[N:18][N:19]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[N:19]([C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[N:18]=[C:17]([CH:34]([CH3:36])[CH3:35])[C:16]=2/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:23]=1
Reactant: CC(C)c1nn(-c2cnccn2)c(-c2ccc(F)cc2)c1Br
Reactant: C=CC(=O)OCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1c(C(C)C)nn(-c2cnccn2)c1-c1ccc(F)cc1
Yield: 58.6 %

Procedure:
Bis(triphenylphosphine) palladium (II) chloride (2.55 g, 3.6 mmol) and ethyl acrylate (49.2 mL, 454 mmol) were dissolved in DMF (200 mL) and Et3N (200 mL) at reflux under an inert atmosphere. The bromopyrazole (32.82 g, 91 mmol, Step B) was then added and the reaction was refluxed overnight. An additional 0.005 eq of catalyst and 10 mL of ethyl acrylate were added to push the reaction to completion. The reaction was cooled and partitioned between H2O and EtOAc. The organic layer was dried (MgSO4) and evaporated to give a brown oil. Elution from a 6-inch silica column gave 20.3 g (59%) of a tan solid. Recrystallization from hexanes produced a brilliant white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([Cl:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O.[C-]#N.[Li+].[C:19](P(=O)(OCC)OCC)#[N:20]>O1CCCC1>[C:19]([CH2:13][O:12][C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][C:10]=1[Cl:14])[CH:7]=[CH:6][CH2:5][CH2:4]2)#[N:20]
Reactant: COc1c(Cl)cc2c(c1Cl)CCCC2=O
Reactant: CCOP(=O)(C#N)OCC
Agent: [C-]#N
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCOc1c(Cl)cc2c(c1Cl)CCC=C2
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The product from Example 96 (0.2 g) was dissolved in tetrahydrofuran (15 ml), cooled to -15° C. and treated with lithium cyanide (20 mg) and diethyl cyanophosphonate (0.2 ml). After 30 minutes, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and the solvent evaporated. The residue was dissolved in benzene (30 ml) and a catalytic amount of p-toluenesulfonic acid was added. The reaction was refluxed for 30 minutes, quenched with 5% sodium bicarbonate, and extracted with ether. The organic layer was separated, dried and the solvent evaporated in vacuo affording the desired product in 95% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].Br[CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: CCCBr
Reactant: COc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(Br)c(OC)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
1.50 g (7.39 mmol) 4-bromo-3-methoxy-phenol are added to 1.36 g (11.1 mmol) 1-bromopropane in 10 mL DMF. 2.04 g (14.8 mmol) K2CO3 are added and the mixture is stirred at 80° C. for 12 h. After that time, the mixture is diluted with water and extracted with DCM. The organic layer is dried over sodium sulphate and the solvent is removed in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4](F)[N:3]=1.[CH:14]([O:17][CH2:18][CH2:19][CH2:20][NH2:21])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCOCC1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([NH:21][CH2:20][CH2:19][CH2:18][O:17][CH:14]([CH3:16])[CH3:15])[N:3]=1
Reactant: Nc1nc(F)nc(C(F)(F)F)c1F
Reactant: CC(C)OCCCN
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)OCCCNc1nc(N)c(F)c(C(F)(F)F)n1
Temperature: 0 °C
Yield: 54 %

Procedure:
5 g (0.025 mole) of 4-amino-2,5-difluoro-6-trifluoromethylpyrimidine are dissolved in 150 ml of dioxane. 2.9 g (0.025 mole) of 3-isopropoxypropylamine and 2.5 g (0.025 mole) of triethylamine are added dropwise thereto and the reaction mixture is heated to the boil for five hours. It is cooled and stirred into ice water, and the resulting solid is filtered off, dried and recrystallised from white spirit. 4 g (54% of theory) of the desired pyrimidine, melting point 87° C., are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH:12]=[CH:16][N:17]([CH3:19])[CH3:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: COC(OC)N(C)C
Product: COc1ccc(C(=O)C=CN(C)C)cc1OC

Procedure:
A mixture of 50.0 g. of 3',4'-dimethoxyacetophenone and 50 ml. of dimethylformamide dimethylacetal is refluxed for 16 hours. On cooling the desired compound crystallizes from solution. Hexane is added and the material is recovered by filtration, m.p. 124°-125° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([Cl:15])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1)=[O:4].[CH3:16][CH:17]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(=O)CC>[Cl:15][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH2:2][N:26]([CH:17]([CH3:16])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:10][C:9]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: CC(CCc1ccccc1)NCc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Solvent: CCC(C)=O
Product: CC(CCc1ccccc1)N(Cc1ccccc1)CC(O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 0.5 h

Procedure:
A mixture of 5-(2-bromoacetyl)-2-chlorobenzenesulphonamide (3.13 g) in butanone (50 ml) and N-(1-methyl-3-phenylpropyl)-N-(phenylmethyl)amine (4.8 g) was heated under reflux for 30 minutes. The solvent was removed under reduced pressure and the residue triturated with dry ether and filtered. The ether solution was evaporated to dryness and the product dissolved in ethanol (50 ml) and treated with sodium borohydride (0.3 g). The mixture was stirred for 30 minutes and a further aliquot of sodium borohydride (0.3 g) was added. The reaction mixture was acidified with 2N hydrochloric acid and the ethanol removed under reduced pressure. The concentrate was bastified with 5N sodium hydroxide and the mixture extracted with ethyl acetate (2 × 50 ml). The extracts were washed with water (2 × 50 ml), dried (MgSO4) and evaporated to dryness to give the product as a yellow oil, 4.6 g. This oil was purified by chromatography on preparative chromatographic plates (silica, CHCl3 /5% MeOH) and converted into a hydrochloride salt m.p. 120-125°.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:26])[C:14]3[C:19]([Br:20])=[CH:18][N:17]=[C:16]([O:21][CH2:22][C@@H:23]4[CH2:25][O:24]4)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:27][NH2:28]>O1CCOCC1>[C:1]12([CH2:11][NH:12][C:13](=[O:26])[C:14]3[C:19]([Br:20])=[CH:18][N:17]=[C:16]([O:21][CH2:22][C@@H:23]([OH:24])[CH2:25][NH:28][CH3:27])[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OC[C@@H]2CO2)ncc1Br
Reactant: CN
Solvent: C1COCCO1
Product: CNC[C@H](O)COc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Br)cn1
Reaction time: 4 h

Procedure:
A mixture of N-(1-adamantylmethyl)-5-bromo-2-[(2S)-oxiran-2-ylmethoxy]isonicotinamide (0.12 g) (Example 35(iii)), 40% aqueous methylamine (4 ml) and 1,4-dioxane (4 ml) was stirred for 4 hours. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel eluting with ethyl acetate:ethanol:0.880 ammonia solution (4:1:0.1 to 1.5:1:0.1). The isolated material was dissolved in a solution of hydrogen chloride in 1,4-dioxane (10 ml of a 4M solution) and concentrated to afford the titled compound (0.039 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O-:18])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.C(N([CH2:24][CH3:25])CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].[Cl-].[NH4+]>ClCCl>[CH3:26][S:27]([O:1][C@@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:24][CH3:25])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: COC(=O)N1CC2CCC(O)CC2CC1C(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H]2C[C@H](OS(C)(=O)=O)CC[C@H]2CN1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To an ice-cooled solution of ethyl (3S, 4aS, 6R, SaR)6-hydroxy-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (760 mg, 2.66 mmol) in dry dichloromethane (10 mL) under nitrogen, triethylamine (0.60 mL, 4.3 mmol) and methanesulfonyl chloride (0.33 mL, 4.3 mmol) were added. The resulting mixture was stirred overnight at room temperature and a saturated solution of ammonium chloride was added (10 mL). The layers were separated and the aqueous layer extracted with dichloromethane (10 mL×2). The combined organic phases were washed with 1 N hydrochloric acid (10 mL), dried over sodium sulfate and concentrated in vacuo to give the title compound as an oil (0.965 g, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]CC)=O)[CH2:4][CH2:3]1.[NH2:13][NH2:14]>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH:13][NH2:14])=[O:10])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: NN
Solvent: CO
Product: NNC(=O)C1CCC(O)CC1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 4-hydroxycyclohexanecarboxylate (2.0 g, 12 mmol) and hydrazine (1.5 g, 46 mmol) in methanol (20 mL) was stirred at 55° C. for 4 h and then cooled to room temperature (about 25° C.). After cooling, the solvent and excess hydrazine were removed by distillation under reduced pressure to provide a residue. The residue was co-evaporated with methanol (2×), and was then dried under high vacuum to provide the crude product 4-hydroxycyclohexanecarbohydrazide, which was used in the next synthesis step without further purification. LCMS: (M+H)+=155.2.
Reaction SMILES: N.C([S:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=O)C>CO>[SH:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: CC(=O)SC1CCCC1C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1C(=O)C1CCCC1S
Temperature: 0 °C

Procedure:
A mixture of 100 ml of anhydrous methanol and 100 ml of ammonia saturated anhydrous methanol, is added dropwise to a solution of 24.5 g (0.086 mole) of 1-[(2-acetylthiocyclopentyl)carbonyl]-L-proline in 50 ml of methanol cooled to 0° C. and maintained with stirring under nitrogen atmosphere. Once the addition is terminated the reaction mixture is stirred at room temperature under nitrogen for further four hours, then the solvent is evaporated and the residue is purified by column chromatography on Dowex 50® (a polystirene sulfonated resin) eluting with distilled water. Yield: 18.5 g (88%) of 1-[(2-mercaptocyclopentyl)carbonyl]-L-proline with the following characteristics: [α]D25 =-139.°3 (C=1% in CHCl3).
Reaction SMILES: [CH:1]1[C:13]2[C:12]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:28](Br)[CH:29]=[CH2:30].C([O-])([O-])=O.[K+].[K+].[CH3:38][C:39]([CH3:41])=O>>[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:12]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:41][CH:39]=[CH2:38])=[CH:16][CH:15]=3)[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:26][CH:25]=1)[CH:29]=[CH2:30]
Reactant: CC(C)=O
Reactant: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(C2(c3ccc(OCC=C)cc3)c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C

Procedure:
Into a 1,000 ml two-necked flask equipped with a refluxing condenser, 10.0 g of 4,4′-(9H-fluorene-9,9-diyl)diphenol (Sigma-Aldrich), 6.17 ml of allyl bromide (Sigma-Aldrich), 23.68 g of K2CO3, and 500 ml of acetone were charged and mixed at room temperature. Then, the temperature was set to 80° C., and the homogeneous mixture thus obtained was refluxed overnight. After finishing the reaction, the reaction mixture was cooled to room temperature and was filtered using Celite. Organic solvent was evaporated to obtain a coarse product. A target product was extracted from the coarse product using ethyl acetate, washed three times using water, and dried using MgSO4. MgSO4 was filtered off, and solvent was removed by using an evaporator to obtain an intermediate product (11), 9,9-bis(4-(allyloxy)phenyl)-9H-fluorene. The reaction scheme in the 1st step and the NMR data of the intermediate product (11) are as follows.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[SH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O1CCOCC1>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([S:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:3][C:4]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][CH:11]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
A 25 mL round-bottomed flask was charged with 5-bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine (350 mg, 0.966 mmol), Pd2dba3 (22.1 mg, 0.024 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (27.9 mg, 0.048 mmol), N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.9 mmol), methyl 3-mercaptopropanoate (0.12 mL, 1.1 mmol), and dioxane (10 mL). The reaction mixture was heated to 100° C. under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by silica gel chromatography (40% EtOAc in hexanes) to afford the title compound (328 mg, 84.5% yield) as a pale yellow solid. HCl salt made for characterization. 1H NMR (d6-DMSO) 8.18 (d, 1H), 7.45 (m, 2H), 7.36 (d, 1H), 7.22 (t, 1H), 7.13 (d, 2H), 6.79 (s, 1H), 3.55 (s, 3H), 3.07 (t, 2H), 2.57 (t, 2H), 2.29 (s, 3H); Mass spectrum (esi) m/z=402.2 (100)(M+H—HCl).
Reaction SMILES: [CH3:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:5]2[N:6]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:8][CH2:9][C:10](=O)[C:4]=2[CH:3]=1.[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH:15]([O:14][C:12]([N:6]1[CH2:7][CH2:8][CH2:9][CH:10]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:4]2[CH:3]=[C:2]([CH3:1])[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:5]1=2)=[O:13])([CH3:17])[CH3:16]
Reactant: Nc1cccnc1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCCC2Nc1cccnc1
Temperature: 130 °C
Reaction time: 96 h
Yield: 13.2 %

Procedure:
Add isopropyl 7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 3, Step 8) (1.16 g, 3.52 mmol), 3-aminopyridine (465 mg, 5.10 mmol), p-toluenesulfonic acid (210 mg, 1.10 mmol) and toluene (8.0 mL) to a sealed tube and stir vigorously for 4 days at 130° C. Evaporate the toluene, dissolve the residue with MeOH (10.0 mL), and add sodium borohydride (146 mg, 3.86 mmol) portionwise. Reflux overnight and evaporate the MeOH. Partition the resulting residue between water (10 mL) and EtOAc (10 mL). Wash the organic layer with 2-mL portions of water and brine, dry (MgSO4), and concentrate. Purify via column chromatography (silica gel; 30% to 70% EtOAc:hexanes to 100% EtOAc gradient) to give 189 mg (13%) of the title compound as a white solid. APCI MS m/z 408 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:25]2[CH:24]=[C:23]([C:22]3[CH2:21][C:20](=[O:36])[NH:19][C:9]4[CH:10]=[C:11]([O:14][C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccc(OC(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethoxy-phenyl}-carbamic acid tert-butyl ester (Example M167) (238 mg, 0.46 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (137 mg, 75%).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4](=[O:21])[CH:5]=[C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9](=[O:16])[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7]1)[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:22]([N:3]([CH2:1][CH3:2])[C:4](=[O:21])[CH:5]([C:6]1[CH:11]=[C:10]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH3:23]
Reactant: CCN(CC)C(=O)C=C1C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Reactant: C1COCCN1
Product: CCN(CC)C(=O)C(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N1CCOCC1

Procedure:
Synthesized as in Example 51 from Intermediate 21 (1.84 g, 5.8 mmol) and morpholine (1.06 g, 12.2 mmol). This gave 1.65 g (70%) of pure product.