Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][CH2:13][CH:14]([OH:16])[CH3:15].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24](F)[CH:25]=1)[C:21]#[N:22].O>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:16][CH:14]([CH3:15])[CH2:13][O:12][CH3:11])[CH:25]=1)[C:21]#[N:22]
Reactant: COCC(C)O
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)Oc1cc(Br)cc(C#N)c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
NaHMDS (148 mmol; 27.2 g) was charged to a 1000 ml round-bottomed flask (4 necks, thermometer, pressure-equalising dropping funnel, stopper, nitrogen inlet, magnetically stirred, oven dried, nitrogen purged), followed by DMF (300 ml). The mixture was stirred for 5 minutes then 1-methoxy-2-propanol (1.50 equiv; 148 mmol; 14.3 ml; 13.4 g) was added dropwise over a 10-minute period. The reaction temperature increased to 25° C. The mixture was cooled using a cold-water bath to 23° C., then 3-bromo-5-fluorobenzonitrile (1.00 equiv; 99.0 mmol; 20.0 g) in DMF (90 ml) was added over a 5 minutes period (cold water bath still present). The mixture warmed to 27° C. during addition, turning from yellow to brown. A line wash of DMF (10 ml) was added. The mixture was stirred at ambient temperature for 30 minutes, then quenched by addition of HCl solution (2M, aqueous, 200 ml), the dark brown reaction mixture turning pale yellow. The mixture was poured into water (400 ml) and extracted with EtOAc (3×400 ml). The combined organic extracts were washed with water (3×400 ml) and dried over MgSO4, filtered and the solvent removed in vacuo affording 3-bromo-5-(2-methoxy-1-methylethoxy)benzonitrile as an orange oil (25.38 g, 95%). 1H NMR (400 MHz, CDCl3) δ: 7.32 (s, 1H), 7.26 (s, 1H), 7.11 (s, 1H), 4.58-4.55 (m, 1H), 3.59-3.48 (m, 2H), 3.41 (s, 3H), 1.33-1.31 (d, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][C:2]1=[O:7].[F:8][C:9]([F:18])([F:17])[C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1>[Cu]>[F:8][C:9]([F:18])([F:17])[C:10]1[CH:15]=[CH:14][C:13]([N:1]2[CH2:6][CH2:5][S:4][CH2:3][C:2]2=[O:7])=[CH:12][CH:11]=1
Reactant: O=C1CSCCN1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Cu]
Product: O=C1CSCCN1c1ccc(C(F)(F)F)cc1
Temperature: 192.5 °C
Yield: 23.3 %

Procedure:
A mixture of thiomorpholin-3-one (500 mg, 4.27 mmol), 4-trifluoromethyl-1-iodobenzene (1.25 mL, 8.5 mmol) and copper metal (814 mg, 12.8 mmol) was heated in a sealed glass tube at 185-200° C. for 18 hours. The residue was then purified by flash chromatography to give 260 mg of the title product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccc(F)cc2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4ccc(F)cc4)C3)CC2)cc1
Yield: 70 %

Procedure:
The title compound (D150) (75 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(4-fluorophenoxy)azetidin-1-yl)nicotinic acid (D102) (70 mg, 0.216 mmol) and solution methyl 4-(1-aminocyclopropyl)benzoate (D7) (49.18 mg, 0.216 mmol).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH2:12][C@H:13]1[C@@H:18]([O:19][CH3:20])[CH2:17][CH2:16][CH2:15][N:14]1[C:21]([C:23]1[N:24]=[C:25]([CH3:35])[S:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:22]>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][CH2:12][C@H:13]1[C@@H:18]([O:19][CH3:20])[CH2:17][CH2:16][CH2:15][N:14]1[C:21]([C:23]1[N:24]=[C:25]([CH3:35])[S:26][C:27]=1[C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)=[O:22]
Reactant: CO[C@H]1CCCN(C(=O)c2nc(C)sc2-c2ccc(F)cc2)[C@H]1CN
Reactant: Clc1nc2ccccc2s1
Product: CO[C@H]1CCCN(C(=O)c2nc(C)sc2-c2ccc(F)cc2)[C@H]1CNc1nc2ccccc2s1

Procedure:
The title compound was prepared following the same general protocol as described for Example 12 using 2-chlorobenzothiazole and rac-cis-(2-(aminomethyl)-3-methoxypiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. MS (ESI) 497.0 (M+H).
Reaction SMILES: Cl.F[C:3](F)([O:15][NH2:16])[C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:5]=1[F:14].[N:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([C:21]3=O)[CH2:19]1)[CH2:25]2>C(O)C>[F:10][C:9]1[C:4]([CH2:3][O:15][N:16]=[C:21]2[CH:22]3[CH2:27][N:18]4[CH2:25][CH:24]([CH2:26][CH:20]2[CH2:19]4)[CH2:23]3)=[C:5]([F:14])[C:6]([F:13])=[C:7]([F:12])[C:8]=1[F:11]
Reactant: NOC(F)(F)c1c(F)c(F)c(F)c(F)c1F
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: Cl
Solvent: CCO
Product: Fc1c(F)c(F)c(CON=C2C3CC4CC2CN(C4)C3)c(F)c1F
Temperature: 25 °C

Procedure:
Solid O-(perfluorobenzyl)hydroxylamine HCl (167 mg, 0.669 mmol, Aldrich Chemical Co.) was added to a warm solution of 1-azatricyclo[3.3.1.13,7]decan-4-one (102 mg, 0.675 mmol) (prepared as reported in: Becker, D. P. and Flynn, D. L. Synthesis 1992, 1080-1082) in ethanol (1 mL). The mixture was swirled with warming to dissolve all solids. The nearly colorless solution was allowed to cool to room temperature overnight. The solvent was removed under vacuum, and the residue was crystallized from 10% ethanol in ethyl acetate (3 mL) to provide the title compound as hydrochloride salt. 1H NMR (300 MHz, CD3OD) δ 1.87-2.06 (m, 2 H), 2.22 (q, J=3 Hz, 1 H), 2.24-2.37 (m, 2 H), 2.83 (s, 1H), 3.30, (m, 1H), 3.43-3.57 (m, 2 H), 3.64 (s, 2 H), 3.66-3.78 (m, 2 H), 5.15-5.24 ppm (m, 2 H); MS (DCI/NH3) m/z 347 (M+H)+; Anal. C16H15N2OF5—HCl requires C, 50.21; H, 4.21; N, 7.32. Found C, 50.20; H, 3.99; N, 7.22.
Reaction SMILES: [Si:1]([C:23]1(Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:16]1(Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:9]1(Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1(Br)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:3]1([CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Si:1]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C=Cc1ccccc1
Product: C(=Cc1ccccc1[Si](c1ccccc1C=Cc1ccccc1)(c1ccccc1C=Cc1ccccc1)c1ccccc1C=Cc1ccccc1)c1ccccc1
Yield: 52 %

Procedure:
Use of tetrakis(4-bromophenyl)silane (Si(C6H4Br)4) gives access to structural analogs containing a silicon atom at the tetrahedral junction. Thus, reaction of Si(C6H4Br)4 with excess styrene gives tetrastilbenylsilane (Si(STB)4) in 52% yield using Pd(OAc)2 under phase transfer conditions. Similarly, (Si(C6H4Br)4) and 4,4′-tert-butylvinylstilbene yields tetrakis(4-tert-butylstyrylstilbenyl)silane (Si(tBuSSB)4) in 40% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[NH:14][C:13]2=[O:20])=[CH:5][CH:4]=1.[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][C:12]1([CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13](=[O:20])[NH:14][C:15](=[O:19])[NH:16][C:17]1=[O:18]
Reactant: COc1ccc(CCCC2C(=O)NC(=O)NC2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CCCC2(Br)C(=O)NC(=O)NC2=O)cc1
Yield: 87.1 %

Procedure:
A mixture of 5-[3-(4-methoxyphenyl)propyl]barbituric acid (2.5 g), N-bromosuccinimide (2 g) and dibenzoyl peroxide (catalytic amount) in 110 ml of carbon tetrachloride is refluxed for about 1 hour then the solid which separated is filtered. The solid is redissolved in ethyl acetate and filtered through a silica gel cake in order to eliminate the succinimide residue. The organic phase is then concentrated to dryness and the residue is crystallized from diethylether/carbon tetrachloride mixture. A pale yellow solid separates which is filtered and dried under vacuum at 60° C. to give 2.8 g of the product. m.p. 113-114° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](Cl)=[O:19])([CH3:14])([CH3:13])[CH3:12]>COCCOC>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:18](=[O:19])[C:17]1[CH:21]=[C:22]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:23]([OH:24])=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:16]=1)([OH:10])=[O:9]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccccc2C(=O)O)cc(C(C)(C)C)c1O
Temperature: 75 °C
Reaction time: 48 h
Yield: 48.1 %

Procedure:
A solution of 8.6g (0.063 mole) of anthranilic acid in 50 ml of 1,2-dimethoxyethane was added to a suspension of 8.0g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 150 ml of 1,2-dimethoxyethane. The reaction mixture was heated at approximately 75° C. for 30 minutes after which time it was stirred for 48 hours at room temperature. The reaction mixture was then filtered, and the filtrate was evaporated to give the crude product as an oil. This oil was triturated with a mixture of ethanol and water to give a solid which was recrystallized twice from a mixture of ethanol and water to give 5.3 g of white crystalline N-(2-carboxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 202°-203° C. Analysis: Calculated for C22H27NO4 ; %C, 71.5; %H, 7.4; %N, 3.8; Found: %C, 71.4; %H, 7.5; %N, 3.7.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[S:7]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH:26]([OH:28])[CH3:27])[C:20]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)=[CH:19][N:18]=2)=[CH:12][CH:11]=1)([CH3:9])=[O:8])=[O:5])[CH3:2].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:3][C:4]([N:6]=[S:7]([C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[C:20]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)=[CH:19][N:18]=2)=[CH:14][CH:15]=1)([CH3:9])=[O:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(NCCC(C)O)n2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(NCCC(C)=O)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(RS)—N(ethoxycarbonyl)-(4-{[4-{(3-hydroxybutyl)amino}-5-(thiophen-2-yl)-pyrimidin-2-yl]amino}phenyl)-S-methylsulfoximide (169 mg, 0.35 mmol) is dissolved in dichloromethane (15 ml) and N-methylmorpholin-N-oxid (123 mg, 1.05 mmol) and molecular sieve (4 A, 496 mg) is added. The mixture is stirred for 15 min at RT. Then tetrapropylammoniumperruthenat (6.3 mg, 0.018 mmol) is added, the reaction mixture is stirred for 24 h at RT. Additional tetrapropylammoniumperruthenat (10.4 mg, 0.03 mmol) is added and the reaction mixture is stirred for 24 h at RT. For workup the mixture is filtered through celite and washed with dichloromethane. The solvent is evaporated resulting in the crude product which is purified by column chromatography: 39 mg, 23%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH:6]1[CH2:9][NH:8][CH2:7]1)[CH3:2].C1COCC1.[C:16](Cl)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(=O)(O)[O-].[Na+]>[CH2:19]([O:18][C:16]([N:8]1[CH2:9][CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])[CH2:7]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
To a stirring mixture of azetidin-3-yl-acetic acid ethyl ester (1.0 g, 6.98 mmol), in saturated aqueous sodium bicarbonate (5 mL) and THF (5 mL) at 0° C. was added carbobenzyloxy chloride (1.1 mL, 7.68 mmol) dropwise. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 hrs, then extracted with ethyl acetate acetate (3×20 mL). The combined ethyl acetate layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane to give 0.30 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[O:16][CH3:17])(O)=[O:2].Cl.CN.Cl.[CH2:22]([N:24]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:17][O:16][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:4]=1[C:1](=[O:2])[NH:24][CH3:22])[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C=Cc1ccc(C(=O)O)c(OC)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)OC)cc1OC
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a solution of methyl 4-carboxy-3-methoxycinnamate (400 mg) in N,N-dimethylformamide were added methylamine hydrochloride (126 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (390 mg) and 1-hydroxybenzotriazole (320 mg) at ambient temperature, and the mixture was stirred for 18 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform methanol=40:1, v/v) to give methyl 3-methoxy-4-(methylcarbamoyl)cinnamate (319 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].I[CH3:12].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:12])=[CH:4][N:3]=1
Reactant: CI
Reactant: Oc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)nc1
Reaction time: 72 h
Yield: 79 %

Procedure:
2-Bromo-5-hydroxypyridine (5 mmol) is dissolved in DMF (10 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min iodomethane (2 eq.) is added and the reaction solution is stirred 3 days. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. 2-Bromo-5-methoxy-pyridine is obtained as yellow oil in a yield of 79%; HPLC (method C): 1.49 min; LC-MS (method A): 1.16 min, 187.95 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:15])[N:6]([CH3:14])[C:7](=[O:13])[NH:8]2.[H-].[Na+].Br[CH2:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22]>CN(C)C=O.O>[CH2:4]([CH:3]([CH2:12][CH3:11])[CH2:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:15])[N:6]([CH3:14])[C:7](=[O:13])[N:8]2[CH2:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:5]
Reactant: COc1cccc2[nH]c(=O)n(C)c(=O)c12
Reactant: CCC(CC)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)COc1cccc2c1c(=O)n(C)c(=O)n2CC(CC)CC
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 33.2 %

Procedure:
To a solution of 5-methoxy-3-methylquinazoline-2,4(1H,3H)-dione (47 mg, 0.228 mmol) [example 5] in N,N-dimethylformamide (1 ml) was added sodium hydride (8.6 mg, 0.342 mmol). The mixture was stirred at 80° C. for 15 min and 1-bromo-2-ethylbutane (0.064 ml, 0.0753 mmol) was added. The resulting mixture was stirred at 80° C. for 18 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting 50% ethyl acetate/n-hexane to afford 20 mg (32%) of 1-(2-ethylbutyl)-5-hydroxy-3-methyl-2,4(1H,3H)-dione (A) and 9 mg (11%) of 5-(2-ethylbutoxy)-1-(2-ethylbutyl)-3-methylquinazoline-2,4(1H,3H)-dione (B).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([NH:38][CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]4=[O:16])[CH2:34][CH2:33]3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: NC1CCN(Cc2ccc3c(c2)OCCO3)CC1
Reactant: COC(=O)c1cc(=O)n(CC=O)c2cc(OC)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(=O)n(CCNC2CCN(Cc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To 10 mL of a chloroform solution containing 111 mg of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate and 93 mg of 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamine, 23 μL of acetic acid was added and stirred at room temperature for 1 hour. To the reaction mixture, 132 mg of sodium triacetoxyborohydride was added and stirred for 0.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=3:1], to give 134 mg of methyl 1-(2-(1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamino)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[CH3:13][Mg]I>>[F:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[CH2:6][CH2:7][CH:8]=[C:9]2[CH3:13]
Reactant: O=C1CCCc2ccc(F)cc21
Reactant: C[Mg]I
Product: CC1=CCCc2ccc(F)cc21

Procedure:
Using general procedure A (Exp. 1.1), 7-fluoro-3,4-dihydro-2H-naphthalen-1-one (Lit. 16) was reacted with MeMgI to give 6-fluoro-4-methyl-1,2-dihydro-naphthalene as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[N+:17]([CH3:20])([O-:19])=[O:18]>>[N+:17]([CH2:20][CH:9]([OH:10])[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)([O-:19])=[O:18]
Reactant: O=CC(c1ccccc1)c1cccc(Cl)c1
Reactant: C[N+](=O)[O-]
Product: O=[N+]([O-])CC(O)C(c1ccccc1)c1cccc(Cl)c1

Procedure:
the reaction of m-chlorophenyl-phenylacetaldehyde with nitromethane in the presence of a base to yield 3-nitro-1-phenyl-1-(m-chlorophenyl)propan-2-ol
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:16])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:20]=1[CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1.COC(C)(C)C>[CH3:16][C:9]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=[C:2]([O:1][CH2:21][C:20]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:19]=3[F:18])[N:7]2[N:8]=1
Reactant: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Reactant: OCc1c(F)ccc(F)c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)ccc(F)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
1.2 g (5.25 mmol) of ethyl 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 8A were dissolved in 48 ml of THF. 1.7 g (10.50 mmol) of 2,3,6-trifluorobenzyl alcohol and 2.9 g (11.03 mmol) of triphenylphosphine were added. Subsequently, 2.2 ml (11.03 mmol) of diisopropyl (E)-diazene-1,2-dicarboxylate were added to the solution, which was stirred at RT for 1 h. 120 ml of tert-butyl methyl ether were added, then the mixture was stirred briefly, and the solids formed were filtered off and dried under high vacuum. 1.2 g of the target compound were obtained (62% of theory).
Reaction SMILES: C([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][C@H:24]3[C@:22]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)([CH2:23]3)[CH2:21]2)[C:10]1=[O:36])(=O)C1C=CC=CC=1>N.CO>[I:16][C:13]1[C:14](=[O:15])[NH:9][C:10](=[O:36])[N:11]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][C@H:24]3[C@:22]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=4)([CH2:23]3)[CH2:21]2)[CH:12]=1
Reactant: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c1=O
Agent: N
Solvent: CO
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
3-Benzoyl-5-iodo-1-{3-[(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-propyl}-1H-pyrimidine-2,4-dione (Prep 39, 840 mg, 1.38 mmol) was dissolved in 10% NH3 in MeOH solution (5 mL). The mixture was stirred at room temperature for 1 hour, the solvent was then evaporated under vacuum and the crude purified by flash chromatography with DCM-MeOH—NH4OH (98-2-1) to give the title compound as a white solid (515 mg, 74% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH:13]([C:15]([OH:17])=[O:16])[CH2:14][C:6]=3[C:5]=2[CH:4]=1.Cl.[CH2:19](O)[CH3:20]>>[CH2:19]([O:16][C:15]([CH:13]1[CH2:12][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:6]=2[CH2:14]1)=[O:17])[CH3:20]
Reactant: CCO
Reactant: COc1ccc2[nH]c3c(c2c1)CC(C(=O)O)C3
Agent: Cl
Product: CCOC(=O)C1Cc2[nH]c3ccc(OC)cc3c2C1
Temperature: 25 °C

Procedure:
To a suspension of 1,2,3,4-tetrahydro-7-methoxycyclopent[b]indole-2-carboxylic acid (10 g, 0.043 mole) in 100 ml of absolute ethanol, was added 3 ml of ethereal HCl solution, and the mixture was stirred at ambient temperature for twenty hours. The mixture was concentrated to a brown oil (10 g), which was eluted on a silica gel column with 1% ethyl acetate/dichloromethane via HPLC. The desired fractions were combined and concentrated to afford a brown oil, which solidified on cooling to give 8.0 g of a lavender solid ,mp 82°-3° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Nc1cccc(F)c1
Product: Cc1cc(Nc2cccc(F)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and 3-fluoroaniline (47 μl, 0.486 mmol) similar to Example 11 and isolated as a light brown solid (74 mg, 54%). 1H NMR (CDCl3): 8.83 (d, J=4.8 Hz, 1H), 8.47 (d, J=9 Hz, 1H), 7.88 (m, 1H), 7.44-7.30 (m, 4H), 7.18-7.14 (m, 1H), 6.92-6.86 (m, 1H), 6.80 (s, 1H), 2.55 (s, 3H).