Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][N:11]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:12][CH2:13][OH:14])=[CH:6][C:5](=[O:27])[N:4]([CH3:28])[C:3]1=[O:29].[C:30](OC(=O)C)(=[O:32])[CH3:31].O>N1C=CC=CC=1>[CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][N:11]([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)[CH2:12][CH2:13][O:14][C:30](=[O:32])[CH3:31])=[CH:6][C:5](=[O:27])[N:4]([CH3:28])[C:3]1=[O:29]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(NCCN(CCO)CCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCN(CCCc1ccc([N+](=O)[O-])cc1)CCNc1cc(=O)n(C)c(=O)n1C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
1.6 g of 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione (Compound d) and 0.8 g of acetic anhydride were dissolved in 5 ml of pyridine. The resultant mixture was stirred at room temperature for 24 hours and then at 60° C. for 1 hour. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and then concentrated. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol=25/1-10/1, by volume), thereby obtaining 1.65 g of 1,3-dimethyl-6-{2-[N-(2-acetoxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH2:18][CH2:19]Cl)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[N:3]=1.[I-].[Na+].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(#N)C.O>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH2:18][CH2:19][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[N:3]=1
Reactant: Nc1nc(-c2ccccc2O)cc(-c2cccc(NC(=O)CCCl)c2)c1CO
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1nc(-c2ccccc2O)cc(-c2cccc(NC(=O)CCN3CCCCC3)c2)c1CO
Temperature: 75 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of N-{3-[2-amino-3-(hydroxymethyl)-6-(2-hydroxyphenyl)-4-pyridinyl]phenyl}-3-chloropropanamide (0.065 g, 0.16 mmol) and sodium iodide (0.007 g, 0.05 mmol) in acetonitrile (5 mL) was added piperidine (0.16 mL, 1.63 mmol), and the mixture was stirred at 75° C. overnight. After cooled to room temperature, the resulting mixture was diluted with water and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (chloroform:methanol, 85:15) to give N-{3-[2-amino-3-(hydroxymethyl)-6-(2-hydroxyphenyl)-4-pyridinyl]phenyl}-3-(1-piperidinyl)propanamide as a white foam (0.055 g, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:47]=[CH:46][C:5]2[N:6]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[C:7](=[O:36])[CH:8]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[N:19](C(OC(C)(C)C)=O)[C:18](=[O:27])[NH:17][C:14]4=[N:15][CH:16]=3)[C:4]=2[CH:3]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:47]=[CH:46][C:5]2[N:6]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)[C:7](=[O:36])[CH:8]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[NH:19][C:18](=[O:27])[NH:17][C:14]4=[N:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3cnc4[nH]c(=O)n(C(=O)OC(C)(C)C)c4c3)c3cc(Cl)ccc32)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3cnc4[nH]c(=O)[nH]c4c3)c3cc(Cl)ccc32)cc1
Yield: 95 %

Procedure:
tert-Butyl 6-(7-chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxylate (308 mg) was dissolved in 4 N HCl in dioxane (20 mL) and it was held at room temperature for an hour, then partitioned between aqueous sodium bicarbonate and EtOAc. The organic fraction was washed with brine, then dried over sodium sulfate, then concentrated and used further without purification (250 mg, 95% yield). 1H-NMR (300 MHz, CDCl3) δ 8.60 (bs, 1H), 8.10 (s, 1H), 7.80-7.10 (m, 14H), 6.90 (d, 2H), 6.62 (d, 2H), 5.65 (d, 1H), 4.55 (d, 1H), 3.95 (m, 1H), 3.80-3.60 (m, 8H), 1.60 (bs, 2H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:6]2[CH:21]=[C:20]([O:22]CC3C=CC=CC=3)[CH:19]=[CH:18][C:7]=2[S:8][C:9]=1[C:10]([NH:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:11])[CH3:3]>[Pd].C(O)(=O)C>[CH3:3][CH:2]([O:4][C:5]1[C:6]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:7]=2[S:8][C:9]=1[C:10]([NH:12][C:13]1[NH:14][N:15]=[N:16][N:17]=1)=[O:11])[CH3:1]
Reactant: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)sc2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)sc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.8 %

Procedure:
A warm slurry of 3-(1-methylethoxy)-5-(phenylmethoxy)-N-1H-tetrazol-5-yl-benzo[b]thiophene-2carboxamide (1.9 g, 5 mmoles) and 20% palladium on carbon (0.5 g) in acetic acid (250 mls) is shaken under hydrogen (50 psig) in a Parr apparatus. After three hours additional catalyst (0.5 g) is added and the mixture shaken at ambient temperature for 15 hours. The catalyst is removed by filtration and rinsed with warm acetic acid (200 mls). The filtrate is stripped of solvent under reduced pressure and two portions (50 mls) of toluene are added to, then stripped from the residue, leaving the crystalline product. Recrystallization from methanol gave the pure 3-(1-methylethoxy)-5-hydroxy -N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide (0.7 g): mp=258° C. (dec).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]CCC(N)=O)=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=2)[CH:4]=[N:3]1.CC(C)([O-])C.[Na+].[C:29]([C:31]1([NH:34][C:35]([C@H:37]2[N:41]([C:42]([C:44]3([C:47]([F:50])([F:49])[F:48])[CH2:46][CH2:45]3)=[O:43])[CH2:40][C@@H:39](OS(C3C=CC=CC=3)(=O)=O)[CH2:38]2)=[O:36])[CH2:33][CH2:32]1)#[N:30]>O1CCCC1.CN(C)C(=O)C.O>[C:29]([C:31]1([NH:34][C:35]([C@@H:37]2[CH2:38][C@@H:39]([S:13][C:10]3[CH:11]=[CH:12][C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[CH:8][C:9]=3[C:19]([F:21])([F:20])[F:22])[CH2:40][N:41]2[C:42]([C:44]2([C:47]([F:49])([F:50])[F:48])[CH2:46][CH2:45]2)=[O:43])=[O:36])[CH2:33][CH2:32]1)#[N:30]
Reactant: Cn1cc(-c2ccc(SCCC(N)=O)c(C(F)(F)F)c2)cn1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccccc3)CN2C(=O)C2(C(F)(F)F)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2ccc(S[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)N(C(=O)C4(C(F)(F)F)CC4)C3)c(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.8 %

Procedure:
3-[4-(1-Methyl-1H-pyrazol-4-yl)-2-trifluoromethyl-phenylsulfanyl]-propionamide (16.3 g, 49.6 mmol) was dissolved in tetrahydrofuran (80 mL) before sodium tert-butoxide (4.7 g, 48.9 mmol) was added and the fine suspension was stirred for 2 h at room temperature. N,N-dimethylacetamide (40 mL) was added and the mixture was stirred for further 2.5 h at room temperature. A solution of benzenesulfonic acid (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (20 g, 42.4 mmol) in N,N-dimethylacetamide (40 mL) was added and the yellow, fine suspension was stirred for 42 h at room temperature. The mixture was diluted with water (240 mL) and extracted with tert-butyl methyl ether (1×160 mL, 3×80 mL). The combined organic extracts were washed with an aqueous sodium carbonate solution (1 M, 80 mL) and brine (80 mL), dried over sodium sulfate and concentrated in vacuo to yield the title compound as a light brown foam (27.1 g). The crude product (containing dimethylacetamide) was used in the next step without further purification. For characterization purposes, a 2 g sample of crude material was purified by column chromagraphy on silica gel (eluent: gradient ethyl acetate/heptane 4:1 (v/v) to ethyl acetate). Likewise, 1.7 g of purified material were obtained. MS (ESI & APCI): m/z=572.1 [M+H]+, 589.2 [M+NH4]+. 1H NMR (CDCl3, 600 MHz): δ 1.12-1.22 (m, 3H), 1.28-1.34 (m, 3H), 1.49-1.54 (m, 2H), 2.02 (ddd, J=5.6 Hz, 8.2 Hz, 13.6 Hz, 1H), 2.88 (ddd, J=5.7 Hz, 5.7 Hz, 13.7 Hz, 1H), 3.89-3.99 (m, 2H), 3.97 (s, 3H), 4.04-4.09 (m, 1H), 4.69 (dd, J=5.2 Hz, 8.2 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.60 (bs, 1H), 7.62 (dd, J=1.8 Hz, 8.2 Hz, 1H), 7.69 (s, 1H), 7.77 (d, J=1.8 Hz, 1H), 7.79 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[CH:16]=[CH:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(Br)C=CC=1CC=CC1C=CC(C(O)=O)=CC=1)C1C=CC=CC=1.C(OC1C=C(Br)C=CC=1C=O)C1C=CC=CC=1.[Br-].C(C1C=CC(CC[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1)(O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CC=Cc2ccc(Br)cc2OCc2ccccc2)cc1
Agent: O=C(O)c1ccc(C=CCc2ccc(Br)cc2OCc2ccccc2)cc1
Agent: O=C(O)c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=Cc1ccc(Br)cc1OCc1ccccc1
Product: O=C(O)c1ccc(CCCc2ccc(Br)cc2OCc2ccccc2)cc1

Procedure:
4-[3-(2-Benzyloxy-4-bromophenyl)propyl]benzoic acid (mpt 141°-142° C.) was prepared from a mixture of 4-[3-(2-benzyloxy-4-bromophenyl)prop-2-enyl]benzoic acid and 4-[3-(2-benzyloxy-4-bromophenyl)prop-1-enyl]benzoic acid by a similar method to that of Example 7, (E). The mixture of alkenes was prepared from 2-benzyloxy-4-bromobenzaldehyde and 4-carboxyphenethyltriphenylphosphonium bromide by a similar method to that of Example 1, (G).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][C:24]1[O:32][C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][C:24]2[O:32][C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: c1cnc2cc(CC3CCCCN3)oc2c1
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3ncccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared using the method of Example 4, from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (120 mg, 0.5 mmol) and (RS)-2-piperidin-2-ylmethyl-furo[3,2-b]pyridine, D47 (108 mg, 0.5 mmol), as a colourless solid (95 mg, 43%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][CH2:26][Cl:27])=[O:23]>>[Cl:27][CH2:26][CH2:25][O:24][C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)OCCCl
Product: CCOC(=NC(=O)OCCCl)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2-chloroethyl chloroformate, there is obtained ethyl N-(2-chloroethoxycarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as an oil, mass spectrum m/e: M+ 372 (4), 343 (12), 293 (10), 263 (72), 194 (100), 178 (86), 165 (79);
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=O)[CH:3]([CH2:4]2)[CH2:2]1.C(N(CC)CC)C.[NH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[C:23]#[N:24]>C(Cl)Cl>[NH2:24][C:23]1[C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=2[N:16]=[C:7]2[C:6]=1[CH:5]1[CH2:4][CH:3]2[CH2:2][CH2:1]1
Reactant: N#CC1=C(N)CCCC1
Reactant: O=C1CC2CCC1C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1c2c(nc3c1C1CCC3C1)CCCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 12.8 %

Procedure:
To a stirred solution of norcamphor (0.9 g, 8.2 mmole) in methylene chloride (8.0 ml) at -20° C., a mixture of triethylamine (1.7 g, 16.4 mmole) and 2-amino-1-cyano-1-cyclohexene (1.0 g, 8.2 mmole) in methylene chloride (24 ml) was added and the resulting mixture was stirred at 25° C. for 15 hours. The reaction mixture was then quenched with 12% aqueous NaCH (60 ml) and was stirred vigorously with methylene chloride (60 ml). The reaction mixture was then filtered through a 2" pad of diatomaceous earth (Celite (trademark)). The organic phase was separated, washed with water (2×50 ml) and then dried (anhydrous MgSO4). Methylene chloride was then removed under reduced pressure to afford an oil which was triturated with pentane to give the title compound as a off-white solid (225 mg, 13%, m.p. 131°-133° C.). 1H-NMR (CDCl3, 300 MHz, δ): 2H, m, 1.15-2.38 ppm; 1H, d, 1.5 ppm; 7H, m, 165-2.0 ppm; 2H, bs, 2.4 ppm; 2H, bd, 2.8 ppm; 2H, bd 3.3 ppm; 2H, s, 3.95 ppm. HRMS: Calculated--214.3096; Found--214.1466. TLC: (90:10:1-methylene chloride: methanol:28% aqueous ammonia) Rf =0.25
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([C@@H:15]([NH:17][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)[CH3:16])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[C:3]=1[C:35](O)=[O:36].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([C@@H:15]([NH:17][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[CH3:16])[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:4]=2[C:3]=1[C:35]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:36]
Reactant: C1COCCN1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C(=O)O)c2n1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of 5-fluoro-3-phenyl-2-{(S)-1-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid (200 mg, 0.39 mmol) and morpholine (42 μL, 0.48 mmol) in DCM (10 mL) was added HATU (197 mg, 0.52 mmol) and the reaction stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) LCMS (Method C): RT=2.60 min, [M+H]+=571. The product was dissolved HCl in methanol (5 mL, 2.5M) and the reaction stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue loaded onto an SCX 2 cartridge, washed with methanol then eluted with ammonia in methanol (2M). The eluent was concentrated in vacuo and the residue subjected to HPLC purification (C18, 10-90% MeCN in H2O, 0.1% formic acid, 20 min gradient) to give 273 as a white solid (107 mg, 55%) 1H NMR (DMSO-d6+TFA-D, 400 MHz, 80° C.): δ 8.52 (1H, br s), 8.46 (1H, d, J=6.25 Hz), 7.83-7.75 (1H, m), 7.57-7.43 (5H, m), 7.32-7.15 (2H, m), 5.66 (1H, br s), 3.50-3.24 (5H, m), 3.15-3.05 (1H, m), 3.04-2.95 (1H, m), 2.70-2.58 (1H, m), 1.74-1.65 (3H, m). LCMS (Method K): RT=2.63 min, [M+H]+=487, RT=2.66 min, [M+H]+=487
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>ClCCl>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([NH:15][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=2)=[O:27])[N:12]=[CH:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCCn1cnc(N)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCn1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)c1
Reaction time: 0.1 h
Yield: 75 %

Procedure:
To a solution of compound 39.3 in dichloromethane under nitrogen was added 3-trifluoromethylphenyl isocyanate dropwise. After about 0.1 hour, a white precipitate formed. The precipitate was filtered off, washed with dichloromethane and dried under high-vacuum to yield 485 mg (75%) of (2-{4-[3-(3-trifluoromethyl-phenyl)-ureido]-imidazol-1-yl}ethyl)-carbamic acid tert-butyl ester (compound 39.4) as a white solid, ES (+) MS m/e=414 (M+H+).
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[N:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[C:14]([F:26])=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]>CO.[Pd]>[F:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[O:17][C:15]1[C:14]([F:26])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:16]=1
Reactant: CCOC(=O)c1cc(F)c(Oc2ccc(F)c(F)c2)nc1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1cnc(Oc2ccc(F)c(F)c2)c(F)c1
Temperature: 65 °C
Reaction time: 10 h
Yield: 74.8 %

Procedure:
To a solution of ammonium formate (28.5 g, 452 mmol) and ethyl 2-chloro-6-(3,4-difluorophenoxy)-5-fluoronicotinate (30 g, 90 mmol) in methanol (300 mL) was added Pd/C (3 g, 2.82 mmol). The reaction mixture was stirred at 65° C. for 10 hr. and then filtered. The filtrate was concentrated under reduced pressure to get ethyl 6-(3,4-difluoro phenoxy)-5-fluoronicotinate (20 g, 48.4%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].C1(=O)OCC1.C([NH-])C=C>>[CH2:18]([CH:2]1[CH2:3][CH2:4][CH2:5][O:6][C:1]1=[O:7])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: O=C1CCCCO1
Reactant: C=CCCCCCCCCBr
Agent: C=CC[NH-]
Agent: O=C1CCO1
Product: C=CCCCCCCCCC1CCCOC1=O
Yield: 60 %

Procedure:
14.30 g of tetrahydro-3-(9-decenyl)-2H-pyrane-2-one of interest was prepared in the same manner as in Example 1 except that 10.01 g (100.0 mmol) of δ-valerolactone and 26.30 g (110.0 mmol) of 10-bromo-1-decene were used instead of β-propiolactone and allyl amide described in Preparation Example 1.
Reaction SMILES: C(OCC(COC(=O)C)CCN1C=NC2C1=NC(N)=NC=2)(=O)C.OCC(CO)CCN1C=NC2C(=O)NC(N)=NC1=2.[NH2:42][C:43]1[N:51]=[C:50]2[C:46]([NH:47][CH:48]=[N:49]2)=[C:45]([Cl:52])[N:44]=1.Br[CH2:54][CH2:55][C:56]([C:67]([O:69][CH2:70][CH3:71])=[O:68])([C:62]([O:64][CH2:65][CH3:66])=[O:63])[C:57]([O:59][CH2:60][CH3:61])=[O:58]>>[NH2:42][C:43]1[N:51]=[C:50]2[C:46]([N:47]=[CH:48][N:49]2[CH2:54][CH2:55][C:56]([C:57]([O:59][CH2:60][CH3:61])=[O:58])([C:67]([O:69][CH2:70][CH3:71])=[O:68])[C:62]([O:64][CH2:65][CH3:66])=[O:63])=[C:45]([Cl:52])[N:44]=1
Reactant: CCOC(=O)C(CCBr)(C(=O)OCC)C(=O)OCC
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: CC(=O)OCC(CCn1cnc2cnc(N)nc21)COC(C)=O
Agent: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Product: CCOC(=O)C(CCn1cnc2c(Cl)nc(N)nc21)(C(=O)OCC)C(=O)OCC

Procedure:
Nucleosides and Nucleotides, 15(5), 981-994 (1996) and WO 95/28404 disclose a process for the manufacture of the anti-viral agents 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (famciclovir) and 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (penciclovir). According to this process, the ‘bromotriester’ route, 2-amino-6-chloropurine is reacted with triethyl 3-bromopropane-1,1,1-tricarboxylate in the presence of base to form diethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]-2-carbethoxymalonate. The crude isolate from this alkylation reaction is then treated with sodium methoxide in methanol to form dimethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl] malonate. This product is purified by crystallisation and then successively reduced using sodium borohydride and O-acetylated to give 9-(4-acetoxy-3-acetoxymethylbutyl)-2-amino-6-chloropurine. Famciclovir is produced directly from the latter compound by hydrogenation over a supported palladium catalyst; and penciclovir is produced from this compound by acid hydrolysis of the acetoxy groups.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CN(C=O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10]([CH2:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:22])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(CBr)Oc1ccccc1
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cn1ccc2cc([N+](=O)[O-])cnc21)Oc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 13.7 %

Procedure:
To a solution of 5-nitro-1H-pyrrolo[2,3-b]pyridine (0.200 g, 1.226 mmol) and anhydrous potassium carbonate (254.2 mg, 1.839 mmol) in anhydrous DMF (6.0 mL) at room temperature was added phenyl 2-bromoacetate (0.755 mg, 3.678 mmol). After 20 h stirring at room temperature, additional phenyl 2-bromoacetate (1.256 g, 6.13 mmol) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with methylene chloride (70 mL), quenched with an aqueous pH 7 phosphate buffer solution (30 mL). The aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic extracts were then successively washed with an aqueous pH 7 phosphate buffer solution (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated. The crude residue was purified by C18 reverse phase chromatography (H2O:CH3CN eluant gradient) to give phenyl 2-(5-nitro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetate (C-7) as a beige solid (50.0 mg, 13% yield). MS (M+1): m/e 298.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C(Cl)[Cl:23].[ClH:25]>O1CCOCC1>[ClH:23].[ClH:25].[N:1]1[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:9][CH2:10][C@H:11]([NH2:14])[CH2:12][CH2:13]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccncc2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](Oc2ccncc2)CC1
Reaction time: 2 h

Procedure:
A mixture of tert-butyl [trans-4-(pyridin-4-yloxy)cyclohexyl]carbamate in a solution of methylene chloride (1 mL) and 4.0 M of hydrogen chloride in 1,4-dioxane (2 mL) was stirred at r.t for 2 hours. The mixture was concentrated to yield 45% of trans-4-(pyridin-4-yloxy)cyclohexanamine dihydrochloride (2-step).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][N:7]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:8]([NH2:10])=[S:9].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)=O>>[CH:11]1([N:7]([C:8]2[S:9][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[N:10]=2)[CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)CCCN(C(N)=S)C1CCCC1
Reactant: CC(C)c1ccc(C(=O)CBr)cc1
Product: CC(C)c1ccc(-c2csc(N(CCCC(=O)O)C3CCCC3)n2)cc1

Procedure:
4-{Cyclopentyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-butyric acid was prepared according to general procedure B using 4-(1-cyclopentyl-thioureido)-butyric acid methyl ester (70 mg, 0.3 mmol) and 2-bromo-4′-isopropylacetophenone (80.0 mg, 0.3 mmol). Purification (Silica gel, ethyl acetate/hexane 5:95) provided the ester, which was hydrolyzed following general procedure T. LCMS m/z: 374 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([NH:12]C(=O)OCC)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH3:18][O-:19].[Na+].CO>O>[CH3:18][O:19][C:2]1[C:3]2[N:11]=[C:10]([NH2:12])[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: C[O-]
Reactant: CCOC(=O)Nc1nc2c(Cl)nc(C)nc2s1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C)nc2sc(N)nc12
Temperature: 25 °C
Yield: 55.6 %

Procedure:
Ethyl 7-chloro-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbamate (300 mg, 1.100 mmol) was suspended in a 25% w/w solution of sodium methoxide in methanol (5 mL, 23.14 mmol) and the mixture was refluxed overnight. The mixture was cooled to ambient temperature, diluted with water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-amine (120 mg, 0.612 mmol, 55.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (s, 2 H) 3.98 (s, 3 H) 2.52 (s, 3 H).