Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:48])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:45]([CH3:47])[CH3:46])[C:29](=[O:44])[C:30]([F:43])([F:42])[C:31](=[O:41])[NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=O)C1C=CC=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.C1(OC)C=CC=CC=1>[NH2:11][C:12]1[C:13](=[O:48])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:45]([CH3:46])[CH3:47])[C:29](=[O:44])[C:30]([F:43])([F:42])[C:31](=[O:41])[NH:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)C(=O)NCCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(=O)C(F)(F)C(=O)NCCc1ccccc1
Reaction time: 1.5 h
Yield: 33.1 %

Procedure:
To a solution of 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-[3,3-difluoro-1-isopropyl-2-oxo-3-(N-phenethylcarbamoyl)propyl]acetamide (0.451 g) in dichloromethane (7 mL) and anisole (0.22 mL) was added trifluoromethanesulfonic acid (0.30 mL). After 1.5 h, the reaction was quenched with saturated sodium bicarbonate. The mixture was extracted with dichloromethane, and the extracts were washed (saturated sodium bicarbonate, brine), dried, and evaporated. The crude product was purified by chromatography, twice, with dichloromethane:methanol (first column: gradient, 99:1, 92:8; second column: gradient, 99:1, 92:8) as the eluent. The resulting material was crystallized from ether and petroleum ether to give the title compound (0.119 g) as a tan solid; TLC: Rf =0.27, dichloromethane:methanol (98:2); 300 MHz NMR: 9.20 (t,1), 8.42 (d,1), 7.38-7.18 (m,10), 6.51 (d,1), 5.97 (d,1), 5.15 (d,2), 4.80 (dd,1), 4.43 (broad s,2), 3.43-3.29 (m,2), 2.76 (t,2), 2.29-2.13 (m,1), 0.85 (d,3), 0.74 (d,3); MS: m/z=525(M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5](Cl)[S:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1>>[NH2:1][C:2]1[CH:6]=[C:5]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:12])[CH:18]=2)[S:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: Clc1ccccc1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Product: Nc1cc(-c2cccc(Cl)c2)sc1S(N)(=O)=O

Procedure:
The title compound was prepared from 3-chlorobenzene boronic acide and 3b by following the procedure in example 3c. This compound is a white solid: MS (ES) 289 (M+H)+; 1H NMR (400 MHz, CD3OD) δ7.62 (s 1 H), 7.53 (m, 1 H), 7.40 (m, 2 H), 6.92 (s, 1 H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[CH2:11]([O:13][CH:14]([O:19][CH2:20][CH3:21])[CH2:15][CH2:16][CH2:17][NH2:18])[CH3:12].C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:20]([O:19][CH:14]([O:13][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][NH:18][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[CH3:21]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(CCCN)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCOC(CCCNCc1ccc(C#N)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
4-Formylbenzonitrile (612.0 mg) was dissolved in methanol (18.4 ml), and 4,4-diethoxybutylamine (752.5 mg) and trimethyl orthoformate (1.53 ml) were added thereto. The whole was stirred at room temperature for 18 hours. Subsequently, the solution was added with sodium borohydride (529.7 mg) under ice-cooling and stirred at room temperature for additional 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was added with water and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.16 g) as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[NH2:18])[CH2:7][CH2:8][CH3:9])[CH3:2].C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]([N:10]1[C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:25]1=[O:26])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)Nc1cc(C)ccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a solution of 3-(2-Amino-5-methyl-phenylamino)-hexanoic acid ethyl ester (1.4 g, 5.3 mmol) in THF (20 mL) was added CDI (1.0 g, 6.4 mmol). The reaction mixture was stirred at room temperature for 16 h. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 1.3 g of the desired product as dark brown solid. The resulting residue was used for the next reaction without further purification. LCMS (ESMS): m/z 291.40 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:33])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=2)=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1nc(CO)cs1)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.8 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (100 mg, 0.22 mmol) in diethyl ether (10 mL) was cooled to 0° C. and then treated with lithium aluminum hydride (13 mg, 0.32 mmol). The reaction mixture was slowly warmed to 25° C. where it was stirred for 16 h. After this time, the reaction mixture was slowly diluted with water (5 mL) and then extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-phenoxy-phenyl)-propionamide (50 mg, 55%) as a white solid: mp 83.7-87° C.; EI-HRMS m/e calcd for C24H26N2O3S (M+) 422.1664, found 422.1674.
Reaction SMILES: COC1C=CC(C[C:8]2[C:16]([O:17][C:18](=[O:34])[C@H:19]([CH:31]([CH3:33])[CH3:32])[NH:20][C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([O-:12])=[O:11])=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH2:24]([O:23][C:21]([NH:20][C@H:19]([C:18]([O:17][C:16]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:34])[CH:31]([CH3:33])[CH3:32])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(Cc2c(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)cccc2C(=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methoxybenzyl-3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate (13.7 g, 27.8 mmole) in dichloromethane (150 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred for 2 hours at room temperature. The solution was evaporated under reduced pressure and the product crystallized from toluene. Yield: 10.1 g=87%. The compound can be activated and esterified to a drug or further modified as described below
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][N:11]=3)[N:6]([C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[S:19][C:20]([C:23]([OH:25])=O)=[CH:21][N:22]=4)[CH2:14]3)[C:5]2=[O:26])[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH:1]1([N:4]2[C:12]3=[N:11][CH:10]=[CH:9][N:8]=[C:7]3[N:6]([C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[S:19][C:20]([C:23]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:25])=[CH:21][N:22]=4)[CH2:14]3)[C:5]2=[O:26])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cnc(N[C@H]2C[C@H](n3c(=O)n(C4CC4)c4nccnc43)C2)s1
Reactant: C1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnc(N[C@H]2C[C@H](n3c(=O)n(C4CC4)c4nccnc43)C2)s1)N1CCOCC1

Procedure:
The title compound was prepared following the procedure for EXAMPLE 151, using a mixture of 2-((trans-3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)amino)thiazole-5-carboxylic acid, EXAMPLE 149, (0.07 g, 0.188 mmol), morpholine (0.025 ml, 0.282 mmol), diisopropylethylamine (0.049 ml, 0.282 mmol), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.125 g, 0.282 mmol) to give 1-cyclopropyl-3-(trans-3-((5-(morpholine-4-carbonyl)thiazol-2-yl)amino)cyclobutyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.025 g, 0.057 mmol, 30.1% yield). m/z: 442.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ: ppm 8.30 (d, J=5.67 Hz, 1 H), 7.81-8.10 (m, 2 H), 7.13 (s, 1 H), 5.13 (t, J=8.31 Hz, 1 H), 4.32 (d, J=4.50 Hz, 1 H), 3.77 (br. s., 2 H), 3.58 (br. s., 6 H), 3.12-3.27 (m, 2 H), 2.85-3.03 (m, 1 H), 2.28-2.46 (m, 2 H), 0.89-1.10 (m, 4 H).
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:19])[C:11]([C:16](O)=[O:17])=[CH:12][NH:13][C:14]=2[CH3:15])[CH:6]=[CH:7][CH:8]=1.[CH3:21][N:22](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C>[CH3:21][NH:22][C:16]([C:11]1[C:10](=[O:19])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]([F:20])[F:1])[CH:4]=2)=[C:14]([CH3:15])[NH:13][CH:12]=1)=[O:17]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1[nH]cc(C(=O)O)c(=O)c1-c1cccc(C(F)F)c1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c[nH]c(C)c(-c2cccc(C(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 16a, 931 mg, 3.33 mmol), TBTU (1.17 g, 3.64 mmol), triethylamine (0.94 mL, 6.70 mmol) in DMF (3 mL) is stirred for 30 min. Then, methylamine (5.23 mL of 2M solution in THF, 10.5 mmol) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is concentrated under reduced pressure and purified by preparative reversed-phase HPLC (XBridge, gradient of acetonitrile in water, 0.3% NH4OH, 60° C.). Yield: 0.25 g (25% of theory); ESI mass spectrum: [M+H]+=293; Retention time HPLC: 0.59 min (Z011_S03).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.[H-].[Na+].[C:25]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:36]=[C:35]([C:37]3[CH:38]=[C:39]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:40]=[CH:41][CH:42]=3)[N:34]=[C:33](Cl)[N:32]=2)[CH:26]=1>CN(C)C=O.C1COCC1>[C:39]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:40]=[CH:41][CH:42]=[C:37]([C:35]2[N:36]=[C:31]([C:27]3[CH:26]=[C:25]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH:30]=[CH:29][CH:28]=3)[N:32]=[C:33]([N:13]3[C:12]4[CH:11]=[C:10]5[C:2]([CH3:22])([CH3:1])[C:3]6[C:8]([C:9]5=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:7][CH:6]=[CH:5][CH:4]=6)[N:34]=2)[CH:38]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Reactant: Clc1nc(-c2cccc(-c3ccccc3)c2)nc(-c2cccc(-c3ccccc3)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4nc(-c5cccc(-c6ccccc6)c5)nc(-c5cccc(-c6ccccc6)c5)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18.6 g (64.6 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene are dissolved in 400 ml of dimethylformamide under a protective-gas atmosphere, and 3.1 g of 60% NaH in mineral oil (77.5 mmol) are added. After 1 h at room temperature, a solution of 2,4-bisbiphenyl-3-yl-6-chloro-1,3,5-triazine (32.6 g, 64.6 mmol) in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. Yield: 41.5 g (61 mmol), 80% of theory.
Reaction SMILES: [F-].[K+].[F:3][C:4]([Si](C)(C)C)([F:6])[F:5].[Br:11][C:12]1[CH:13]=[N:14][C:15](I)=[N:16][CH:17]=1.N>CN1C(=O)CCC1.CN(C)C=O>[Br:11][C:12]1[CH:13]=[N:14][C:15]([C:4]([F:6])([F:5])[F:3])=[N:16][CH:17]=1
Reactant: Brc1cnc(I)nc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: N
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ncc(Br)cn1

Procedure:
A mixture of potassium fluoride (1.77 g) and cuprous iodide (5.79 g) was stirred and heated together using a heat gun under vacuum (˜1 mm) for 20 min. After cooling, dimethyl formamide (20 ml) and N-methyl pyrrolidinone (20 ml) were added followed by (trifluoromethyl)trimethylsilane (4.1 ml) and 5-bromo-2-iodopyrimidine (6.5 g). The mixture was stirred at rt for 5 h and then the brown solution was poured into 6N ammonia solution. The product was extracted into ethyl acetate and the extracts were washed with sodium bicarbonate solution and brine and then dried (Na2SO4) and evaporated. Chromatography on silica gel (elution with 20-50% dichloromethane in pentane) gave the title compound (D30) as a white solid (2.4 g). 1H NMR (CDCl3): 8.97 (2H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:32]=[N:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[C:36]([OH:41])[CH:35]=2>CN(C=O)C>[F:30][C:31]1[CH:32]=[N:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[C:36]([O:41][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)[CH:35]=2
Reactant: Oc1ccc2cc(F)cnc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cc(F)cnc4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (144 mg, 0.43 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (91 mg, 0.66 mmol) and 3-fluoro-7-hydroxyquinoline (77 mg, 0.47 mmol), (prepared as described for the starting material in Example 157), in DMF (3 ml) was stirred at 100° C. for 2 hours and then allowed to cool to ambient temperature. The reaction mixture was evaporated to dryness and the residue chromatographed on silica eluting with methanol/dichloromethane/aqueous ammonia (0.880) (5/100/1). The relevant fractions were combined and evaporated to dryness to give 4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (87 mg, 44%).
Reaction SMILES: Br[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@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[H][H]>C(O)C.[Pd]>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:2][CH:3]=2)[NH:7][CH:6]=1
Reactant: [H][H]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [Pd]
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccccc12
Yield: 65.3 %

Procedure:
(R)-5-Bromo-3-(N-methylpyrrolidin-2-yl-methyl)-1H-indole (60 mg, 0.2 mmol) was dissolved in ethanol (1 mL) and hydrogenated over 10% palladium on carbon (45 mg) at 60 p.s.i. of hydrogen pressure at room temperature for 16 hours. The reaction mixture was evaporated to dryness, and the residue partitioned between ethyl acetate and 10% aqueous sodium carbonate. The organic phase was dried (Na2SO4), and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluting with 89:10:1 CH2Cl2 :MeOH:NH4OH) to give the title compound (28 mg). Anal. Calcd for C14H18N2 ·1/8 CH2Cl2C,75.42; H,8.18; N,12 46 Found: C,75 50; H,8 51; N,12 09. [α]25D =+60.2° (c=0.088, CHCl3).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:53][C:54]1([F:58])[CH2:57][NH:56][CH2:55]1.CCN(C(C)C)C(C)C>C1COCC1>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][N:23]=[C:22]([N:56]4[CH2:57][C:54]([F:58])([F:53])[CH2:55]4)[N:21]=3)[C@H:14]2[CH3:49])[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:50])[CH:8]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(N3CC(F)(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-tert-butyl-1,3-thiazol-2-yl}-3-methylbenzoic acid (INTERMEDIATE 52, 80 mg, 0.106 mmol) in THF (5 mL) was added 3,3-difluoroazetidine hydrochloride (41.1 mg, 0.317 mmol) and DIEA (0.092 mL, 0.529 mmol). The reaction mixture was stirred at 60° C. for 15 minutes to see complete conversion by LCMS. The solvent was evaporated, and the residue was purified on reverse phase HPLC, eluting with water and acetonitrile (10% to 100%), to give the title compound as a yellowish solid after lyophilization (72 mg, 88% yield). LCMS (M+H)+: 770.1. 1H NMR (CDCl3, 500 MHz): δ 8.35 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.87 (m, 1H), 7.79 (s, 2H), 5.82 (d, 9.0 Hz, 1H), 5.50 (m, 1H), 4.75 (m, 1H), 4.58-4.34 (m, 4H), 4.09 (m, 1H), 3.75 (s, 3H), 1.33 (s, 9H), 0.81 (d, 7.0 Hz, 3H). RTA IC50: 800 nM.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1.Cl.C([OH:16])C>>[OH:16][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1
Reactant: CSc1nc2cccccc-2n1
Reactant: CCO
Agent: Cl
Product: Oc1nc2cccccc-2n1
Temperature: 25 °C

Procedure:
First, 60 g of 2-methylthiocycloheptimidazole as synthesized according to Synthetic example 1 (c) with reference to the method disclosed in Journal of the American Chemical Society, vol. 76, pages 3352 and 3353 (1954) was added to 300 ml of concentrated hydrochloric acid (hydrogen chloride 35%), and refluxed with heating for 2 hours and 30 minutes. Then, 500 ml of ethanol was added, and after stirring at room temperature, deposited crystals were collected by filtration. The crystals were dissolved in 0.5 of water, and pH was adjusted to around 7 with sodium bicarbonate. Deposited crystals were collected by filtration, washed with water and dried.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(N(C(C)C)CC)(C)C>>[NH2:9][C:3]1[NH:4][C:5](=[O:8])[N:6]=[CH:7][C:2]=1[N:13]1[CH2:14][CH2:15][CH2:16][CH:11]([F:10])[CH2:12]1
Reactant: Nc1nc(=O)[nH]cc1Br
Reactant: FC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1[nH]c(=O)ncc1N1CCCC(F)C1

Procedure:
Method 8 was followed using 1 eq. of 5-bromocytosine, 1.25 eq. of 3-fluoropiperidine and 2.5 eq. of diisopropylethylamine at 120° C. for 2 days yielding 6-amino-5-(3-fluoropiperidin-1-yl)pyrimidin-2(1H)-one as an orange crunchy solid (24%). LCMS (m/z): 213.0 (MH+); LC Rt=1.07 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=[O:33])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:33])=[CH:27][CH:26]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCO)CC2)c1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCOC(=O)Cc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxybutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and (4-fluorophenyl)acetyl chloride: ESMS m/e: 455.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[O:22][CH2:23][CH2:24][NH2:25].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[O:22][CH2:23][CH2:24][NH:25][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1ccccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccccc3F)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 25.6 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(2-fluorophenoxy)ethylamine hydrochloride (700 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(2-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile hydrochloride (126 mg).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[S:18][C:19]([N+:22]([O-])=O)=[CH:20][N:21]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:30](O)(=[O:32])[CH3:31]>C(OC(=O)C)(=O)C.[Fe]>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[S:18][C:19]([NH:22][C:30](=[O:32])[CH3:31])=[CH:20][N:21]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Iron powder (162 mg, 2.9 mmol) was added to a stirred solution of 3-cyclobutyl-7-[(5-nitro-1,3-thiazol-2-yl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E210a) (162 mg, 0.47 mmol) in acetic acid (1 ml) and acetic anhydride (1 ml). The reaction mixture was stirred at 80° C. for 16 hours then cooled and poured onto ice. The solution was basified to pH 8 (sodium bicarbonate) and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried (sodium sulfate). Concentration in vacuo and subsequent purification of the resulting residue by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.3:2.7:97) afforded the title compound (E210). MS (ES+) m/e 358 [M+H]+.