Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:43]([NH:50][C:15]([C:11]1[S:10][C:9]([N:8]([CH3:18])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:13][C:12]=1[CH3:14])=[O:17])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(N(C)C(=O)OC(C)(C)C)sc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(N(C)C(=O)OC(C)(C)C)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl(methyl)amino)-4-methylthiazole-5-carboxylic acid (0.070 g, 0.26 mmol) in dichloromethane (2 mL) at 0° C. was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.15 g, 0.39 mmol), followed by the addition of benzylamine (29.5 μL, 0.27 mmol), 4-dimethylaminopyridine (catalytical amount), and triethylamine (72 μL, 0.52 mmol). The reaction mixture was allowed to warm to ambient temperature over 3 h, followed by the addition of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (5/95 to 100/0) to afford tert-butyl 5-(benzylcarbamoyl)-4-methylthiazol-2-yl(methyl)carbamate (0.030 g, 0.083 mmol).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:37][C@H:36]([CH2:38][NH:39][C:40]([C:42]4[S:43][C:44]([Cl:47])=[CH:45][CH:46]=4)=[O:41])[O:35][C:34]3=[O:48])=[CH:29][C:28]=2[C:49]([F:52])([F:51])[F:50])[C:22]1=[O:53])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:47][C:44]1[S:43][C:42]([C:40]([NH:39][CH2:38][C@@H:36]2[O:35][C:34](=[O:48])[N:33]([C:30]3[CH:31]=[CH:32][C:27]([N:23]4[CH2:24][CH2:25][CH2:26][N:21]([CH2:20][CH2:19][OH:18])[C:22]4=[O:53])=[C:28]([C:49]([F:51])([F:50])[F:52])[CH:29]=3)[CH2:37]2)=[O:41])=[CH:46][CH:45]=1
Reactant: CC(C)(C)[Si](OCCN1CCCN(c2ccc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2C(F)(F)F)C1=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NC[C@H]1CN(c2ccc(N3CCCN(CCO)C3=O)c(C(F)(F)F)c2)C(=O)O1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 8.88 g (11.3 mmol) of the product from example 73A in 225 ml of THF is admixed with 6.95 g (26.6 mmol) of a 1 molar solution of tetrabutylammonium fluoride in THF. The mixture is stirred at RT for 45 min. Then it is freed of the solvent and the residue is purified by chromatography on silica gel (40:1→10:1 dichloromethane/methanol). This affords 5.24 g (80% of theory) of the desired product.
Reaction SMILES: CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:35][C:36]([F:47])([F:46])[O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][OH:43])=[CH:40][CH:39]=1>C(#N)C>[F:35][C:36]([F:46])([F:47])[O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][O:43][C:32]([N:29]2[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][CH2:28]2)=[O:33])=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: OCc1ccc(OC(F)(F)F)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
652 mg (1.5 mmol) PS-BEMP and 373 mg (1.5 mmol) 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester was added to a solution of 192 mg (1.0 mmol) 4-trifluoromethoxybenzyl alcohol in 5 ml acetonitrile. The mixture was heated to reflux for 24 h then cooled to rt, diluted with 5 ml acetonitrile, 666 mg (4.5 mmol) PS-NH2 added and shaken at rt for 16 h. After filtration and evaporation the crude product is purified by flash chromatography on silica gel with hexane/AcOEt 50:50: 180 mg colourless crystalline solid. 1H-NMR (CDCl3): 1.45 s, 9H, 3.35–3.55 m, 8H, 5.14 s, 2H, 7.20 d, 2H and 7.40 d, 2H, AB-system.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].C1(S(O)(=O)=O)C=CC=CC=1.[Cl:16][CH2:17][CH2:18][C:19]#[N:20]>C(Cl)Cl.CC(C)=O>[S:1]([NH:5][C:19](=[NH:20])[CH2:18][CH2:17][Cl:16])(=[O:3])(=[O:2])[NH2:4]
Reactant: NS(N)(=O)=O
Reactant: N#CCCCl
Agent: O=S(=O)(O)c1ccccc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: N=C(CCCl)NS(N)(=O)=O
Temperature: 57.5 °C

Procedure:
Sulfamide (9.6 g, 0.1 mole) was added to a suspension of benzenesulfonic acid (31.6 g, 0.2 mole) in 3-chloropropionitrile (51.3 g, 0.6 mole). The suspension was heated at 55-60° C., for 18 hours. At the end of the heating period, the mixture was cooled to room temperature, diluted with methylene chloride (150 ml), and filtered. The solid, thus obtained, was suspended in acetone (50 ml), and the suspension filtered and the product dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[C:7]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([N+:22]([O-])=O)[C:5]1=[S:25](=[O:27])=[O:26].C>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH:4]1[CH:9]=[C:8]([N:10]2[CH:11]=[CH:12][CH:13]=[CH:14]2)[C:7]([S:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([NH2:22])[C:5]1=[S:25](=[O:27])=[O:26]
Reactant: COC(=O)C1C=C(n2cccc2)C(Sc2ccccc2)=C([N+](=O)[O-])C1=S(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1C=C(n2cccc2)C(Sc2ccccc2)=C(N)C1=S(=O)=O
Yield: 80 %

Procedure:
20 g of 3-nitro-4-phenylthio-5-pyrrol-1-yl-sulfonylbenzoic acid methyl ester in 1 liter of ethyl acetate are hydrogenated in the presence of 2 g of palladium on active charcoal, initially at room temperature and then at 40°-50° C. After filtering off the catalyst and concentrating the filtrate under reduced pressure, the residue is chromatographed over a silica gel column, using methylene chloride. The fractions containing the desired product are freed from solvent and the residue is recrystallized from methanol. 3-Amino-4-phenylthio-5-pyrrol-1-yl-sulfonylbenzoic acid methyl ester of melting point 118°-119° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br>O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: COc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1
Agent: Br
Solvent: O
Product: Oc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
A suspension of 10.0 g (34.8 mmol) of 3-chloro-2-(4-methoxyphenyl)-5-trifluoromethylpyridine in 50 ml of 47% strength hydrobromic acid was heated at reflux temperatures for two hours. After cooling, the reaction mixture was diluted with 200 ml of water. After cooling for a few hours, the resulting crystals were separated off, washed with water and dried under reduced pressure. Yield: 8.0 g (84%) of colorless crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH:10]=[N:9][C:7](=[O:8])[NH:6][C:4]1=[O:5])[CH3:2].[H][H]>[Rh].O>[CH2:1]([N:3]1[CH2:10][NH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCn1cnc(=O)[nH]c1=O
Agent: [Rh]
Solvent: O
Product: CCN1CNC(=O)NC1=O
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a quantity [370 gm., 2.62 mole] of the 1-ethyl-5-azauracil prepared in Part B, above is added 2200 ml. water and 40 gm. of 5 percent rhodium on activated charcoal. This mixture is put in a Parr hydrogenation chamber and hydrogen gas is introduced to a pressure of 50 pounds per square inch (p.s.i.) and the reaction system is heated to 100° C. When uptake of hydrogen ceases, the hydrogen pressure is increased to 200 p.s.i. and held there for 18 hours. The hydrogenated reaction mixture is rinsed out of the reaction chamber with hot water, filtered while hot, and the filter is washed with one liter of water at 80° C. The aqueous solution is set aside at 25° C. for 18 hours, during which interval crystals form. The crystals are collected on a filter and dried at 50° C. under reduced pressure. There is thus obtained 70 gm. of 5-ethyl-5,6-dihydro-s-triazine-2,4-(1H, 3H)-dione having a melting range between 220° C. and 224° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4Cl)[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[K+].C([O-])([O-])=O.[K+].[K+].[CH3:31][N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[CH2:37][OH:38]>C(Cl)(Cl)Cl.CO.C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[O:38][CH2:37][CH:33]4[CH2:34][CH2:35][CH2:36][N:32]4[CH3:31])[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CN1CCCC1CO
Reactant: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN1CCCC1COc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 4.8 %

Procedure:
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one (I-180a: 100 mg, 0.3023 mmol) was added to a stirred mixture of KOH (68 mg, 1.2092 mmol), K2CO3 (42 mg, 0.3023 mmol) and toluene (3 mL) and the reaction mixture was stirred at RT for 5 mins. This was followed by the addition of (1-methyl-pyrrolidin-2-yl)-methanol (52 mg, 0.4534 mmol) and 18 crown ether (8 mg, 0.0302 mmol) and the resulting mixture was refluxed for 24 hrs. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated and the concentrate was partitioned between ethylacetate and water. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by preparative HPLC afforded 6 mg of the product (5% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]=1.[Br:17]N1C(=O)CCC1=O>ClCCl>[Br:17][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[CH:8][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccc(C)c([N+](=O)[O-])c2)no1
Solvent: ClCCl
Product: Cc1nc(-c2ccc(CBr)c([N+](=O)[O-])c2)no1
Yield: 81.1 %

Procedure:
A solution of compound 1b (21 g, 96 mmol) and N-bromosuccinimide (20.5 g, 115 mmol) in dichloromethane (500 mL) was irradiated with a sun lamp for 2 h at rt. The reaction mixture was filtered through a short column of silica gel in dichloromethane and concentrated on a rotary evaporator. The residue was recrystallized (ethyl acetate/hexane/petroleum ether) to afford compound 1c as a white solid (23.2 g, 82%). ESI-MS m/e 300.1 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[N:14]2)=[CH:9][C:8]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[CH:13]=[N:14]2)=[CH:9][C:8]=1[O:26][CH3:27]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
1-Bromo-3-chloropropane (0.97 ml, 9.8 mmol) was added to a solution of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.5 g, 8.17 mmol), (prepared as described for the starting material in Example 7), in DMF (40 ml) containing potassium carbonate (2.8 g, 20 mmol). The mixture was stirred overnight at ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO4) and evaporated to give 7-(3-chloropropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (3.10 g, 100%).
Reaction SMILES: CS([C:4]1[NH:5][CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22]>CO>[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:4]1[NH:5][CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CS(=O)c1[nH]ccc1[N+](=O)[O-]
Solvent: CO
Product: Cc1[nH]cnc1CSCCNc1[nH]ccc1[N+](=O)[O-]
Yield: 34.1 %

Procedure:
A solution of 2-methylsulphinyl-3-nitropyrrole (2 g, 0.01 mol) and 2-(5-methyl-4-imidazolylmethylthio)ethylamine (2 g, 0.01 mol) in methanol (50 ml) was refluxed for 7 days and evaporated to dryness. The residue was chromatographed on a silica gel column eluted with ethyl acetate, and the eluate was evaporated to dryness and recrystallised from propan-2-ol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitropyrrole (0.96 g, 31%) m.p. 161°-162°.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[CH:32]1([C:35](O)=[O:36])[CH2:34][CH2:33]1>CN(C=O)C>[CH:32]1([C:35]([N:29]2[CH2:30][CH2:31][CH:26]([N:24]3[CH:25]=[C:21]([C:7]4[C:6]5[C:10](=[CH:11][C:3]([F:2])=[CH:4][CH:5]=5)[N:9]([S:12]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)(=[O:13])=[O:14])[CH:8]=4)[CH:22]=[N:23]3)[CH2:27][CH2:28]2)=[O:36])[CH2:34][CH2:33]1
Reactant: O=C(O)C1CC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(C1CC1)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 107.8 %

Procedure:
Following the general method as outlined in Example 83, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 300 mg; 0.65 mmol) and cyclopropanecarboxylic acid (122 mg; 1.42 mmol) in DMF (6 mL), 345 mg of the title compound was obtained as a yellow oil, which was used directly without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:34]([CH2:36][NH:37][C:38]([CH:40]1[CH:45]([CH2:46]O)[CH:44]2[CH2:48][CH:41]1[CH:42]=[CH:43]2)=[O:39])#[N:35].[F:49][C:50]1[CH:55]=[CH:54][C:53]([SH:56])=[CH:52][CH:51]=1>CN(C)C=O>[C:34]([CH2:36][NH:37][C:38]([CH:40]1[CH:45]([CH2:46][S:56][C:53]2[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=2)[CH:44]2[CH2:48][CH:41]1[CH2:42][CH2:43]2)=[O:39])#[N:35]
Reactant: Fc1ccc(S)cc1
Reactant: N#CCNC(=O)C1C2C=CC(C2)C1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1C2CCC(C2)C1CSc1ccc(F)cc1
Reaction time: 19 h

Procedure:
A solution of triphenylphosphine (140 mg, 540 mmol) in dimethylformamide (1.0 mL) was cooled to 0° C. Diisopropyl azodicarboxylate (98 μL, 500 μmol) was added and the reaction mixture was stirred for 2 min. (1R/S,2R/S,3R/S,4S/R)-N-(Cyanomethyl)-3-(hydroxymethyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide (94 mg, 450 μmol) and 4-fluorothiophenol (53 μL, 500 μmol) were added. After stirring the reaction mixture for 19 h, it was partitioned between ethyl acetate (20 mL) and 1:1 water:saturated aqueous sodium chloride (20 mL). The product was extracted into ethyl acetate and the combined organics were washed with 1 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated using a rotary evaporator. Chromatography of the residue on silica gel eluting with 1:2 ethyl acetate:hexanes provided (1S/R,2R/S,3R/S,4R/S)-N-(cyanomethyl)-3-{[(4-fluorophenyl)sulfanyl]methyl}bicyclo[2.2.1]heptane-2-carboxamide as a colorless syrup.
Reaction SMILES: O1CCCC1.[C:6]([O:10][C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[OH:21][CH2:20][C:19]1[CH:23]=[CH:24][C:16]([CH2:15][CH2:14][NH:13][C:11](=[O:12])[O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (100 mL, 100 mmol) was added directly to solid (4-(2-(tert-butoxycarbonylamino)ethyl)benzoic acid (12.4 g, 46.7 mmol). The resulting solution was stirred at ambient temperature for 1 hour, carefully quenched with water (250 mL), and extracted with ethyl acetate (500 mL). The organic layer was washed with saturated sodium bicarbonate (200 mL) and brine (100 mL), dried over sodium sulfate and concentrated to afford tert-butyl 4-(hydroxymethyl)phenethylcarbamate as a pale yellow oil (10.0 g, 85% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][O:12][CH3:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([Li])CCC.C([O:22][B:23]([O:28]C(C)C)[O:24]C(C)C)(C)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][O:12][CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:22][B:23]([OH:28])[OH:24]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCc1cc(OC)cc(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dimethoxy(methoxymethyl)benzene (23.7 g) in tetrahydrofuran (500 mL) was added n-butyllithium (1.56M hexane solution; 100 mL) at −78° C., and the reaction mixture was stirred for 30 minutes while cooling with ice. After cooling the internal temperature of the obtained reaction mixture to −78° C., to a reaction mixture was added triisopropoxyborane (39 mL), and the internal temperature was raised to room temperature while stirring. After completion of the reaction, saturated aqueous ammonium chloride was added to the reaction mixture while cooling with ice, and then ethyl acetate was added to the reaction mixture, the organic extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (7.5 g) was obtained as a yellow oil from the ethyl acetate fraction.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[F:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[F:15])[NH2:11].O>N1C=CC=CC=1.CC(C)=O.CCCCCC>[F:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[F:15])[NH:11][C:4](=[O:5])[CH2:3][CH2:2][Cl:1]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(F)c(F)c1
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: O=C(CCCl)Nc1ccc(F)c(F)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
3-Chloropropionyl chloride (139.16 g) is added with stirring in the course of 1 hour and a half to a solution, heated to a temperature in the region of 55° C., of 3,4-difluoroaniline (125 g) in pyridine (80 cc) and acetone (1.5 liters), and the mixture is maintained at this temperature for 1 hour and a half. After cooling to approximately 20° C., the solution is poured with stirring into a mixture of water (1 liter) and crushed ice (500 g). The temperature is allowed to rise to approximately 20° C. and the product is extracted with dichloromethane (3×500 cc). The combined organic extracts are washed with N hydrochloric acid (500 cc) and water (5×500 cc), dried over magnesium sulphate, filtered and concentrated under reduced pressure (20 kPa) at approximately 50° C. The solid obtained is taken up in n-hexane (500 cc), drained and washed with the same solvent (2×100 cc). 3',4'-Difluoro-3-chloropropionanilide (202.9 g) is obtained in the form of a beige solid, m.p. 76° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=O)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=1.C(Cl)(Cl)Cl>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:17])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(=O)n3cc(C#N)ccc3nc2s1

Procedure:
2-Methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyridimine-7-carboxamide (Example 21), 2.6 g (0.010 mol), in 30 ml of phosphorus oxychloride and 30 ml of chloroform is refluxed on a steam bath for three hours. The chloroform and excess phosphorus oxychloride are evaporated in vacuo and the residue is treated with 200 ml of ice water. The resulting precipitate is filtered to give 2.1 g of 2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 256°-258° C. after recrystallization from glacial acetic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:56]=[CH:55][C:54]([NH:57][CH3:58])=[CH:53][CH:52]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1>ClCCl>[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:52]=[CH:53][C:54]([N:57]([CH3:58])[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:9])=[CH:55][CH:56]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cn1cc(C(=O)O)cn1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C(=O)c1cnn(C)c1)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
A mixture of 1-methyl-1H-pyrazole-4-carboxylic acid (22 mg, 0.17 mmol) in dichloromethane (2.0 mL) at 25° C. was treated with triphenylphosphine (54 mg, 0.21 mmol). This mixture was cooled to 0° C. and then treated with N-chlorosuccinimide (28 mg, 0.21 mmol). This mixture was stirred at 0° C. for 30 min and then was warmed to 25° C. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (150 mg, 0.34 mmol). The reaction was then stirred at 25° C. for 2 days. At this time, the reaction was diluted with dichloromethane and then was washed with a saturated aqueous sodium bicarbonate solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3:97 methanol/dichloromethane) afforded 1-methyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (87 mg, 92.8%) as an off-white solid: LR-MS for C29H28FN7O3 (M+H)+ at m/z=542.
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].O.[NH2:23][NH2:24]>C(O)C>[NH2:6][C:5]1[NH:24][N:23]=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[C:4]=1[C:7]#[N:8]
Reactant: NN
Reactant: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Solvent: O
Solvent: CCO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a solution of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (80 g, 290 mmol) in ethanol (200 mL) was added hydrazine hydrate (20 mL). The mixture was stirred at RT for 16 hr then was concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a off-white solid. 1H NMR (DMSO-d6) δ 12.11 (br s, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.46-7.39 (m, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.12-7.04 (m, 4H), 6.43 (br s, 2H).