Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc(OCCCCl)cc1

Procedure:
A mixture of 0.47 g (0.004 mol) of 4-hydroxybenzonitrile, 0.63 g (0.004 mol) of 1-bromo-3-chloropropane and 1.95 g (0.006 mol) of caesium carbonate in 10 ml of acetonitrile is heated at reflux for 5 hours.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[N:14][CH:13]=[CH:12][N:11]=2)=[O:9])[S:5][CH:6]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([F:17])[CH:19]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Nc1cccc(F)c1
Reactant: Cc1csc(NC(=O)c2nccnc2Br)n1
Product: Cc1csc(NC(=O)c2nccnc2Nc2cccc(F)c2)n1

Procedure:
The title compound, MS: m/e=330.1 (M+H+), was prepared in accordance with the general method of example 4, step 2 from 3-bromo-pyrazine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide and 3-fluoroaniline.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH3:15])=[S:4].[IH:16].[CH3:17]I>CO>[IH:16].[IH:16].[CH3:1][NH:2][C:3](=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH3:15])[S:4][CH3:17]
Reactant: CNC(=S)NCCSCc1nc[nH]c1C
Reactant: CI
Agent: I
Solvent: CO
Product: CNC(=NCCSCc1nc[nH]c1C)SC

Procedure:
N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea (10.0 g) was dissolved in methanol (400 ml) and 55% aqueous hydriodic acid (12.2 ml) was added, followed by methyl iodide (5.3 ml). The solution was heated under reflux for 4 hours and concentrated. The residue was dissolved in methanol (100 ml) and ether was added to afford the title product as the dihydriodide (5.48 g) m.p. 185°-186° (from isopropyl alcohol). (Found: C, 23.4; H, 3.9; N, 10.9; I, 49.6; S, 12.6; C10H18N4S2.2HI requires: C, 23.4; H, 3.9; N, 10.9; I, 49.4; S, 12.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][C:5]=1[F:11].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:6][C:5]=1[F:11]
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(F)nc1F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NCc2ccc(Cl)cc2)nc1F
Reaction time: 2 h

Procedure:
To 2,6-difluoro-nicotinic acid methyl ester (60, 2.00 g, 0.0116 mol) in N,N-dimethylformamide (20.0 mL), under an atmosphere of nitrogen at −40° C., was added p-chlorobenzylamine (61, 2.60 mL, 0.0214 mol). The reaction was stirred at −40° C. to −20° C. for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to give compound (62, 2.0 g, 58.7%).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])=[C:19]([F:30])[C:15]3[N:16]=[CH:17][S:18][C:14]=3[CH:13]=2)=[O:11])[CH2:4][O:3]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[C:19]([F:30])[C:15]2[N:16]=[CH:17][S:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CC1(C)OCC(CONC(=O)c2cc3scnc3c(F)c2Nc2ccc(I)cc2F)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NOCC(O)CO)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Yield: 70 %

Procedure:
To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxamide (475 mg, 0.85 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and neutralized with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH2Cl2 (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 20:1, v/v) to afford the desired product (white solid, 310 mg, 45.4% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 11.82 (s, 1H), 9.56 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.57 (d, 1H), 7.32 (d, 1H), 6.47 (m, 1H), 4.85 (d, 1H), 4.62 (m, 1H), 3.86 (m, 1H), 3.71 (m, 2H), 3.35 (m, 2H). MS APCI (+) m/z: 522.5 [M+H].
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>N1C=CC=CC=1>[C:20]([CH2:19][CH2:18][C:17]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)=[O:23])([OH:22])=[O:21]
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: Nc1nc2c(ncn2COCCOC(=O)CCC(=O)O)c(=O)[nH]1
Yield: 44 %

Procedure:
A mixture of 9-(2-hydroxyethoxymethyl)guanine (0.25 g), succinic anhydride (0.55 g) and pyridine (50 ml) was heated under anhydrous conditions on a steam bath overnight. The solvent was evaporated under reduced pressure at <40° C., the last trace being removed azeotropically with toluene. The residue was triturated with acetone and the product removed by filtration. Recrystallization from methanol afforded 9-{2-(3-carboxypropionyloxy)ethoxymethyl}guanine, m.p. 203°-207° C. (sinter 190° C.), in 44% yield.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=[O:12].C(N(CC)CC)C.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>ClCCl>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:1][C:2](=[O:12])[CH2:3][CH2:4]2)=[O:28])=[CH:30][CH:31]=1)([O-:22])=[O:21]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCNc2ccccc2N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of 1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (0.87 g) and triethylamine (0.55 g) in dichloromethane (5 ml) was added a solution of 4-nitrobenzoyl chloride (1.00 g) in dichloromethane (5 ml) at ambient temperature. After being stirred at ambient temperature for 2 hours, the solution was washed successively with 0.5N hydrochloric acid, saturated sodium bicarbonate aqueous solution, and brine. The organic layer was dried over magnesium sulfate, filtered and the solvents was evaporated. Trituration with a mixture of diethyl ether and diisopropyl ether (1:1) of a crude product afforded 5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.60 g) as a slightly brown powder.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:12][O:13][CH2:14][C:15]1([N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CC(NC(C)C)C>CC(C)CC(=O)C>[C:3]([CH:2]([N:18]1[CH2:19][CH2:20][C:15]([N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22](=[O:25])[CH2:23][CH3:24])([CH2:14][O:13][CH3:12])[CH2:16][CH2:17]1)[CH3:11])(=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)CC(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(C(C)C(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 3.6 parts of 2-bromo-1-phenyl-1-propanone, 4.1 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, 3.5 parts of N-(1-methylethyl)-2-propanamine and 80 parts of 4-methyl-2-pentanone is stirred and refluxed for 16 hours. The reaction mixture is cooled to room temperature and the precipitate is filtered off. The filtrate is evaporated. The oily residue is purified by column-chromatography over silicagel, using a mixture of trichloromethane and 3% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue solidifies on triturating in petroleumether. The product is filtered off and crystallized from 2,2'-oxybispropane. It is filtered off again and dried, yielding N-[1-(1-benzoylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide; mp. 123° C.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11]Br>CCCCCC.Br.C(OCC)(=O)C>[Br:11][C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH3:10])[CH2:8][NH2:9])=[CH:2][CH:3]=1
Reactant: BrBr
Reactant: CC(CN)c1ccccc1
Agent: Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(CN)c1ccc(Br)cc1
Yield: 23 %

Procedure:
2-Phenyl-propylamine (1 g, 7.4 mmol) was dissolved in n-hexane (30 mL) and HBr/aq (5 drops) together with ZnBr on silica (1.75 mmol/g, 1 g). Br2 (14.8 mmol, 900 μL) was slowly added and the slurry was stirred over night. The slurry was diluted with ethyl acetate (300 mL) and washed with 2M Na2CO3 (300 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. Purification and separation of regioisomers was done on semi prep-HPLC C18-column (H2O:CH3CN, 1% NH4OAc buffer, gradient 10% to 60% CH3CN, 30 min). Yield 23%
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[C:14](=[O:18])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]Br.CCOCC>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[C:14]([OH:18])([CH3:27])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Yield: 56 %

Procedure:
To a solution of benzyl-(3R,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-oxopiperidine-1-carboxylate (1.61 g, 4.44 mmol) in THF (30 mL) at −78° C. a solution of methylmagnesium bromide in ether (3.0 M, 4.4 mL, 13 mmol) was added. The reaction was then quenched by adding aq. NH4Cl, and the resulting mixture was extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20-80% EtOAc in hexanes to give a mixture of the two diastereoisomers of the sub-title compound as a colorless oil (0.95 g, 56%). LCMS calc. for C20H30N2NaO5 (M+Na)+ m/z=401.2. found 401.0.40% of unreacted starting material was also isolated.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([Br:19])=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[N:13]=[C:12]([CH3:18])[CH:11]=[CH:10]2)(=O)=O.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[Cl-].[Li+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:19][C:8]1[C:7]([CH:22]=[CH2:23])=[C:16]([CH3:17])[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12]([CH3:18])=[N:13]2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc2c(Br)c(OS(=O)(=O)C(F)(F)F)c(C)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc2nc(C)ccc2c1Br
Temperature: 80 °C
Yield: 87.7 %

Procedure:
PdCl2(PPh3)2 (207 mg, 0.30 mmol) was added to a mixture of 5-bromo-2,7-dimethylquinolin-6-yl trifluoromethanesulfonate (5A) (1.13 g, 2.95 mmol), tributyl(vinyl)stannane (0.95 mL, 3.25 mmol) and lithium chloride (375 mg, 8.85 mmol) in DMF (30 mL). The reaction mixture was flushed with argon, heated at 80° C. for 4 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide 5B (678 mg, 88%). LCMS-ESI+ (m/z): 262.1, 264.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][CH:12]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1)[CH3:10].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][CH:12]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:13]1[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1)[CH3:10]
Reactant: COc1ccc(C(NC(C)c2ccc(F)cc2F)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(NC(C)c2ccc(F)cc2F)c2cccc(N)c2)cc1
Yield: 86.1 %

Procedure:
Following a similar procedure to that described in Example (1b), 2.80 g of N-[1-(2,4-difluorophenyl)ethyl]-N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 3.34 g of nickel chloride hexahydrate and 1.12 g of sodium borohydride were reacted, to obtain 2.23 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:17]1[N:22]=[N:21][C:20]([N:23]2[CH2:28][C@@H:27]([CH3:29])[NH:26][CH2:25][C@@H:24]2[CH3:30])=[C:19]2[CH:31]=[N:32][CH:33]=[CH:34][C:18]=12>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>[CH3:30][C@H:24]1[CH2:25][NH:26][C@H:27]([CH3:29])[CH2:28][N:23]1[C:20]1[N:21]=[N:22][C:17]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:18]2[CH:34]=[CH:33][N:32]=[CH:31][C:19]=12
Reactant: OB(O)c1ccccc1
Reactant: C[C@@H]1CN(c2nnc(Cl)c3ccncc23)[C@@H](C)CN1
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+]
Product: C[C@@H]1CN(c2nnc(-c3ccccc3)c3ccncc23)[C@@H](C)CN1
Temperature: 100 °C
Yield: 93.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (146 mg, 126 μmol), phenylboronic acid (461 mg, 3.78 mmol), 2 M sodium carbonate (2520 μl, 5.04 mmol), and 1-chloro-4-(trans-2,5-dimethylpiperazine-1-yl)pyrido[3,4-d]pyridazine 43 (700 mg, 2.52 mmol) were added to a round bottom flask. The reaction vessel was purged with nitrogen and toluene (25 mL) was added. The reaction was heated to 100° C. overnight. After cooling to RT, the reaction was diluted with 250 mL of ethyl acetate and washed with 1×50 mL of sat. NaHCO3 and 1×50 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (10:0.5:0.1 CH2Cl2:MeOH, Et3N) afforded racemic 4-(trans-2,5-dimethylpiperazine-1-yl)-1-phenylpyrido[3,4-d]pyridazine 44 (750 mg, 93% yield). 1H-NMR (400 MHz, CDCl3): δ 9.76 (d, J=1.2 Hz, 1H), 8.94 (d, J=5.5 Hz, 1H), 7.84 (dd, J=5.9, 1.2 Hz, 1H), 7.78 (m, 2H), 7.57 (m, 2H), 3.83 (dqd, J=10.2, 5.9, 3.1 Hz, 1H), 3.47 (dd, J=12.1, 2.7 Hz, 1H), 3.30 (dqd, J=9.8, 6.3, 2.7 Hz, 1H), 3.25 (dd, J=12.5, 3.1 Hz, 1H), 2.94 (dq J=12.1, 10.2 Hz, 1H), 2.73 (dd, J=12.1, 9.8 Hz, 1H), 1.17 (d, J=6.3 Hz, 1H), 1.11 (d, J=6.6 Hz, 1H). MS 319.2 (calc'd) 320.2 (M+H, found).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2([C:35](O)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH:10]([NH:12][C:35]([C:29]2([O:28][C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:36])[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)C1(Oc2ccc(Cl)cc2)CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)C1(Oc2ccc(Cl)cc2)CCCCC1)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride (Diastereomer α, Reference Example 1) (60 mg, 0.19 mmol) and 1-(4-chlorophenyloxy)cyclohexanecarboxylic acid (60 mg, 0.24 mmol) in 1 mL of methylene chloride was added N,N-diisopropylethylamine (0.10 mL, 0.58 mmol) and tris(pyrrolindinyl)phosphonium hexafluorophosphate (0.10 g, 0.19 mmol). After stirring at room temperature overnight, the reaction mixture was loaded onto a silica gel column eluted with 6:1 hexane/ether to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.22 (d, 2H), 7.19 (d, 2H), 7.03 (d, 2H), 6.99 (d, 2H), 6.91 (d, 2H), 6.71 (d, 2H), 4.24 (m, 1H), 2.99 (dd, 1H), 2.80 (ddd, 1H), 2.63 (dd, 1H), 2.3-1.2 (m, 10H), 0.82 (d, 3H). LC-MS: m/e 530 (M+H)+ (5.0 min).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:17])[C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1>C(OCC)(=O)C.[Pt](=O)=O>[NH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:17])=[O:16]
Reactant: COCCN(C)C(=O)c1cccc([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COCCN(C)C(=O)c1cccc(N)c1
Reaction time: 8 h
Yield: 103.6 %

Procedure:
To a stirred solution of N-(2-methoxyethyl)-N-methyl-3-nitrobenzamide (840 mg) in ethyl acetate (8 ml) was added platinum dioxide (160 mg) and the resulting heterogeneous mixture was stirred under hydrogen atmosphere for 8 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate to give 3-amino-N-(2-methoxyethyl)N-methylbenzamide (761 mg) as a brown viscous oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].C=O.[C:28]([BH3-])#N.[Na+]>C(O)(=O)C>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[N:22]([CH3:28])[CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCCC1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 38 %

Procedure:
Compound 117 was prepared according to General Method 5 (EXAMPLE 2) from (±)-3,4-dihydro-8-isopropoxy-3-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (18 mg, 0.05 mmol), 37% aqueous formaldehyde (0.01 mL, 0.3 mmol, 5 eq), sodium cyanoborohydride (16 mg, 0.3 mmol, 5 eq) in 1 mL acetic acid (0.05 M) stirred at rt for 12 h to afford 7 mg of (3R/S)-3,4-dihydro-8-isopropoxy-4-methyl-3-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (7 mg, 0.02 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 4 mL of a 1:1 acetic acid:concentrated HCl (5 mM) and heated at 90° C. for 6 h to afford 5 mg (83%) of Compound 117 after column chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 10.83 (bs, 1H), 7.11 (s, 1H), 6.99 (d, J=8.8, 1H), 6.87 (d, J=8.8, 1H), 4.28 (dd, J=10.7, 2.2, 1H), 4.07 (dd, J=10.7, 2.4, 1H), 3.24 (m, 1H), 2.97 (s, 3H), 1.48 (m, 4H), 0.96 (t, J=7.3, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]([O:22]CC)=[O:21])[C:9]1=[S:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]([OH:22])=[O:21])[C:9]1=[S:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1c(=S)n(Cc2ccccc2)c(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1c(=S)n(Cc2ccccc2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 2-[2-(N-benzylcarbamoyl)-anilino]acetate (1.5 g) and N,N'-thiocarbonyldiimidazole (2.85 g) was stirred at 120° C. for 30 minutes. After cooling, the reaction mixture was diluted with chloroform and chromatographed on silica gel. Elution with chloroform gave ethyl 2-(3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl)acetate. A mixture of ethyl 2-(3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl)acetate and 1N sodium hydroxide (2 ml) in methanol (10 ml) was stirred for 4 hours at room temperature. The reaction mixture was poured into dilute hydrochloric acid and extracted with chloroform. The extract was washed with brine and dried. Removal of the solvent gave 2-(3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl)acetic acid (280 mg).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[C:11]([C:16]#[N:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][NH:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[CH3:29][O:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25][N:4]1[CH:5]=[C:6]([C:10]2[C:11]([C:16]#[N:17])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:7](=[O:9])[NH:8][C:3]1=[O:2]
Reactant: N#Cc1ncccc1-c1c[nH]c(=O)[nH]c1=O
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2cccnc2C#N)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
A mixture of 3-(2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-pyridine-2-carbonitrile hydrochloride (Prep103, 500 mg, 2 mmol), and K2CO3 (413 mg, 3 mmol) in DMF (7 ml) was stirred for one hour at room temperature. 3-Bromo-1,1dimethoxy-propane (402 mg, 2.2 mmol) was added and stirring continued for 48 hours. Water was added and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 210 mg of a yellow oil (33% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12]([OH:22])[C:11]1=[O:23])=[O:4].O[Li].O.Cl.[CH2:34]1COCC1.O.CO>>[CH3:28][C:26]([CH3:29])([CH3:27])[C:25]#[C:24][C:7]1[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]2[C@H:15]([CH:16]([CH2:21][CH3:20])[CH2:17][CH2:18][CH2:19][CH3:34])[CH2:14][CH2:13][C@H:12]([OH:22])[C:11]2=[O:23])[CH:8]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](O)CC[C@H]1C1CCCCC1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CCCCC(CC)[C@@H]1CC[C@H](O)C(=O)N1c1cc(C#CC(C)(C)C)sc1C(=O)O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a solution of 3-((3S,6S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (1.5 g, 3.59 mmol, 1 equiv.) in THF/H2O/MeOH (5.0 mL/5.0 mL/1.0 mL) was added LiOH.H2O (0.79 g, 17.56 mmol, 5.0 equiv.) at room temperature. The reaction mixture was stirred at 50° C. for 20 minutes. The reaction was then acidified to pH=5 by addition of 3.0 N HCl aq. solution and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated. The residue was purified by prep-HPLC (XBridge Prep C 18 5 um, 30×50 mm) in basic condition (0.1% NH4OH, 10%˜45% CH3CN/H2O, 10 min run, 40 ml/min) to give 850 mg of product (yield 57%). MS: 404 [M+H+]. 1H-NMR (400 MHz, MeOD): δ 6.95 (s, 1H), 4.09 (m, 1H), 3.74 (m, 1H), 2.09 (m, 1H), 1.94-1.67 (m, 8H), 1.38 (m, 1H), 1.33 (s, 9H), 1.17 (m, 5H).