Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[C:13]([CH2:14][NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.CCN(CC)CC.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:22][O:21][CH:3]([O:2][CH3:1])[C:4]1[C:13]([CH2:14][N:15]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:30](=[O:32])[CH3:31])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: CC(=O)Cl
Reactant: COC(OC)c1nc2c(cc1CNCCN(C)C)CCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1CN(CCN(C)C)C(C)=O)CCCN2
Reaction time: 0.17 h

Procedure:
To a solution of N1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N2,N2-dimethylethane-1,2-diamine (intermediate 199, 300 mg, 0.973 mmol) and NEt3 (0.270 mL, 1.937 mmol) in DCM (10 ml) was added acetyl chloride (0.075 mL, 1.055 mmol) at room temperature and the reaction mixture was stirred for approximately 10 min. The reaction mixture was quenched with saturated aqueous NaHCO3 and diluted with DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined, dried using Na2SO4, filtered and concentrated to yield the title compound, which was directly used in the next step without further purification. (UPLC-MS 3) tR 0.30 min, ESI-MS 351.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6) (indicates an overlapping mixture of rotamers of the title compound in an approximate mixture of 0.5:0.5) δ 6.94 (s, 0.5H), 6.92 (s, 0.5H), 6.52-6.48 (m, 0.5H), 6.48-6.43 (m, 0.5H), 4.98 (s, 0.5H), 4.96 (s, 0.5H), 4.53 (s, 2H), 3.32 (s, 3H), 3.31 (s, 3H), 3.28-3.22 (m, 3H), 3.19 (t, 1H), 2.65 (t, 1H), 2.61 (t, 1H), 2.31 (t, 1H), 2.26 (t, 1H), 2.15-2.06 (m, 7.5H), 1.97 (s, 1.5H), 1.79-1.71 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[C:19](=O)[CH3:20])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[CH:19]([NH2:28])[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1nc(C)c2ccccc2c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1nc(C(C)N)c(-c2cccc(F)c2)c2ccccc12
Temperature: 65 °C

Procedure:
A mixture of 1-[4-(3-fluorophenyl)-1-methylisoquinolin-3-yl]ethanone (222 mg, 0.795 mmol) and ammonium acetate (613 mg, 7.95 mmol) in methanol (4.5 mL) and acetonitrile (4.5 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (99.9 mg, 1.59 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in the next step (215 mg, 97%). LCMS calculated for C18H18FN2 (M+H)+: m/z=281.1; Found: 281.1.
Reaction SMILES: [CH2:1]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1C=CC([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:35][CH:34]=2)=CC=1.[Br-].[Br-]>CO>[CH2:1]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH:39][C:36]2[CH:35]=[CH:34][C:33]([CH:32]=[CH:21][C:20]3[CH:23]=[CH:24][C:17]([O:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=3)=[CH:38][CH:37]=2)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCOc1ccc(C=O)cc1
Reactant: c1ccc([P+](Cc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CO
Product: CCCCCCCCCCCCCCCOc1ccc(C=Cc2ccc(C=Cc3ccc(OCCCCCCCCCCCCCCC)cc3)cc2)cc1
Yield: 92.9 %

Procedure:
In a 30 ml four-necked flask, 7.87 g (23.7 mM) of the p-pentadecanoxybenzaldehyde synthesized above and 8.65 g (11.0 mM) of p-xylylenebis(triphenylphosphonium bromide) were suspended in 100 ml of methanol, and 6.87 g (35.6 mM) of 28 wt % methylate was added dropwise at room temperature (25° C.). The resultant mixture was aged at a refluxing temperature of 65° C. for 3 hours. Methanol was removed by evaporation, and 200 ml of water was added to the residue, and the resultant was stirred. The precipitate formed was collected by filtration, washed with water and acetone, and dried to give 7.49 g of a 1,4-bis(4′-pentadecanoxystyryl)benzene isomeric mixture (compound (1a)). The 1H-NMR data for identification were as follows.
Reaction SMILES: [N:1]#CBr.[CH3:4][N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[O:13])[CH2:6]1>C1C=CC=CC=1>[C:4]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[O:13])[CH2:6]1)#[N:1]
Reactant: N#CBr
Reactant: CN1CCCC(CC(=O)c2ccccc2F)C1
Solvent: c1ccccc1
Product: N#CN1CCCC(CC(=O)c2ccccc2F)C1
Yield: 66.8 %

Procedure:
The procedure of Example 19 was repeated, using 9.5 g of cyanogen bromide, 19.3 g of 1-methyl-3-(2-fluorophenacyl)piperidine (Example 5), and an additional 130 ml of benzene. The final residue, 16.3 g, was vacuum distilled to give 13.5 g of 1-cyano-3-(2-fluorophenacyl)piperidine, bp 190°-195°/0.5 mm. The following elemental analysis was obtained:
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14][CH:15]([CH2:19][CH2:20]Br)[C:16](Br)=[O:17]>CC#N>[CH2:7]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:20][CH2:19][C@@H:15]([Br:14])[C:16]2=[O:17])[CH2:9]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(Br)C(Br)CCBr
Solvent: CC#N
Product: O=C1[C@H](Br)CCN1C1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A solution of 5.0 g of (R)-1-(phenylmethyl)-3-pyrrolidinamine in 50.0 ml CH3CN was treated at rt with 2.72 g of Na3PO4. The resulting fine light yellow suspension was cooled to 0° C. and treated with a solution of 10.07 g of 2,4-dibromobutyrylbromide (prepared according to Marinelli, E. R.; Arunachalam, T.; Diamantidis, G.; Emswiler, J.; Fan, H.; Neubeck, R.; Pillai, K. M. R.; Wagler, T. R.; Chen, C.-K.; et al. Tetrahedron (1996), 52(34), 11177-11214) in 5.0 ml of CH3CN over 20 min. After 30 min the very fine suspension was filtered and concentrated to a volume of 30 ml, and then treated with 130.1 ml of 0.497 M NaOH solution at room temperature. The resultant turbid orange solution was stirred for 2 h, concentrated and the resultant aqueous phase extracted with three portions of 50 ml of TBME. The combined organic phases were washed with H2O until neutral, dried over MgSO4 and concentrated to give 5.79 g (63%) of (R)-(1′-benzyl-3-bromo-[1,3′]bipyrrolidinyl-2-one) as yellow waxy crystals.
Reaction SMILES: [F:1][C:2]([F:15])([CH:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=CN=1)[C:3]([NH:5][NH2:6])=[O:4].FC(F)(C(O)C1[S:25]C=CC=1)C(OCC)=O.NN>>[F:1][C:2]([F:15])([CH:7]([OH:14])[C:8]1[S:25][CH:11]=[CH:12][CH:13]=1)[C:3]([NH:5][NH2:6])=[O:4]
Reactant: CCOC(=O)C(F)(F)C(O)c1cccs1
Reactant: NNC(=O)C(F)(F)C(O)c1ccccn1
Agent: NN
Product: NNC(=O)C(F)(F)C(O)c1cccs1

Procedure:
α,α-difluoro-β-hydroxy-2-thiophenepropanoic acid, hydrazide (26) was prepared in the same manner as α,α-difluoro-β-hydroxy-3-(2-pyridinyl)-propanoic acid, hydrazide (10), as described above in Example 10, on a 1.4 mmol scale from ethyl α,α-difluoro-β-hydroxy-2-thiophenepropanoate and hydrazine to yield 0.23 g (74%) of product. Analysis calculated for C7H8N2O2F2S (M.W. 222.21): C, 37.84; H, 3.63; N, 12.61. Found: C, 37.72; H, 3.51; N, 12.42.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2O.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Cl:30][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[C:7]([CH3:12])[C:6]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2ccc(I)cc2c(O)c1S(C)(=O)=O
Solvent: Cc1ccccc1
Solvent: Cc1ccc(N(C)C)cc1
Product: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Reaction time: 9.5 h
Yield: 77.6 %

Procedure:
6-Iodo-3-methanesulfonyl-2-methyl-quinolin-4-ol (example C.2) (14.7 g, 40.5 mmol) and N,N-dimethyl-p-toluidine (11.7 mL, 81 mmol) were dissolved in toluene (150 mL) and heated under argon to reflux. Then phosphorous oxychloride (4.1 mL, 44.5 mmol) was added and heating at reflux continued for 9.5 h. The thick suspension became gradually a dark solution. The reaction mixture was allowed to cool and then extracted with dichloromethane (not soluble in toluene), cold 1 N HCl (2×), and sat. NaCl (2×). The product was crystallized from heptane/dichloromethane. One obtained 12 g (78%) of white crystals. MS: m/z=381 (M).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].Cl>CN(C=O)C>[CH3:27][O:26][C:24]([C:23]1[CH:22]=[C:21]([CH2:20][N:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]2=[O:18])[CH:30]=[CH:29][CH:28]=1)=[O:25]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)[nH]c2=O)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To 2,3-dihydro-4,5-diphenyl-1H-imidazol-2-one (4.76 g, 20 mmol) in 50 mL DMF was added to a suspension of Nail (0.8 g, 20 mmol) in 25 mL DMF. The suspension was stirred at ambient temperatures for 30 minutes, then heated to 50° C. for 30 minutes. A solution of methyl 3-bromomethylbenzoate (2.86 g, 12.5 mmol) in 20 mL DMF was then added and the reaction stirred for 10 min at 50° C. The mixture was poured into 1 N HCl, filtered, washed with water and dried. Chromatography on silica gel (2% EtOH in 7:3 methylene chloride/ethyl acetate) afforded 1.2 g of 3-(3-methoxycarbonylphenyl)methyl-4,5-diphenyl-1H-imidazol-2-one as a white solid.
Reaction SMILES: [Si:1]([CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]([OH:16])[CH2:14][NH2:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>C(Cl)Cl>[OH:16][CH:13]([CH2:12][O:11][CH2:10][CH2:9][CH2:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:14][NH:15][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: CC(C)(C)[Si](C)(C)CCCOCC(O)CN
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)NCC(O)COCCC[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(3-(t-Butyldimethylsilyl)propyloxy)-2-hydroxypropylamine (19.0 g, 0.077 mol), triethylamine (7.8 g, 10.8 mL, 0.08 mol), and methylene chloride (57 mL) were mixed in a 250 mL one-neck flask which was placed in an ice bath. To the above mixture, methacryloyl chloride (8.3 g, 7.73 mL, 077 mol) was added dropwise through an additional funnel at 0° C. After the completion of the addition of methacryloyl chloride, the whole mixture was allowed to warm up to room temperature and stirred at ambient temperature for two days. The reaction suspension was diluted with 100 mL of methylene chloride and washed with deionized water, 0.5 N sodium hydroxide aqueous solution, 5% sodium chloride solution in water twice and saturated sodium chloride aqueous solution in sequence. The organic phase was dried over sodium sulfate. After the removal of sodium sulfate by filtration, the solvent was evaporated by using a rotary evaporator under vacuum. N-[2-Hydroxy-3-(3-(t-butyldimethylsilyl)propyloxy)propyl]-2-methyl acrylamide was obtained as a white solid after purification by silica gel column chromatography.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:15]=2)=[CH:9][C:8]=1[CH3:34])C.[OH-].[Na+].Cl>C(O)C>[CH2:30]([O:29][C:16]1[CH:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([CH3:34])[CH:9]=2)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:17]=1)[CH:31]([CH3:33])[CH3:32]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (140 mg; 0.28 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 130 mg. HPLC-MS: m/z: 470.0 (M+); Rt: 1.76 min. δH (400 MHz; CDCl3) 1.00 (d, 6H), 1.98-2.09 (m, 1H), 2.27 (s, 3H), 3.13-3.29 (m, 2H), 3.43-3.57 (m, 2H), 3.66 (d, 2H), 3.92-4.09 (m, 4H), 4.12 (s, 2H), 4.71 (s, 2H), 6.55 (m, 1H), 6.71-6.75 (m, 2H), 6.79 (m, 1H), 7.25-7.29 (m, 1H), 7.30 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH3:14]>O1CCCC1>[NH2:14][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[F:1][C:2]1[C:7]([F:8])=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: Fc1ccc(C(F)(F)F)c(F)c1F
Reactant: N
Solvent: C1CCOC1
Product: Nc1c(C(F)(F)F)ccc(F)c1F
Product: Nc1ccc(C(F)(F)F)c(F)c1F
Temperature: 130 °C
Reaction time: 6 h

Procedure:
200 g of 2,3,4-trifluorobenzotrifluoride in 500 ml of tetrahydrofuran were initially introduced into an autoclave and it was pressurized using 60 ml of liquid ammonia. After stirring for 6 hours at 130° C. (maximum pressure 18 bar), the mixture was cooled and the pressure was released. By distillation, 72 g of 2-amino-3,4-difluoro-benzotrifluoride were obtained with a boiling point of 60° to 64° C. at 26 mbar and 92 g of 2,3-difluoro-4-amino-benzotrifluoride with a boiling point of 92° to 93° C. at 26 mbar.
Reaction SMILES: [Na].[NH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:2]2[CH2:6][CH2:5][CH2:4][C:3]2=[O:7])=[O:15])=[CH:12][CH:11]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20.2 g. of the sodium salt of 2-pyrrolidinone (prepared using sodium hydride) suspended in 270 ml. of dimethylformamide are added in four portions at -10° C. to a solution of 37.0 g. of p-methoxybenzoyl chloride in 50 ml. of dimethylformamide. Subsequently, the mixture is stirred at room temperature for 1 hour and then at 40° C. for 4 hours. The solvent is evaporated and the residue is treated with diethyl ether and with cold sodium bicarbonate solution. The insoluble crystalline constituents are filtered off, washed with water and diethyl ether and dried in vacuo over phosphorus pentoxide. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 120°-121° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=[O:12].[C:13]12[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:18]C(=O)O[C:14]2=[O:15].[F:25]C1C=C2NC(=O)OC(=O)C2=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:25])[N:7]1[C:6](=[N:18][C:19]3[C:13]([C:14]1=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2=[O:12]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2cc(F)c(F)cc2-n2c1nc1ccccc1c2=O
Yield: 2 %

Procedure:
Using the procedure in Example 36 and substituting 5,6-difluoroisatin for 5-fluoroisatin and isatoic anhydride for 4-fluoroisatoic anhydride gave the title compound in 2% yield: mp >250° C. (dec); 1H NMR (300 MHz, DMSO-d6) δ 8.54 (dd, 1H) 8.42 (d, 1H), 8.25 (d, 1H), 7.9 (dd, 1H), 7.78-7.68 (q, 2H); MS (M+H)+ 285.
Reaction SMILES: [Cl:1][C:2](CCl)=[CH2:3].[CH3:6][C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[O:10].[C:13]1(C)C=CC=CC=1>[Zn].O>[Cl:1][C:2]([CH2:11][C:9]([CH3:13])([OH:10])[CH:8]=[C:7]([CH3:12])[CH3:6])=[CH2:3]
Reactant: Cc1ccccc1
Reactant: C=C(Cl)CCl
Reactant: CC(=O)C=C(C)C
Agent: [Zn]
Solvent: O
Product: C=C(Cl)CC(C)(O)C=C(C)C

Procedure:
45.23 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 20.00 g of methyl 2-methyl-1-propenyl ketone, 60 g of toluene, 60 g of water and 26.65 g of zinc powder at 35° C., and after the addition, the resultant mixture was maintained at the same temperature for 5 hours. After the reaction was completed, zinc-derived insolubles were filtered off, and the filtrate was separated. The organic phase was washed with 7% sodium carbonate aqueous solution and dried over magnesium sulfate. The desiccant was filtered off and the toluene was distilled off under reduced pressure. The resultant oily substance was purified by silica gel column chromatography to give 31.11 g of 2-chloro-4,6-dimethyl-1,5-heptadien-4-ol; nD25 =1.474, FI-MS m/e 174(M), 176(M+2).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21]C)[N:12]2[CH2:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O.C(=O)(O)[O-].[Na+]>CO.O1CCOCC1>[NH2:23][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:21])[N:12]2[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1

Procedure:
2-Butoxy-8-methoxy-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-6-amine (Isomer 2, 178 mg) was suspended in methanol (2 ml) and 4N HCl in dioxan (1 ml) added. The resulting clear solution was stripped and the residue treated with water and basified with saturated aqueous sodium bicarbonate. The solid obtained was filtered, washed with water and dried to give the title compound (isomer 2), yield 72 mg (low due to mechanical losses).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[CH3:10][NH:11][C:12]([NH:14][CH3:15])=[O:13].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:10][N:11]1[CH2:7][CH:3]([C:2]([F:9])([F:8])[F:1])[C:4](=[O:5])[N:14]([CH3:15])[C:12]1=[O:13]
Reactant: CNC(=O)NC
Reactant: C=C(C(=O)O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CN1CC(C(F)(F)F)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and 1,3-dimethylurea (419 mg; 4.8 mmoles) in DMF (5 ml) was cooled to 0° C., and then a solution of DCC (1.21 g; 5.9 mmoles) in DMF (3 ml) was added dropwise. The mixture was stirred at 0° C. for 1 hour. The precipitated solid was filtered off, and washed with ethyl acetate. The solvents were evaporated under reduced pressure from the combined filtrates. The residue was purified by a column chromatography on silica gel to give 566 mg (yield 57%) of 1,3-dimethyl-5-trifluoromethyl-5,6-dihydrouracil (OF-1).
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.CO.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=2)(=[O:26])=[O:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a slurry of methyl 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylate (5.0 g, 17.66 mmol, prepared as in Example 113) in chloroform (20 mL) under nitrogen was added N,N,N-diisopropylethylamine (3.72 mL, 26.49 mmol). 4-Methylbenzenesulfonyl chloride (4.04 g, 21.20 mmol) was added over 5 minutes and the reaction was heated to 40 degrees C. and stirred one hour. The completed reaction was cooled to 25 degrees C. and 1:1 methanol:water was added to precipitate the product which was filtered, washed with more 1:1 methanol:water and dried in vacuo. This afforded the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][C:6]1[C:7](=[O:14])[NH:8][C:9](SC)=[N:10][CH:11]=1.[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH2:29]>CO>[ClH:1].[ClH:1].[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH:29][C:9]1[NH:8][C:7](=[O:14])[C:6]([CH2:5][C:4]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:2]([Cl:1])[CH:3]=2)=[CH:11][N:10]=1
Reactant: CSc1ncc(Cc2ccc(Cl)c(Cl)c2)c(=O)[nH]1
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CO
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccc(Cl)c(Cl)c2)c(=O)[nH]1
Product: Cl

Procedure:
5-(3,4-Dichlorobenzyl)-2-methylthio-4-pyrimidone (2.1 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.2 g) by the procedure of Example 3 to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3,4-dichlorobenzyl)-4-pyrimidone dihydrochloride, m.p. 235.5°-238.5° (aqueous methanol)
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-])=O)=[CH:6][CH:5]=1.[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][NH2:18].O.OC1C2N=N[NH:28]C=2C=CC=1>CN(C=O)C.C(OCC)(=O)C>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:18][CH2:17][CH2:16][C:15]([CH3:20])([CH3:19])[CH3:14])=[O:13])=[CH:12][CH:11]=1)#[N:28]
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(C)(C)CCN
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)CCNC(=O)c1ccc(C#N)cc1
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A solution of methyl 4-cyanobenzoic acid (1, 735 mg, 5.0 mmol) in 12 mL of DMF under argon at room temperature was treated 3,3-dimethylbutylamine (2, 505 mg, 5.0 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide hydrochloride (1.5 g, 5.0 mmol) and hydroxybenzotriazole monohydrate (685 mg, 5.0 mmol) and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with 10 percent citric acid, water, dilute sodium bicarbonate, water and brine. The dried (anhydrous magnesium sulfate) organic fraction was concentrated to give 1.5 g. Flash chromatography on 150 mL of EM-60 silica gel, eluting with ethyl acetate/hexanes (1:4) gave the title compound (1.06 g, 92%), mp 154-157° C. Analysis calculated for C14H18N2O: C, 73.01; H, 7.88; N, 12.16. Found: C, 73.00; H, 7.92; N, 12.17.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[CH:4][C:5]([Br:13])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2.[NH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[OH:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]([NH:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[OH:24])=[O:16])=[CH:4][C:5]([Br:13])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2
Reactant: CN1CCCc2c(Br)cc(C(=O)O)c(N)c21
Reactant: N[C@H]1CCCC[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCCc2c(Br)cc(C(=O)N[C@H]3CCCC[C@@H]3O)c(N)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-amino-5-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (600 mg, 2.10 mmol) in DMF (7 mL) at rt was added (1S,2S)-2-aminocyclohexanol (242 mg, 2.10 mmol), BOP (1.16 g, 2.63 mmol), and Et3N (0.59 mL, 4.21 mmol). The mixture was stirred at rt for 2 h. The resulting solution was quenched with 10% aqueous NaHCO3 and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (Na2SO4), and concentrated to afford 8-amino-5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxamide in pure form.