Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:9]=2)[N:4]=1.[CH2:18]([N:20](CC)[CH2:21][CH3:22])[CH3:19].C(NCC)C>CN(C=O)C>[CH2:18]([N:20]([CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:9]=2)[N:4]=1)[CH2:21][CH3:22])[CH3:19]
Reactant: COC(=O)c1ccc2c(=O)[nH]c(CCl)nc2c1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)Cc1nc2cc(C(=O)OC)ccc2c(=O)[nH]1
Temperature: 100 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a solution of methyl 2-(chloromethyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (160 mg, 0.63 mmol) in DMF (3 mL) was added triethylamine (0.176 mL, 1.27 mmol) and diethylamine (0.33 mL, 3.17 mmol). The reaction mixture was heated to 100° C. and stirred for 3 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 10% MeOH/DCM) to afford methyl 2-[(diethylamino)methyl]-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.15 g, 81%). LC-MS: (FA) ES+ 290.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32]OS(C)(=O)=O)[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:19][CH:18]=2)[C:13]1=[O:31])[CH3:11].[NH:39]1[CH:43]=[N:42][CH:41]=[N:40]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:38])([CH2:32][N:39]1[CH:43]=[N:42][CH:41]=[N:40]1)[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])=[CH:21][CH:22]=2)[C:13]1=[O:31])[CH3:11]
Reactant: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 90 °C
Yield: 47.7 %

Procedure:
1-[(1R, 2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H, 3H)-imidazolone(0.55 g) was dissolved in 15 ml of dimethylformamide, to which 0.329 g of 1H-1,2,4-triazole and 1.34 g of potassium carbonate were added. The mixture was heated at 90° C. for 5 hours. After cooling, the reaction solution was diluted with 60 ml of ethyl acetate, and washed with 30 ml of water, 1N-hydrochloric acid (30 ml×2) and 30 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=2:1). The desired fraction was concentrated and the residue was recrystallized from a mixture of 2 ml of ethyl acetate and 10 ml of diisopropyl ether to give 0.25 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (yield: 47%) as colorless powdery crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C@H:22]([CH2:26][C:27]3[CH:35]=[C:34]([CH3:36])[C:33]4[C:29](=[CH:30][N:31]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:32]=4)[CH:28]=3)[C:23](O)=[O:24])=[O:20])[CH2:15][CH2:14]1)=[CH:7]2.C(N(CC)C(C)C)(C)C.[N:54]1([CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C@H:22]([CH2:26][C:27]3[CH:35]=[C:34]([CH3:36])[C:33]4[C:29](=[CH:30][N:31]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[N:32]=4)[CH:28]=3)[C:23](=[O:24])[N:63]3[CH2:64][CH2:65][CH:60]([N:54]4[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]4)[CH2:61][CH2:62]3)=[O:20])[CH2:17][CH2:18]1)=[CH:7]2
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4cccc(F)c4[nH]c3=O)CC2)C(=O)O)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4cccc(F)c4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
(R)-2-(4-(8-Fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)propanoic acid (105 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (3 mL). N,N-Diisopropylethylamine (100 μL, 0.57 mmol) was added to the mixture followed by o-benzotriazol-1-yl-N,N,N′-tetramethyluronium tetrafluoroborate (65 mg, 0.20 mmol). The reaction was stirred at room temperature for 5 min. 4-Piperidinopiperidine (41 mg, 0.22 mmol) was added to the mixture. The reaction was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetae (25 mL), washed successively with water (3×), and brine. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The title compound was obtained without further purification as white solid in 96% yield. Mass spec.: 773.3 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25](O)[CH2:26][CH2:27][OH:28]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:28][CH2:27][CH2:26][CH2:25][O:12]1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C12OCCCO2
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A mixture of 5-chloroisatin (5.00 g, 27.5 mmol), p-toluenesulfonic acid monohydrate (1.05 g, 5.5 mmol, 0.2 mole %) and 1,3 propanediol (6.04 mL, 83 mmol, 3 eq) in benzene (535 mL) was refluxed with a Dean Stark Trap for 7.5 hr. After cooling to room temperature the solution was decanted from the reaction mixture and concentrated The residue was washed with sat. aq. NaHCO3 (2×), brine (1×), dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with 70/30 Petroleum ether/EtOAc to give the title compound as a pale yellow solid (4.77 g, 72.5% ). A portion was dried at 42° C. in vacuo to give the analytically pure sample. Anal: Calc'd for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.84. Found: C, 55.31; H, 4.34; N, 5.78. NMR (300 Mz, DMSO-d6): consistent. IR: consistent. MS: (ES−) m/z 238 [M−H]; one Cl pattern observed, consistent. m.p.: 184-185° C.
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(NCc4ccccc4)cc23)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(N)cc23)C1
Yield: 16.4 %

Procedure:
A mixture of 5-benzylamino-3-(N-methylpyrrolidin-3-yl)-1H-indole (7.80 g, 25.5 mmol), ammonium formate (16.10 g, 255 mmol, 10 eq), and 10% Pd on carbon (0.78 g) in absolute ethanol (250 mL) was heated at reflux under nitrogen for 1 hour. The reaction was filtered, and filtrate evaporated under reduced pressure. The residual oil was column chromatographed using silica gel (approximately 200 g) and elution with 0.3% triethylamine in methanol to afford the title compound (0.90 g, 16%) as a pale yellow oil: 1H NMR (CD3OD) δ7.13 (d, J=8.5 Hz, 1H), 6.94 (br s, 2H), 6.65 (dd, J=2.0 and 8.5 Hz, 1H), 4.91 (s, 2-NH), 3.66-3.50 (m, 1H), 3.17-3.08 (br t, 1H), 2.96-2.85 (m, 1H), 2.67-2.50 (m, 2H), 2.40 (s, 3H), 2.37-2.24 (m, 1H), 2.08-1.93 (m, 1H); FAB LRMS (m/z, relative intensity) 216 (MH+, 100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][N:13]=[CH:14][C:8]=2[CH2:7]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[CH:4]([NH2:15])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][N:13]=[CH:14][C:8]=2[CH2:7]1
Reactant: COC(=O)C(CN1CCc2[nH]ncc2C1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(N)CN1CCc2[nH]ncc2C1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of 2-(di-tert-butoxycarbonylamino)-3-(1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propionic acid methyl ester (0.55 g, 1 equiv.) in methylene chloride (5 mL, 0° C.) was added trifluoroacetic acid (1.5 mL). The ice bath was removed and stirring continued for 2 h. The solution was concentrated, redissolved in methanol, and passed onto a column of strong cation exchange resin. After flushing with methanol, the product was removed from the column by eluting with 2 M ammonia in methanol to afford the product as its free base (275 mg, 95%). 1H-NMR (CDCl3, 500 MHz) δ 2.71 (dd, J=12.8, 8.6, 1H), 2.74-2.91 (m, 6H), 3.48 (s, 2H), 3.54 (d, J=13.4, 1H), 3.62 (d, J=13.4, 1H), 3.69 (dd, J=8.2, 4.9, 1H), 3.73 (s, 3H), 7.27 (s, 1H). Mass spec.: 225.16 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([CH2:19][NH:20][CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([N:20]([CH2:21][CH2:22][OH:23])[CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:25][CH:24]=1)=[O:7]
Reactant: COc1ccc(CNCCO)cc1
Reactant: Cc1c(Br)ccc(F)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(CCO)C(=O)c2c(F)ccc(Br)c2C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 420.6 %

Procedure:
To a solution of 3-bromo-6-fluoro-2-methylbenzoic acid (Cpd QQ, 4.8 g, 2.4 mmol), 2-[(4-methoxybenzyl)amino]ethanol (130a, 5.5 g, 23 mmol) and DIPEA (8 g, 62 mmol) in dry DMF (80 mL) was added HATU (12 g, 31 mmol). The mixture was stirred at room temperature for 14 hours. To the reaction mixture was added EtOAc (130 mL). The solution was washed with brine (4×60 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 2/1) to give 3-bromo-6-fluoro-N-(2-hydroxyethyl)-N-(4-methoxybenzyl)-2-methylbenzamide (130b, 4 g, 48.8%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.C(O[CH:21]=[N:22][C:23]1[S:24][C:25]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])=[C:26]([CH3:33])[C:27]=1[C:28](OCC)=[O:29])C>C(O)C>[CH3:33][C:26]1[C:27]2[C:28](=[O:29])[N:1]([CH2:2][CH2:3][N:4]3[CH2:5][CH2:6][N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[O:16][CH3:17])[CH2:8][CH2:9]3)[CH:21]=[N:22][C:23]=2[S:24][C:25]=1[C:34](=[O:38])[N:35]([CH3:37])[CH3:36]
Reactant: CCOC=Nc1sc(C(=O)N(C)C)c(C)c1C(=O)OCC
Reactant: COc1ccccc1N1CCN(CCN)CC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CCn2cnc3sc(C(=O)N(C)C)c(C)c3c2=O)CC1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
1.9 g (8.0 mM [sic]) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazine were added to 2.4 g (7.8 mM [sic]) of 2-ethoxymethyleneamino-3-carboethoxy-4-methyl-5-dimethylcarbamoyl thiophene in 30 ml of ethanol and refluxed for 2 h. The product crystallized out after standing overnight and was filtered off with suction and washed with a little ethanol. 2.2 g (62%) of product were isolated with melting point 188-190° C.
Reaction SMILES: [N+:1]([C:4]1[C:14]2[C:15]3[C:7]([CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.C1C2=C3C(=CC=C2)C=CC=C3C1.[N+]([O-])(O)=O.[Sn].NN>Cl.[Ni].C(O)C.C(O)(=O)C>[NH2:1][C:4]1[C:14]2[C:15]3[C:7]([CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c3c(cccc13)CC2
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: c1cc2c3c(cccc3c1)CC2
Product: Nc1ccc2c3c(cccc13)CC2

Procedure:
5-Nitroacenaphthene is made by nitrating acenaphthene with nitric acid in the presence of acetic acid according to the method of Rowe and Davies, J. Chem. Soc. 117, 1346 (1920). Standard reduction methods using tin or stannous chloride in hydrochloric acid or by using Raney nickel with ethanol or hydrazine produces 5-aminoacenaphthene.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)=[C:9]([F:25])[CH:8]=1.[N+:26]([O-])([OH:28])=[O:27]>>[Cl:6][C:7]1[C:12]([N+:26]([O-:28])=[O:27])=[CH:11][C:10]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:18]=2)=[C:9]([F:25])[CH:8]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(Cl)cc2F)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cnc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To 3.3 ml of concentrated sulfuric acid was added 0.50 g of 3-(4chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-11) at 5° C. Furthermore, 0.17 ml of 61% nitric acid was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was added to ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.55 g (yield, 95%) of 3-(4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-17; m.p., 98.3° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][NH:9][C:10](=[O:13])[NH:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][NH:9][C:10](=[O:13])[NH:11][CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1NCc2ccc([N+](=O)[O-])cc2CN1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CNC(=O)NC2
Yield: 70.2 %

Procedure:
Compound 7-nitro-1,2,4,5-tetrahydro-benzo(e)(1,3)diazepin-3-one (2.00 g, 9.65 mmol) was dissolved in methanol (60 mL) and the solution was carefully added to a Parr shaker vessel containing 10% Palladium/Carbon (200 mg) under nitrogen. The reaction was then shaken under 50 psi of hydrogen until uptake of hydrogen had ceased (˜3 hours). Catalyst was then removed via filtration through a Celite pad. The filter cake was rinsed with methanol (3×50 mL) and the filtrate was reduced en vacuo to afford 1.20 g of 7-amino-1,2,4,5-tetrahydro-(2,4)-benzodiazepin-3-one as a white solid. LC/MS (ESI)=178.32 (M+H). Rf: (10% MeOH/DCM)=0.31.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][C:11]([C:23]1[C:31]2[C:26](=[C:27]([CH2:32][S:33][CH3:34])[CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH3:12])(=O)=O.O.ClCCl>CS(C)=O>[CH3:34][S:33][CH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[NH:25][CH:24]=[C:23]2[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][CH:14]=1)([CH3:12])[CH2:10][CH2:9][C:1]#[N:2]
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(C)(CCOS(C)(=O)=O)c3ccc(C(F)(F)F)cc3)c[nH]c12
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(C)(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
33 mg (0.50 mmol) of potassium cyanide were added to 118 mg (0.25 mmol) of the compound from Example 113A in 1.5 ml of DMSO. The mixture was stirred at 80° C. for 4 h, water and dichloromethane were added to the reaction solution, and the phases were separated. The organic phase was extracted with dichloromethane, and the combined organic phases were freed of solvent. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 62 mg (62% of theory) of the target compound were obtained.
Reaction SMILES: C([S:4][CH2:5][CH:6]([C:17]([F:20])([F:19])[F:18])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C>O.N>[SH:4][CH2:5][CH:6]([C:17]([F:20])([F:18])[F:19])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)O)C(F)(F)F
Agent: N
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)C(CS)C(F)(F)F
Temperature: 25 °C

Procedure:
N-(3-Acetylthio-2-trifluoromethylpropanoyl)-L-proline (4 g.) is dissolved in a mixture of water (8 ml.) and concentrated ammonia (8 ml.) under a blanket of nitrogen. After twenty-five minutes stirring at room temperature, the reaction mixture is chilled, acidified and extracted with ethyl acetate. The organic layer is concentrated to dryness in vacuo to yield N-(3-mercapto-2-trifluoromethylpropanoyl)-L-proline.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:14][CH2:13][C@H:12]1[C:21](=O)[NH:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:38]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:14][CH2:13][C@H:12]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)[N:38]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(CNC(=O)[C@@H]1COC2(CCOCC2)N1C(=O)OCc1ccccc1)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1[C@H](c2nc(-c3ccc(Br)cc3)c[nH]2)COC12CCOCC2
Temperature: 140 °C
Yield: 57.1 %

Procedure:
(S)-3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-1,8-dioxa-4-aza-spiro[4.5]decane-4-carboxylic acid benzyl ester (1.13 gm, 2.18 mmol) was dissolved in xylenes (11 mL), ammonium acetate (0.84 gm, 10.94 mmol) was added as a solid and the mixture was heated at 140° C. for 24 h. The mixture was diluted with ethyl acetate (50 mL) and the organic layer was washed (aqueous NaHCO3, water, brine) and dried. This crude product was purified by silica gel chromatography (3:2 mixture of EtOAc:hexanes) to afford 0.62 gm (57%) of the title compound. LCMS 500.9 (M+2)
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].ClCCl.Cl.[NH:10]1[CH2:17][S:16][CH2:15][C@H:11]1[C:12]([NH2:14])=[O:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1.C(N(CC)CC)C>[ClH:1].[NH:10]1[CH2:17][S:16][CH2:15][C@H:11]1[C:12]([NH2:14])=[O:13].[Cl:1][CH2:2][C:3]([N:10]1[C@H:11]([C:12]#[N:14])[CH2:15][S:16][CH2:17]1)=[O:4]
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: NC(=O)[C@@H]1CSCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#C[C@@H]1CSCN1C(=O)CCl
Reaction time: 1 h

Procedure:
L-thioprolineamide hydrochloride was synthesized according to the process described in the literature (Ashworth et. al, Bioorg. Med. Chem. Lett., Vol. 6, pp. 2745-2748, 1996). 2.36 ml of chloroacetyl chloride was added to 150 ml of a dichloromethane solution containing 5.00 g of the thus obtained L-thioprolineamide hydrochloride and 8.67 ml of triethylamine under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added 4.8 ml of pyridine and 8.4 ml of trifluoroacetic anhydride, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was washed with an aqueous 10% HCl solution and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Subsequently, the residue was crystallized from ether to obtain 4.82 g of (R)-3-chloroacetyl-4-cyanothiazolidine as a yellowish brown crystal.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[C:7]([F:25])=[C:8]([N:14]2C(=O)C3=CC=CC=C3C2=O)[CH:9]=[C:10]([F:13])[C:11]=1[F:12]>C(O)C>[CH3:4][O:5][C:6]1[C:7]([F:25])=[C:8]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[NH2:14]
Reactant: COc1c(F)c(F)cc(N2C(=O)c3ccccc3C2=O)c1F
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1c(F)c(N)cc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
1.1 g (0.02 mole) of hydrazine hydrate was added to a suspension of 2.15 g (0.007 mole) of N-(3-methoxy-2,4,5-trifluorophenyl)phthalimide (XXXVI) [prepared as described in Step (F3) above] in 30 ml of ethanol, and the mixture was heated under reflux with stirring for 2 hours. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated by evaporation under reduced pressure, and the residue was dissolved in toluene. The resulting solution was washed with water and dried, and the solvent was then removed by evaporation under reduced pressure to afford 1.06 g of 3-methoxy-2,4,5-trifluoroaniline (XXIII) as pale brown needles.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].CO.[CH3:16][C:17]1([CH:23]=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH3:16][C:17]1([CH2:23][NH:1][C@@H:2]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH3:3])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc([C@@H](C)N)cc1
Reactant: CC1(C=O)CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc([C@@H](C)NCC2(C)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of (R)-methyl 4-(1-aminoethyl)benzoate (0.12 g, 0.67 mmol) in methanol (2.97 mL, 73.33 mmol) was added 1-methylcyclohexane-1-carboxaldehyde (0.093 g, 0.74 mmol) and acetic acid (0.152 mL, 2.67 mmol). The reaction was stirred for 1 hour at room temperature whereupon sodium cyanoborohydride (63.1 mg, 1.00 mmol) was added and the mixture further stirred at room temperature overnight. The solvent was evaporated and the residual sodium cyanoborohydride quenched with saturated aqueous NaHCO3. The mixture was extracted into ethyl acetate, the organic layer washed with brine and the solvent evaporated to dryness. The residue obtained was purified via silica chromatography (0-5% MeOH/DCM) to afford the title compound as a colorless oil (123.0 mg, 63%). LC-MS: (FA) ES+ 290.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[S:20][C:18]=2[N:19]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1OC

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][CH:16]1[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)([O:22][CH3:23])[CH2:20][CH2:19][O:18][CH2:17]1>>[CH3:13][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][O:30][C:26]3[CH:25]=[C:24]([C:21]4([O:22][CH3:23])[CH2:20][CH2:19][O:18][CH2:17][CH:16]4[OH:15])[CH:29]=[CH:28][CH:27]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14]
Reactant: COC1(c2cccc(O)c2)CCOCC1O
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: COC1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOCC1O
Yield: 84 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with (3RS,4SR)-3-hydroxy-4-(3-hydroxyphenyl)-4-methoxytetrahydropyran to give (3RS,4SR)-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-3-hydroxy-4-methoxytetrahydropyran in 84% yield, m.p. 62°-66° C.