Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13]Cl)[C:6]=2[CH:15]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:27]3[CH2:26][CH2:25][N:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=4)[CH2:29][CH2:28]3)[C:6]=2[CH:15]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: ClCCCCn1nnc2ccc(Cl)cc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cccc(N2CCN(CCCCn3nnc4ccc(Cl)cc43)CC2)c1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
6-chloro-1-(4-chlorobutyl)-1H-benzotriazole (8.75 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.5 g compound (I-54) with a yield of 64.7%. ESI-MS [M+H]+: m/z 437.2.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].CS([CH2:19][CH2:20][CH2:21][C@@H:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])(=O)=O.O>CS(C)=O>[CH3:29][C@@H:22]([CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:21][CH2:20][CH2:19][N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3]
Reactant: CC(C)=CCC[C@H](C)CCCS(C)(=O)=O
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)=CCC[C@H](C)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a suspension of sodium theobromine (4.05 g, 20.0 mmol) in dimethylsulfoxide (50 mL) was added 1-methanesulfonyl-4-(S)-methyl-8-methylnon-7-ene and the reaction stirred for 16 hours at 60° C. The mixture was then poured into water (100 mL) and extracted with ethyl acetate (100 mL, 2×50 mL). The organic portions were combined, dried using magnesium sulfate, and evaporated to give a residue which was purified by column chromatography (ethyl acetate/hexane) to yield 1.83 g (30% yield) 1-(4-(S)-Methyl-8-methylnon-7-enyl)-3,7-dimethylxanthine (inventive compound no. 2536S) as a white solid.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.CC(N1[C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=3)[NH:32][CH:31]=[C:30]4[CH:39]3[CH2:44][CH2:43][N:42]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])[CH2:41][CH2:40]3)=[CH:23][CH:22]=2)=[O:18])=[CH:15][C:14](C)=[N:13]1)(C)C.CC(N1C(C(NCC2C=CC(B(O)O)=CC=2)=O)=CC(C)=N1)(C)C>>[CH2:48]([S:45]([N:42]1[CH2:41][CH2:40][CH:39]([C:30]2[C:29]3[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=[C:27]([C:24]4[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:17]([C:16]5[CH:15]=[CH:14][N:13]=[CH:3][CH:2]=5)=[O:18])=[CH:26][CH:25]=4)[CH:28]=3)[NH:32][CH:31]=2)[CH2:44][CH2:43]1)(=[O:47])=[O:46])[CH3:49]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)c5cc(C)nn5C(C)(C)C)cc4)cc23)CC1
Reactant: O=C(O)C(F)(F)F
Agent: Cc1cc(C(=O)NCc2ccc(B(O)O)cc2)n(C(C)(C)C)n1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)c5ccncc5)cc4)cc23)CC1
Yield: 45.8 %

Procedure:
The title compound was prepared according to the general procedure of 5-{-4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (4-{[(4-pyridinylcarbonyl)amino]methyl}phenyl)boronic acid (124 mg, 0.480 mmol) for {4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid to afford 30 mg of the title compound (45.8%).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([O:16][CH3:17])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10].[ClH:18]>O.CO.[OH-].[Na+]>[Cl:18][C:6]1[C:7]([O:16][CH3:17])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: Cl
Reactant: COC(=O)c1cccc(N)c1OC
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(Cl)cccc1C(=O)O
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A solution of 1.2 g of sodium nitrite in 3 mL of water was added dropwise to a solution of 2 g (0.011 mole) of methyl 3-amino-2-methoxybenzoate in 15 mL of conc. HCl kept below 10° C. After completing the addition, stirring was continued for 0.5 hour at 0° C. The cold solution was then added dropwise to a solution of 2.5 g of cuprous chloride in 6 mL of concentrated HCl at 80°-85° C. After stirring at this temperature for 0.5 hour, the solution was chilled to precipitate an oil which was taken up in methylene chloride. After drying and removing the solvent, the oil obtained above was dissolved in 75 mL of methanol containing 7 mL of 10% NaOH. The solution was heated under reflux for 0.5 hour. After evaporation, the oil was treated with 40 mL of dilute HCl. A white solid precipitated to give 0.5 g (24%) of 3-chloro-2-methoxybenzoic acid after crystallization from ethyl acetate-hexane.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C@H:11]([CH2:22][CH3:23])[C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[F:27][C:28]([F:36])([F:35])[C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[NH2:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C@H:11]([CH2:22][CH3:23])[C@:12]([C:15]2[CH:16]=[C:17]([NH:21][C:32]([C:29]3([C:28]([F:36])([F:35])[F:27])[CH2:31][CH2:30]3)=[O:33])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CC[C@H]1C(=O)N(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)c1cccc(N)c1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Product: CC[C@H]1C(=O)N(C)C(N)=N[C@]1(C)c1cccc(NC(=O)C2(C(F)(F)F)CC2)c1

Procedure:
The coupling of give [(4S,5R)-4-(3-amino-phenyl)-5-ethyl-1,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester and 1-trifluoromethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=397.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21
Reactant: CS(=O)(=O)Cl
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4NS(C)(=O)=O)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 4, reaction of (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (example 61) with methanesulfonyl chloride gave the title compound as a colorless solid. MS: 386.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23].[CH:24]1([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:29][C:30]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(NC(=O)CC4CCCC4)cc23)c(OC)c1

Procedure:
Starting from amino-ester (A), and using a similar procedure to that described in Example 4, except using cyclopentylacetyl chloride (see also Example 98), the title compound was obtained in quantitative yield as a foam; partial NMR (250 MHz, DMSOd6): 1.2-1.8(3m,8H, cyclopentyl ring); 2.24(m,3H, CH2CONH and --CHCH2); 3.83(s,3H, OMe); 3.93(s,3H, OMe); 3.99(br s,2H, CH2Ar); 9.57(br s,1H, NHCO); 10.79(br ™d,1H, --NH--).
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:25]C(=O)C1C=CC=CC=1)[CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([OH:25])[CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc2c(c1)c1c(n2C(=O)c2ccccc2)CCC(C(=O)O)C1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C1CCc2c(c3cc(O)ccc3n2C(=O)c2ccccc2)C1

Procedure:
A solution of 8.1 g. of 9-benzoyl-6-benzoyloxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid in 250 ml. of ethyl acetate over 1.5 g. of 10 percent palladium-on-charcoal was subjected to a hydrogen atmosphere at about 40 psig while being heated with a heat lamp. The reaction was stopped when a theoretical amount of hydrogen had been adsorbed (1 hour) and the resulting cooled mixture was filtered and evaporated to dryness under reduced pressure. The residue was crystallized from acetone-n-hexane to yield 4.1 g. of the title compound; m.p. 224°-227°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C)C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]1[C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=1
Reactant: CC1(C)CC(=O)Nc2ccccc2N1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CC1(C)CC(=O)Nc2ccccc2N1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 150 °C
Reaction time: 9 h
Yield: 10.9 %

Procedure:
To a solution of 4,4-dimethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.0 g) in N,N-dimethylaniline (20 ml) was added 4-nitrobenzoyl chloride (0.98 g) at ambient temperature. The mixture was stirred at 150° C. for 9 hours. The resulting mixture was diluted with chloroform and the organic layer was washed successively with 1N hydrochloric acid and saturated aqueous sodium bicarbonate. Drying, filtering and the removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (1% methanol in chloroform) to give 4,4-dimethyl-5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (195 mg) as a slightly yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: Cc1cccc(Br)n1
Product: Cc1cccc(N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)n1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-6-methyl-pyridine.
Reaction SMILES: CC(O)=O.OS(O)(=O)=O.[CH2:10]([N:12]([CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)[CH3:11].ClC[C:37]([NH:39]CO)=O>O>[NH2:39][CH2:37][C:21]1[CH:20]=[C:19]([CH:16]2[CH2:17][CH2:18][CH:13]([N:12]([CH2:10][CH3:11])[CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:14][CH2:15]2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: O=C(CCl)NCO
Reactant: CCN(CCCc1ccccc1)C1CCC(c2ccc(O)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCN(CCCc1ccccc1)C1CCC(c2ccc(O)c(CN)c2)CC1
Temperature: 10 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
A mixture of HOAc and H2SO4 (1 mL, 9:1, v:v) was cooled to 10° C. 4-{4-[ethyl(3-phenylpropyl)amino]cyclohexyl}phenol (200 mg, 0.53 mmol) and 2-chloro-N-(hydroxymethyl)acetamide (66 mg, 0.53 mmol) were added portionwise. The reaction mixture was warmed to room temperature and stirred for 16 hours. The mixture was poured onto ice (1 g) and water (10 mL) was added. After concentration under reduced pressure, a mixture of EtOH and HCl (6.5 mL, 10:3, v:v) was added, and the mixture was heated under reflux for 1.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography (silica, 90:10:0.5 CH2Cl2:MeOH:NH4OH), followed by formation of the HCl salt, gave 2-aminomethyl-4-{4-[ethyl(3-phenylpropyl)amino]cyclohexyl}phenol (65 mg, 28%), as a yellow solid: mp 168-173° C.; IR (KBr): 2940, 1510, 1453 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 10.16 (br s, 1H), 9.96 (s, 1H), 8.1 (br s, 2H), 7.35-7.17 (m, 6H), 7.06 (dd, J=8 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 3.90 (br d, J=5 Hz, 2H), 3.45-2.98 (m, 4H), 2.71-2.65 (m, 2H), 2.52-2.39 (m, 2M), 2.19-2.10 (m, 2H), 2.10-2.05 (m, 2H), 1.90-1.83 (m, 2H), 1.70-1.49 (m, 4H), 1.27 (t, J=7 Hz, 3H) API-MS (methane) (m/z): 367 [M+H]+; HRMS-API (m/z): [M+H]+ Calcd for C24H34N2O, 367.2749. found: 367.2741. Anal. Calcd for C24H34N2O.02HCl.H2O: C, 64.93; H, 8.29; N, 6.31. Found: C, 64.90; H, 8.53; N, 6.09.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1N1C=NC(C(F)(F)F)=N1)=[O:11].CC1C=CC([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)=[O:11]
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)O)c1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone in Example A51, starting from 5-methyl-2-(pyridin-2-yl)benzoic acid. ESI-MS (m/z): 324 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].Br[CH2:17][CH2:18][O:19][CH3:20]>CN(C=O)C>[CH3:13][O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:1][CH2:17][CH2:18][O:19][CH3:20])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(OC)c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc(OC)cc(C(=O)OC)c1
Temperature: 0 °C
Yield: 77.1 %

Procedure:
To a solution of methyl 3-hydroxy-5-methoxybenzoate (Example 1, step i, 0.5 g, 2.7 mmol) in DMF (10 ml) was added NaH (0.2 g, 5.4 mmol) at 0 under a nitrogen atmosphere. After stirring for minutes, 1-bromo-2-methoxy-ethane (0.75 g, 5.4 mmol) was added and the reaction mixture was stirred at 50 for 1 hour. The solution was poured into 100 ml ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give methyl 3-methoxy-5-(2-methoxyethoxy)benzoate (0.5 g). The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[O:25])[O:23][C:21](=[O:22])[C:20]2=[CH:26][CH:27]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:2]([CH3:15])([CH3:1])[C:3]=3[CH:4]=2)=[O:22])=[C:19]([CH:18]=1)[C:24]([OH:25])=[O:23]
Reactant: CC1(C)c2ccccc2-c2ccccc21
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)c2ccccc2-c2ccc(C(=O)c3ccc(Br)cc3C(=O)O)cc21
Temperature: 25 °C
Yield: 49.8 %

Procedure:
9,9-dimethyl-9H-fluorene (27.78 g, 0.143 mol) and 4-Bromo Phthalic anhydride (48.69 g, 0.214 mol) were placed in a reaction vessel, and added with Dichloromethane (700 ml). At 0° C., aluminum chloride (28.7 g, 0.214 mol) was gradually added thereto, and the temperature was raised up to room temperature. Then, the resultant mixture was stirred for 12 hours. After the reaction was completed, the resultant product was gradually added with distilled water. The resultant product was extracted with an excess of dichloromethane, and washed several times with distilled water. After solvent removal, the produced solid was placed in a Hexane 2 l-containing vessel, washed, filtered, and dried, 5-bromo-2-(9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (30 g, yield 50%) was obtained.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[H-].[Na+].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH:25]([CH:28]1[C:33]2[N:34]=[CH:35][NH:36][C:32]=2[CH2:31][CH2:30][N:29]1[C:37](OCC1SC=CN=1)=[O:38])([CH3:27])[CH3:26]>C1COCC1>[CH:25]([CH:28]1[C:33]2[N:34]=[CH:35][NH:36][C:32]=2[CH2:31][CH2:30][N:29]1[C:37]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:9])([F:8])[F:1])=[O:38])([CH3:27])[CH3:26]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1nccs1
Reactant: OCCOCC(F)(F)F
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCCOCC(F)(F)F
Reaction time: 0.17 h
Yield: 0.5 %

Procedure:
2-(2,2,2-Trifluoroethoxy)ethanol (0.57 mL, 3.60 mmol) was dissolved in THF (5 mL), NaH (146 mg, 60% dispersion in mineral oil, 3.60 mmol) was added and the reaction mixture was stirred for 10 min. 4-Nitrophenyl chloroformate (726 mg, 3.60 mmol) was added and the reaction mixture was stirred for 16 h. Intermediate 1 (297 mg, 1.80 mmol) was dissolved in THF (5 mL) and added to the reaction mixture which was stirred at room temperature. Three additional such portions of NaH, 2-(2,2,2-trifluoroethoxy)ethanol and 4-nitrophenyl chloroformate in THF were added after 8, 24 and 32 h, respectively. After 104 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (6 mL) and stirred for 1.5 h. The solvents were removed in vacuo and the residue dissolved in EtOAc (100 mL). The organic layer was washed with 1 M aq Na2CO3 solution (6×50 mL), brine (2×50 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 50% (over 12 min) to 100% (over 3 min) MeOH in water to give 2-(2,2,2-trifluoroethoxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (3 mg, 0.5%) as a pale yellow gum.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:15]2[CH:16]=[C:17]([C:27]3[CH:28]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=3[F:29])[CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccncc2)(c2cccc(Br)c2)N=C1N
Reactant: OB(O)c1cc(F)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1C(=O)C(c2ccncc2)(c2cccc(-c3cc(F)ccc3F)c2)N=C1N
Yield: 83.7 %

Procedure:
To a solution of 2-amino-5-(3-bromophenyl)-3-methyl-5-pyridin-4-yl-3,5-dihydro-4H-imidazol-4-one (104 mg, 0.3 mmol) in DME (5 mL) is added 2,5-difluorophenylboronic acid (96 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmo) and 2.0M aqueous sodium carbonate (0.6 mL, 1.2 mmol) at room temperature. The reaction mixture is refluxed for 1 hour and cooled. After evaporation of the solvent, the crude mixture is purified by chromatography (silica gel, EtOAc/2M methanolic NH3: 92/8) to give the title compound (95 mg, 84%) as a solid. mp: 200-202° C.; MS(+) ES: 379 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[S:8]([O:1][C@@H:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=C1OCC[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A suspension of (R)-α-hydroxy-γ-butyrolactone (3.5 g, 34.3 mmol), tosyl chloride (10.0 g, 52.6 mmol), and K2CO3 (2.23 g, 16.2 mmol) in dry CH2Cl2 (50 mL) was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate washed with 1M phosphate buffer pH=7 (2×50 mL), 3 M NaCl (aq.) (1×50 mL), dried with Na2SO4, filtered and evaporated to dryness to give the crude product. The crude product was triturated by PE40/60 (50 mL) and stirred for 30 minutes. The precipitate formed was isolated by filtration and washed with PE40/60 to remove trace amounts of tosyl chloride, to give 7.7 g (87%) of enantiopure (R)-α-tosyloxy-γ-butyrolactone. [α]36525=−9.9°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][CH:18]([CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH2:17][CH2:16]3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:30].C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][CH:18]([C:21]([OH:30])([OH:26])[C:22]([F:24])([F:25])[F:23])[CH2:17][CH2:16]3)[C:12]2=[O:27])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)(C)c1ccc(N2CCC3(CCC(C(O)C(F)(F)F)CC3)C2=O)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N2CCC3(CCC(C(O)(O)C(F)(F)F)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of 2-(4-tert-butyl-phenyl)-8-(2,2,2-trifluoro-1-hydroxy-ethyl)-2-aza-spiro[4.5]decan-1-one (100 mg, 319 μmol, described in example 360 and 361) in DCM (1 mL) was added to a stirred suspension of Dess-Martin periodinane (501 mg, 1.18 mmol) in DCM (2.5 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and poured into a 1:7 mixture of aqueous sat. NaHCO3 and Na2S2O3 and the mixture was stirred for 10 min. The organic phase was separated and washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by reverse phase prep HPLC to give the title compound as a white solid (94%). MS (m/e): 400.3 (MH+).