Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[CH:32][CH:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 16 h
Yield: 48.8 %

Procedure:
Into 5 mL MeOH was dissolved 91 mg (0.195 mmol) 2-(4-tert-butylbenzoylamino)-N-(5-chloropyridin-2-yl)-5-methoxycarbonylbenzamide, followed by 0.47 mL of 0.5 N (0.23 mmol) NaOH. The mixture was stirred 16 h, evaporated, diluted with 39.0 mL water, and extracted with 15 mL EtOAc-15 mL hexane mixture. The aquous layer was acidified with dilute HCl and extracted with 30 mL EtOH. The organic layer was dried (MgSO4) and evaporated, giving 43 mg (.49%) title compound.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([NH:44][C:45]([NH2:47])=[NH:46])[CH:35]=[CH:36][C:37]=1[N:38]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]1>>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([NH:44][C:45]2[N:47]=[CH:3][C:4]3[CH2:5][CH2:6][CH2:7][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[CH:12]=4)[C:9]=3[N:46]=2)[CH:35]=[CH:36][C:37]=1[N:38]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=C1CCCC(c2cccc(C(F)(F)F)c2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(c2cccc(C(F)(F)F)c2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 6-[1-dimethylamino-methylidene]-2-(3-trifluoromethyl-phenyl)-cyclohexanone (132 g, 0.44 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (163 mg, 0.44 mmol) using in analogous manner the procedure described in example 45b). Obtained as an off-white solid (62 mg, 29%). MS ISP (m/e): 480.1 [(M+H)−]. mp 213-215° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CN)cc1
Reactant: Brc1cncnc1
Product: COc1ccc(CNc2cncnc2)cc1
Yield: 85 %

Procedure:
Using the general procedure, 5-bromopyrimidine (159 mg, 1.0 mmol) was coupled with 4-methoxybenzylamine (196 μL, 1.5 mmol) at 90° C. for 22 h. Purification of the crude product by column chromatography on silica gel using dichloromethane(saturated with ammonia)/ethyl acetate (1:1) as eluent afforded the desired product as a white solid (183 mg, 85% yield). Rf=0.2 (dichloromethane(saturated with ammonia)/ethyl acetate 1:1).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Br[CH2:29][CH2:30][CH2:31][OH:32]>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:29][CH2:30][CH2:31][OH:32])[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: OCCCBr
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCCCO)cc13)Sc1ccc(Br)cc1-2
Yield: 73 %

Procedure:
According to Example 34, the compound (300 mg) produced in Example 37 was reacted with 3-bromopropanol (78 μL) to obtain the title compound (210 mg; 73%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][C:12]=3[C:11]=2[C:10]=1[Cl:36].[OH-].[Na+]>C(Cl)Cl>[Cl:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28][C:12]=3[C:11]=2[C:10]=1[Cl:36]
Reactant: CCOC(=O)Cn1c2c(c3c(Cl)c(Cl)ccc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1c2c(c3c(Cl)c(Cl)ccc31)CCNCC2
Reaction time: 5 h
Yield: 103.4 %

Procedure:
TFA (10.5 mL, 136 mmol) was added to a solution of tert-butyl 9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (3.0 g, 6.8 mmol) in CH2Cl2 (70 mL). After 5 h, the reaction was made basic with 10% aqueous NaOH and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to give 2.4 g of the crude yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J=8.7 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 4.75 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.45 (m, 2H), 3.10 (t, J=5.1 Hz, 4H), 2.87 (m, 2H 2.28 (br s, 1H) 1.25 (m, 3H); IR (diffuse reflectance) 2979, 2958, 2939, 2904, 2837, 2816, 2797, 2766, 2644, 1744, 1449, 1372, 1279, 1204, 1160 cm−1;MS (EI) m/z 340 (M+), 305, 300, 298, 270, 226, 224, 154, 149, 127; HRMS (FAB) calcd for C16H18CL2N2O2+H 341.0823, found 341.0818.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[CH3:11][O:12][C:13]1[C:18](B(O)O)=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.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>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:18]1[C:13]([O:12][CH3:11])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: COc1ncccc1B(O)O
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+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1-c1cc(C=O)ccc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.9 mmol), (2-methoxypyridin-3-yl)boronic acid (1.2 g, 7 mmol) and sodium hydrogen carbonate (1.5 g, 15 mmol) was stirred in dioxane (20 mL) and water (8 mL). The mixture was degassed for 10 minutes, then tetrakis(triphenylphosphine)palladium (0) (0.130 g, 0.1 mol) was added. The reaction mixture was stirred at 100° C. for 1 hour then cooled and concentrated in vacuo. The resulting residue was partitioned between EtOAc (60 mL) and water (15 mL), dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography eluting with 20% EtOAc in heptane to afford the title compound as a white solid (0.85 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[C:9][CH3:10].CN(C)C=O.[Cl:17][C:18]1[NH:28][C:21]2[CH:22]=[N:23][N:24]([CH3:27])[C:25](=[O:26])[C:20]=2[N:19]=1>C(OCC)(=O)C>[CH2:7]([N:19]1[C:20]2[C:25](=[O:26])[N:24]([CH3:27])[N:23]=[CH:22][C:21]=2[N:28]=[C:18]1[Cl:17])[C:8]#[C:9][CH3:10]
Reactant: CC#CCBr
Reactant: Cn1ncc2[nH]c(Cl)nc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(Cl)nc2cnn(C)c(=O)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.166 g of potassium carbonate and 0.106 μl of 2-butynyl bromide were added to a 10 ml N,N-dimethylformamide solution of 0.184 g of 2-chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one, and the mixture was stirred at room temperature for 18 hours. 50 ml of ethyl acetate was added to the solution, and the mixture was washed three times with 20 ml of water and then with 20 ml of a saturated sodium chloride solution. The organic liquid was dried over magnesium sulfate, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography. Thus, 0.175 g of 3-(2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one was obtained from the fraction eluted with hexane-ethyl acetate (4:1), and 0.033 g of 1-(2-butynyl)-2-chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one was obtained from the fraction eluted with hexane-ethyl acetate (2:3).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:36][OH:37].O>N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:36][OH:37])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Intermediate (18b) (7.2 g, 15.5 mmol) was dissolved in pyridine (30 mL). Hydroxylamine hydrochloride (4.0 g, 57.9 mmol) was added followed by water (20 mL) and the mixture was stirred at 40° C. for 2 hours. The reaction was quenched with water, extracted with 200 mL EtOAc, washed with 3×100 mL 1M phosphoric acid, 1×100 mL saturated sodium bicarbonate solution, and 2×100 mL saturated aqueous NaCl, then dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-80% EtOAc:hexanes) to yield intermediate (18c) as a white solid (7.4 g). Anal. HPLC retention time=4.9 minutes. Gradient conditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent A over 6 minutes. MS m/z: [M+H+] calcd for C27H30FN3O4, 480.23. found 480.4. 1H-NMR (DMSO-d6) 10.99 (1H, s), 8.21 (1H, s), 7.67 (1H, d), 7.54 (1H, m), 7.44 (1H, s), 7.34 (1H, m), 7.11 (2H, m), 6.81 (2H, m), 5.73 (1H, d), 5.36 (2H, s), 5.10 (1H, d), 1.66 (2H, m), 1.13 (9H, s), 0.85 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[N+:19]([CH2:22][CH3:23])([O-:21])=[O:20].C(N)CCC>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](/[CH:13]=[C:22](/[N+:19]([O-:21])=[O:20])\[CH3:23])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: O=Cc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1
Reactant: CC[N+](=O)[O-]
Solvent: CCCCN
Solvent: CC(=O)O
Product: C/C(=C\c1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1)[N+](=O)[O-]
Temperature: 80 °C

Procedure:
5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-carbaldehyde (4.00 g, 14.5 mmol), nitroethane (3.00 ml, 40.7 mmol), n-butylamine (1.7 ml, 17.5 mmol) and acetic acid (7.5 ml) were mixed and heated up to 80° C. for 2 h. After cooling to RT the mixture was filtered. The precipitate was crystallized from ethanol affording 2.58 g of the title product. 1H-NMR (400 MHz; d6-DMSO): δ 2.62 (s, 3H), 7.39 (d, 1H), 7.57 (d, 1H), 7.87 (m, 1H), 8.00 (s, 1H), 8.11 (m, 1H), 8.22 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH2:24].CCOC(C)=O>CS(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH:24][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2ncc(Cl)nc2c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CNc2cnc3ccc(C)cc3n2)c(OC)c1
Yield: 97.2 %

Procedure:
2-Chloro-7-methylquinoxaline (0.51 g, 2.86 mmol), ), prepared according to J. Chem. Soc. 1948 1310-1313, and (2,4-dimethoxyphenyl)methanamine (1.29 mL, 8.57 mmol) were microwaved in DMSO (2.5 mL) for 30 min at 150° C. This was diluted into 150 mL EtOAc and extracted three times with 100 mL brine. The crude product was purified by flash chromatography on a 90 g silica gel cartridge with 20 to 80% EtOAc in hexane, 50 min, at 40 mL/min to afford N-(2,4-dimethoxybenzyl)-7-methylquinoxalin-2-amine (860 mg, 2.78 mmol, 97% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:34])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:32][C:30]1[C:29]([F:33])=[C:28]2[C:23]([CH:24]=[N:25][C:26]([CH3:34])=[N:27]2)=[C:22]([N:21]=[CH:11][C@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH2:9][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:19][CH3:20])[CH3:18])[CH:31]=1
Reactant: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=O)C(F)(F)F
Reactant: Cc1ncc2c(N)cc(F)c(F)c2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=Nc1cc(F)c(F)c2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 170 mg (0.58 mmol) of (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 124 mg (0.60 mmol) of 5-amino-7,8-difluoro-2-methylquinazoline and 0.31 ml of titanium tetraethoxide are reacted to give (2R*,4S*)-1-[(7,8-difluoro-2-methylquinazolin-5-yl)imino]-4-(3-fluoro-2-methoxyphenyl)-2-(trifluoromethyl)pentan-2-ol. 85 mg of imine purified by column chromatography (silica gel, hexane/ethyl acetate 0-30%) are cyclized in the same way as in Example 1 at −20° C. using 0.72 ml (0.72 mmol) of 1 M boron tribromide solution to give the desired product. Preparative thin-layer chromatography on silica gel (hexane/ethyl acetate 50%) yields 15 mg of product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Na+].[C:11]([O:17][CH2:18]Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:18][O:17][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8]
Reactant: O=C([O-])c1cnccn1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)OCOC(=O)c1cnccn1
Reaction time: 6 h
Yield: 72.2 %

Procedure:
A four-necked flask was charged with 14.6 g (0.10 mole) of sodium pyrazinecarboxylate, 15.1 g (0.10 mole) of chloromethyl pivalate and 1.0 g (0.01 mole) of triethylamine and the charge was maintained under stirring at 98°-100° C. for 6 hours. The reaction mixture was then cooled and 100 ml of toluene was added. The solids (sodium chloride) were filtered off. From the filtrate thus obtained the toluene was distilled off and the filtrate was subjected to distillation under reduced pressure to give 17.2 g of pivaloyloxymethyl pyrazinecarboxylate. Yield: 72%
Reaction SMILES: [CH2:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH2:3][CH3:4].[C:10](Cl)(=[O:12])[CH3:11]>ClCCl>[C:10]([C:7]1[S:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:9][CH:8]=1)(=[O:12])[CH3:11]
Reactant: CCCCc1cccs1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CCCCc1ccc(C(C)=O)s1

Procedure:
2-Butylthiophene (obtained by Friedel-Crafts acylation of thiophene with butyryl chloride followed by Wolf-Kizner reduction in accordance with EP-A 0 392 510) is acetylated with acetyl chloride in dichloromethane under AlCl3 catalysis. Customary work-up followed by purification by distillation affords 2-acetyl-5-butylthiophene, b.p. 92° C./0.8 mbar.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=S)[NH:9][C:8](=[S:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)(O)[O-]>CO>[CH:18]1([NH:23][C:10]2[C:11]3[NH:12][C:4]([CH:1]4[CH2:3][CH2:2]4)=[N:5][C:6]=3[N:7]([CH2:15][CH2:16][CH3:17])[C:8](=[S:14])[N:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCC1
Reactant: CCCn1c(=S)[nH]c(=S)c2[nH]c(C3CC3)nc21
Agent: O=C([O-])O
Solvent: CO
Product: CCCn1c(=S)nc(NC2CCCC2)c2[nH]c(C3CC3)nc21

Procedure:
5.33 g (20 mmoles) of 8-cyclopropyl-3-n-propyl-2,6-dithioxantine and 42 ml of cyclopentylamine were heated in a 450 ml pressure reactor to 150° C. (50 psi) with the exclusion of air. After 20 hours the solution was transferred with methanol to a round bottom flask and evaporated in vacuo to dryness. The residue is treated with 60 ml of water and 5N HCl to obtain a pH of 2. The suspension is neutralized with bicarbonate to pH 7, the solid collected, washed, dried, suspended in refluxing acetone and collected again: 5.98 g of thioisoguanine with mp 274-6° C. (decomp).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2SC)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([NH2:29])=[NH:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([N:29]=[C:10]2[NH:11][C:12](=[O:15])[C:13](=[O:14])[N:9]2[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[NH:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: N=C(N)Nc1ccc(Cl)c(Cl)c1
Reactant: CSC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: N=C(N=C1NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1)Nc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 67.5 %

Procedure:
To the solution of the crude dione 15 (0.551 g, 1.907 mmol) in 25 ml of dry CHCl3 was added N-(3,4-dichlorophenyl)guanidine (14) (0.389 g, 1.907 mmol) at room temperature. The reaction mixture was heated at 50° C. overnight. The solid was collected and washed sequentially with CHCl3 and H2O to afford the compound 19 as a light yellow solid (0.573 g, 1.288 mmol, 68%), mp 220° C. 1H NMR (300 MHz, DMSO-d6): δ 7.75(d, J=8.3 Hz, 1H), 7.69 (s, 1H), 7.55–7.40 (m, 3H), 7.15 (d, 7.9 Hz, 1H); 13C NMR: δ 170.54, 169.33, 160.26, 156.74, 136.75, 132.72, 131.15, 131.00, 130.73, 130.52, 129.64, 128.04. MS (m/z) 444 (MH+), 256, 227, 185. Anal. (C16H9Cl4N5O2) C, H, Cl, N.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[N:8][C:7]=1[C:19]([OH:21])=[O:20].[CH2:22](O)[CH3:23]>>[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[N:8][C:7]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(O)c1nnc2ccc([N+](=O)[O-])cc2c1O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nnc2ccc([N+](=O)[O-])cc2c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethanol (200 ml.) was stirred at -40° C. and thionyl chloride (15 ml.) was added dropwise during 5 minutes. After a further 10 minutes at -40° C., 4-hydroxy-6-nitrocinnolin-3-yl carboxylic acid (10 g.) was added. The mixture was stirred overnight and allowed to warm to room temperature. The suspension was heated under reflux on a steam bath for 1 hour, and then kept at 0° C. for several hours. The solid was filtered off, and washed successively with ethanol (2 × 30 ml.) and ether (100 ml.) to give ethyl 4-hydroxy-6-nitrocinnolin-3-yl carboxylate, m.p. 294°-296° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][O:24][CH3:25])=[CH:19][CH:20]=3)[O:15][CH2:14][C:13]2([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=2)[CH3:26])=[CH:4][CH:3]=1.[H-].[Na+].[C:39]([O:43][C:44](=[O:47])[CH2:45]Br)([CH3:42])([CH3:41])[CH3:40].O>O1CCCC1>[C:39]([O:43][C:44]([CH2:45][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][O:24][CH3:25])=[CH:19][CH:20]=3)[O:15][CH2:14][C:13]2([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:31][CH:32]=2)[CH3:26])=[CH:4][CH:3]=1)=[O:47])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCc2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 0.33 h
Yield: 99.5 %

Procedure:
To a solution of 4-[4-(4-hydroxyphenyl)-1-butyl]-7-methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-methylchroman (481 mg, 0.976 mmol) in dry tetrahydrofuran (8 ml) was added sodium hydride (22.7 mg, 1.418 mmol) at room temperature and stirred for 20 minutes. Bromoacetic acid tert-butylester (276.7 mg, 1.418 mmol) was added thereto at the same temperature and stirred for 20 minutes. After the reaction was completed, water was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 589 mg (yield: quant.) of the title compound as a colorless oil. The resulting compound was used in the next reaction without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].P(OC)(OC)(O[CH3:25])=O.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH3:25])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: COP(=O)(OC)OC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Yield: 85.1 %

Procedure:
2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was dissolved in 30 ml of dry dimethylformamide. To this was added 4.2 g of trimethyl phosphate and the mixture was refluxed for 6 hours. After the reaction was complete, the solvent was distilled off from the mixture, and to the residue obtained was added water to precipitate a crude product. The product was recrystallized from acetone to yield 2.5 g of 1-(m-nitrophenyl)-3-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 234°-235°C.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].[C:16]([CH:20](OC(F)(F)F)[OH:21])([F:19])([F:18])[F:17]>CO.C(OCC)(=O)C>[OH:1][C:2]1[C:7](=[O:8])[C:6]([CH:20]([OH:21])[C:16]([F:19])([F:18])[F:17])=[CH:5][NH:4][C:3]=1[CH3:9]
Reactant: OC(OC(F)(F)F)C(F)(F)F
Reactant: Cc1[nH]ccc(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1O

Procedure:
A mixture of 3-hydroxy-2-methyl-1H-pyridin-4-one (6.1 g, 48.7 mmol), potassium carbonate (17 g, 123 mmol), and CF3CH(OH)OCF3 (25 mL, 0.25 mol) was heated to reflux under a blanket of nitrogen for 30 h. The progress of the reaction was monitored by HPLC Method 1 (Example 24), which indicated 63% (peak percent area) of conversion to the product. The reaction mixture was diluted with methanol (50 mL), then filtered to remove solid particulates. The filtrate was evaporated to dryness to afford an oil. The oily residue was taken up in ethyl acetate (150 mL) and washed with a saturated ammonium chloride solution (80 mL). The organic fraction was collected and set aside. The pH of the aqueous fraction was adjusted to 6 with a dilute hydrochloric acid solution, and the resulting aqueous solution was extracted with ethyl acetate (2×40 mL). All the organic fractions were combined, then washed with saturated ammonium chloride, dried over Na2SO4, filtered and then evaporated to dryness to give an oil. On trituration with ether, 3-hydroxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one separated as a solid product and was collected by suction filtration (3.5 g, 33%). NMR data is described in Part C above.