Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]Cl.[CH3:13][O:14][C:15]([CH:17]1[N:22]([C:23](=[O:37])[CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][C:20]2[N:38](CC(=O)C3C=CC=CC=3)[CH2:39][NH:40][C:19]=2[CH2:18]1)=[O:16].C(#N)C>CCOCC>[CH3:13][O:14][C:15]([CH:17]1[N:22]([C:23](=[O:37])[CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:21][C:20]2[N:38]=[CH:39][N:40]([CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:19]=2[CH2:18]1)=[O:16]
Reactant: COC(=O)C1CC2=C(CN1C(=O)C(c1ccccc1)c1ccccc1)N(CC(=O)c1ccccc1)CN2
Reactant: COc1ccc(CCl)cc1OC
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)C1Cc2c(ncn2Cc2ccc(OC)c(OC)c2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
A solution of 1.5 g 3,4-dimethoxybenzyl chloride, 2.5 g methyl-5-diphenylacetyl-3-(2-oxo-2-phenylethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate and 30 mL acetonitrile is heated at reflux 16 hr. The cooled solution is added dropwise to 400 mL vigorously stirred ether and the resulting precipitate is collected by filtration. This precipitate is dissolved in 40 mL methanol and treated with 8 g zinc dust and 40 mL acetic acid. The resulting suspension is sonicated 2 hr then the solution is filtered from excess zinc. The filtrate is dissolved in 400 mL dichloromethane and treated dropwise with 450 mL 10% Na2CO3 with vigorous stirring. The organic phase is separated, dried, concentrated and the major product is isolated by chromatography on silica gel (chloroform-methanol, 99:1) as a crisp foam. NMR (CDCl3) 3.88 (s,3H,0Me); 3.80 (s,3H,0Me); 3.58 (s,3H,0Me).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22]>CN(C1C=CN=CC=1)C.ClCCl>[C:21](=[O:22])([O:23][CH3:24])[O:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=1[Br:1]
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(C(C)(C)C)cc1Br
Temperature: 25 °C
Yield: 90.4 %

Procedure:
2-Bromo-4-tert-butyl phenol (15.0 g, 65.5 mmol) and DMAP (400 mg, 3.3 mmol) was dissolved in dichloromethane (75 mL) and triethylamine (18.25 mL, 130.9 mmol), cooled to 0° C., then treated with methyl chloroformate (7.6 mL, 98.2 mmol) and allowed to warm to room temperature over 2 h. The reaction was quenched with water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined organic extracts dried over Na2SO4. The solution was filtered and concentrated in vacuo to yield an oil that was purified by silica gel chromatography (20% ethyl acetate/hexane) to yield 2-bromo-4-tert-butylphenyl methyl carbonate (17 g, 90% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.67 (d, J=2.3 Hz, 1H), 7.47 (dd, J=2.3, 8.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 3.86 (s, 3H), 1.29-1.26 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.[NH2:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40].[H-].[Na+]>CN(C=O)C>[OH:40][CH2:39][CH:38]([NH:37][C:23]1[N:22]=[C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=1)[CH2:41][OH:42]
Reactant: NC(CO)CO
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(NC(CO)CO)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-methyl-3-(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) and 2-aminopropane-1,3-diol (1.0 equiv.) in DMF (0.05M) was added 60% sodium hydride (1.0 equiv.) at 0° C. The reaction was allowed to warm to room temperature and stir for 24 hours. LCMS analysis indicated the formation of the desired product. The crude material was purified via preparative reverse phase HPLC. Upon lyophilization of the pure fractions, N-(3-(2-((1,3-dihydroxypropan-2-yl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide was isolated as the TFA salt in 28% yield. LCMS (m/z) (M+H)=532.1, Rt=0.68 min. 1H NMR (400 MHz, <cd3od>) δ ppm 2.45 (s, 3H) 3.64-3.71 (m, 1H) 3.79 (s, 10H) 3.85-3.91 (m, 1H) 4.53-4.59 (m, 1H) 4.63-4.69 (m, 1H) 6.67 (s, 1H) 7.44 (d, J=7.43 Hz, 1H) 7.51 (d, J=7.83 Hz, 1H) 7.56 (t, J=8.02 Hz, 1H) 7.93 (d, J=8.22 Hz, 1H) 7.96-8.01 (m, 3H) 8.16 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:12]2[S:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(O)=O.[N:17]([O-])=[O:18].[Na+]>O>[CH3:1][C:2]1[C:12]2[S:11][CH2:10][CH2:9][CH2:8][N:7]([N:17]=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1cccc2c1SCCCN2
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c1SCCCN2N=O
Temperature: 23 °C

Procedure:
To a solution of 9-methyl-2,3,4,5-tetrahydro-1,5-benzothiazepine (500 mg, 2.6 mmol) and AcOH (2 mL) cooled to ˜9° C. was added a solution of NaNO2 (212 mg, 3.1 mmol) and water (1 mL) dropwise over 4 min (internal temperature<12° C.). The cooling bath was removed and the reaction was maintained at 23° C. for 2 h. It was diluted with H2O (50 mL). 9-methyl-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine was obtained (470 mg, 87%) as a yellow solid after it was collected by vacuum filtration and air-dried at 23° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:24]([NH:26][C@H:27]([C:31]([N:33]([CH3:50])[C@@H:34]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:35]([O:44][CH3:45])[CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:24]([NH:26][C@H:27]([C:31]([N:33]([CH3:50])[C@@H:34]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:35]([O:44][CH3:45])[CH2:36][C:37]([OH:39])=[O:38])=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)C(C)C
Reaction time: 18 h

Procedure:
To a solution of #27 (500 mg, 0.723 mmol) in dichloromethane (7 mL, 0.1 M) was added trifluoroacetic acid (3 mL). The reaction mixture initially became orange, then darkened over time. After stirring for 18 hours, the solvent was removed in vacuo to give #28 (460 mg, quantitative) as a dark brown glass, which was used without further purification. LC-MS: m/z 636.3 [M+H+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:16][CH2:15]3)[CH2:11][CH2:10]2)[CH2:3][CH2:2]1>C(O)C.ClCCl>[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([CH2:15][CH2:16][CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19]3)[CH2:11][CH2:10]2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)CC1CCC2(CC1)CCN(CCC1CCNCC1)CC2
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)CC1CCC2(CC1)CCN(CCC1CCNCC1)CC2

Procedure:
0.35 g (1.0 mmol) of the compound from Example 24 were hydrolized in 15 ml ethanol containing 7 drops aqueous sodium hydroxide as described for Example 23. The title acid solidified upon stirring in dichloromethane. It was filtered and dried in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([Cl:19])=[O:15])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: N#Cc1cc(C(=O)O)c2ccccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(C(=O)Cl)c2ccccc2c1
Yield: 100 %

Procedure:
3-Cyano-1-naphthoic acid (see Bioorg. Med. Chem. Lett. 2001, 2769; 1.1 g, 5.6 mmol) was slurried in CH2Cl2 (10 mL) and then oxalyl chloride was added with stirring. A drop of DMF was added and the mixture stirred at room temperature overnight under nitrogen. The solvent was removed by evaporation and there was obtained 1.2 g (100%) of 3-cyano-1-naphthoyl chloride as a pale yellow solid. 1H NMR (300 MHz, CDCl3): 7.7-7.8 (m, 1H), 7.8-7.9 (m, 1H), 8.0-8.1 (m, 1H), 8.5 (s, 1H), 8.7 (s, 1H), 8.8 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N#N.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH:12]=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2
Reactant: CCOC(=O)CC(=O)Cc1c(OC)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: N#N
Agent: O=C[O-]
Solvent: CO
Product: CCOC(=O)Cc1cc2c(OC)cccc2[nH]1
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
(Chart A, Step 2): A solution of ethyl 4-(2-methoxy-6-nitrophenyl)-3-oxobutanoate (10.6 g, 37.5 mmol) in MeOH (350 mL) is purged with N2, and treated with 10% Pd/C (1.10 g) turning the yellow solution black. The suspension is treated with ammonium formate (27.4 g, 43.5 mmol) with a slight exotherm and evolution of H2. After 15 minutes, the reaction mixture is filtered through a pad of celite, and concentrated. The residue is diluted with water and extracted 3 times with ethyl acetate. The combined organics are washed with brine, dried over NaSO4, filtered, and concentrated to give 9.4 g of crude material which is combined with the crude material from a previous 1.5 mmol reaction. The crude material is purified by LC (25% ethyl acetate/heptane) to give 8.08 g of substituting ethyl 2-(4-methoxy-1H-indol-2-yl)acetate as an oil that solidifies overnight. IR (liq.) 3389, 1730, 1617, 1594, 1510, 1438, 1367, 1287, 1250, 1217, 1167, 1151, 1097, 1030, 767 cm−1.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15](=[O:18])[S:16][CH:17]=2)=[CH:9][CH:8]=1)(=O)C>CO.O>[O:18]=[C:15]1[S:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][OH:4])=[CH:12][CH:11]=2)=[CH:17][S:16]1
Reactant: CC(=O)OCCc1ccc(-c2csc(=O)s2)cc1
Solvent: CO
Solvent: O
Product: O=c1scc(-c2ccc(CCO)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A mixture of compound 7 (40.0 g, 0.143 mol) dissolved in 500 ml methanol and 40 g K2C03 dissolved in 300 ml water was stirred at room temperature for 1 hour. The mixture was extracted with 300 ml chloroform. The chloroform solution was washed with water, concentrated, recrystallized (methanol/ether), and dried to give 23.8 g (70.0%) of compound 8. Analysis of the product gave the following results: mp 92°-94° C.; NIR (KBr) 3258, 3060, 2927, 1697, 1632, 1503, 1055, 1046, 868 cm-1 ; 1H NMR (300 MHz) δ 1.55 (s, 1H), 2.89 (t, 2H, J=6.8 Hz), 3.88 (t, 2H, J=6.8 Hz), 6.79 (s, 1H), 7.26-7.38 (m, 4H); 13C NMR (75 MHz) δ 192.52, 140.08, 134.80, 130.89, 129.79, 126.43, 111.19, 63.27, 38.75. Anal. Calcd. for C 11 H10O2S2 : C, 55.44; H, 4.23; Found: C, 56.32; H, 4.56.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:26](=[O:27])[NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1
Reactant: CCCN1CCC(O)N(c2nnc(SC)s2)C1=O
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Product: CCCN1CCC(OC(=O)NC2CCCCC2)N(c2nnc(SC)s2)C1=O
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and cyclohexyl isocyanate (3.5 ml); 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-(N-cyclohexylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:6]=2)[CH2:3][CH2:2]1.[CH3:25][N:26]1[C:30](=[O:31])[CH2:29][NH:28][C:27]1=[O:32].N1CCCCC1>CCO.O>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:29]4\[NH:28][C:27](=[O:32])[N:26]([CH3:25])[C:30]\4=[O:31])=[C:9]3[N:8]=[C:7]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: CN1C(=O)CNC1=O
Reactant: N#Cc1ccc(Nc2cc(NC3CC3)n3ncc(C=O)c3n2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: CN1C(=O)N/C(=C\c2cnn3c(NC4CC4)cc(Nc4ccc(C#N)cc4)nc23)C1=O
Temperature: 80 °C
Reaction time: 15 h
Yield: 67.9 %

Procedure:
4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (51 mg, 0.16 mmol) was suspended in EtOH (1.6 mL). 3-methylimidazolidine-2,4-dione (28 mg, 0.24 mmol) and piperidine (24 μL, 0.24 mmol) were added and the reaction was heated to 80° C. After 15 h, the solution was diluted with H2O (2 mL) and filtered. The filter cake was washed with 50% H2O/50% EtOH (3 mL) and then dried in vacuo (˜1 mmHg) to furnish (Z)-4-(7-(cyclopropylamino)-3-((1-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (45 mg, 68%) as a bright yellow solid. LCMS (ES): >90% pure, tm/z 415 [M+1]+.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:12][CH:11]2[CH:7]([CH2:8][N:9]([C:13](=[O:29])[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21]CC3C=CC=CC=3)[CH2:10]2)[C:6]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])([OH:30])[CH2:5]1)#[N:2]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([CH2:3][CH:4]1[CH2:12][CH:11]2[CH:7]([CH2:8][N:9]([C:13](=[O:29])[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[OH:21])[CH2:10]2)[C:6]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])([OH:30])[CH2:5]1)#[N:2]
Reactant: N#CCC1CC2CN(C(=O)Cc3ccccc3OCc3ccccc3)CC2C(O)(c2ccccc2F)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N#CCC1CC2CN(C(=O)Cc3ccccc3O)CC2C(O)(c2ccccc2F)C1
Yield: 58.1 %

Procedure:
0.032 g of 10% palladium hydroxide on carbon is added to a solution of 0.168 g of (3aRS,4RS,6SR,7aSR)-6-cyanomethyl-4-(2-fluorophenyl)-2-(2-benzyloxyphenylacetyl)perhydroisoindol-4-ol in 10 cm3 of absolute ethanol, and then the reaction mixture is hydrogenated at reflux with stirring. After reaction for 4 hours, the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). Trituration in diisopropyl ether gives 0.08 g of (3aRS,4RS,6SR,7aSR)-6-cyanomethyl-4-(2-fluorophenyl)-2-(2-hydroxyphenylacetyl)perhydroisoindol-4-ol in the form of a thick white foam.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=4)=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Product: CSc1nc(-c2cccc(OC(=O)OCc3ccc([N+](=O)[O-])cc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) with p-nitrobenzyl chloroformate (554 mg) was performed according to the methods described in example 1g. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:17]3[O:16][C:15]([F:19])([F:18])[O:14][C:13]=3[C:12]([Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:24]([O:26][CH3:27])=[O:25])[C:3]=1[Cl:28].[I:29]Cl.OS([O-])=O.[Na+].C(OCC)(=O)C>ClCCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:17]3[O:16][C:15]([F:19])([F:18])[O:14][C:13]=3[C:12]([I:29])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:24]([O:26][CH3:27])=[O:25])[C:3]=1[Cl:28]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c3c2OC(F)(F)O3)c(F)c(N)c1Cl
Reactant: ClI
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(I)c3c2OC(F)(F)O3)c(F)c(N)c1Cl
Temperature: 20 °C
Reaction time: 20 h
Yield: 96.1 %

Procedure:
Methyl 4-amino-3-chloro-6-(2,2-difluoro-7-(trimethylsilyl)benzo[d][1,3]dioxol-4-yl)-5-fluoropicolinate (400 mg, 0.92 mmol) in 1,2-dichloroethane (5 mL) was treated with iodine monochloride (900 mg, 5.5 mmol) and stirred for 20 h at 20° C. The mixture was combined with 10 wt % NaHSO3 solution (30 mL) and ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (15 mL), and the combined organic phases were washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (430 mg, 96%): mp 156-159° C.; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 5.02 (s, 2H), 3.99 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −49.22, −137.49; ESIMS m/z 487 ([M+H]+), 485 ([M−H]−).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9])#[CH:2].[Li]CCCC.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C#Cc1ccccc1F
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 111.6 %

Procedure:
To a −78° C. solution of 1-ethynyl-2-fluorobenzene (0.94 g, 7.83 mmol) in anhyd. THF (25 mL) was added dropwise a solution of n-BuLi (1.6M in hexanes, 5.14 mL, 8.22 mmol). The solution was stirred for 10 min, then ethyl chloroformate (2.24 mL, 23.5 mmol) was added and the reaction mixture was allowed to warm to room temperature. The resulting mixture was poured onto ice water (200 mL) and extracted with Et2O. The organic layer was dried (MgSO4) and concentrated under reduced pressure to give ethyl 3-(2-fluorophenyl)prop-2-ynoate (1.68 g) as a yellow oil. The crude product was dissolved in MeOH (10 mL) and was added to a 5° C. mixture of a 1N NaOH solution (12.5 mL) and MeOH (30 mL). The reaction mixture was allowed to warm to room temperature, stirred for 1 h, treated with a 1N HCl solution (15 mL) and a saturated NaCl solution (20 mL). The resulting mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure to give 3-(2-fluorophenyl)prop-2-ynoic acid (1.22 g, 95% for two steps) as a tan solid: TLC (100% EtOAc) Rf 0.18; 1H NMR (acetone-d6) δ 7.30 (m, 2H), 7.60 (m, 2H), 12.0 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.N.C(O)(=[O:25])C>>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N+:10]2[O-:25]
Reactant: COc1ccc2ncccc2c1Oc1ccc(F)cc1F
Reactant: CC(=O)O
Agent: N
Product: COc1ccc2c(ccc[n+]2[O-])c1Oc1ccc(F)cc1F
Yield: 68 %

Procedure:
The solution of 5-(2,4-difluoro-phenoxy)-6-methoxy-quinoline in glacial acetic acid containing 4 ml hydrogen peroxide was stirred at 80–85° C. for 18 hours. After cooling the reaction mixture was neutralized with aqueous ammonia, and the resultant precipitate was filtered and washed with water. The aqueous layer was extracted with dichloromethane, and the organic layer was dried (MgSO4). Evaporation gave 1.3 g (68%) of 5-(2,4-difluoro-phenoxy)-6-methoxy-quinoline N-oxide as a beige crystalline material.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[O:11][CH3:12])=O.[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14].C(N)C1C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:19][O:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[O:11][CH3:12])[CH3:1]
Reactant: COc1cc(F)ccc1C(C)=O
Reactant: COC(=O)CC#N
Solvent: CC(=O)O
Solvent: NCc1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)=C(C)c1ccc(F)cc1OC
Reaction time: 18 h
Yield: 95.6 %

Procedure:
To a round bottom flask fitted with a Dean-Stark trap was added a mixture of 19.54 g (116 mmol) of 4-fluoro-2-methoxyacetophenone, 15.29 mL (174 mmol) of methyl cyanoacetate, 1.42 mL (13 mmol) of benzylamine, and 6.6 mL of acetic acid in 170 mL of toluene and the mixture was warmed to reflux. The reaction was monitored by TLC (EtOAc-hexanes, 2:8). After 18 hours, the reaction was then cooled and concentrated in vacuo to afford a dark, orange oil. The crude oil was distilled at 130° C. under vacuum (Kugelrohr) to remove unreacted 4-fluoro-2-methoxyactophenone. The crude product was then passed through a pad of silica gel using a 10% EtOAc in a 1:1 mixture of dichloromethane in hexanes to afford 27.64 g (95%) of 2-cyano-3-(4-fluoro-2-methoxyphenyl)but-2-enoic acid methyl ester as a light orange oil which was a mixture of geometric isomers.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:7]([OH:8])=[CH:6][C:5]=1[OH:14])([O-])=O.CO.CC1C2COC(=O)C=2C(O[C@@H]2O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]2O)=C(C/C=C(/CCC(O)=O)\C)C=1OC.[ClH:52]>O.[C].[Pd]>[ClH:52].[ClH:52].[NH2:1][C:4]1[CH:10]=[C:9]([NH2:11])[C:7]([OH:8])=[CH:6][C:5]=1[OH:14]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)cc1O
Agent: [Pd]
Agent: COc1c(C)c2c(c(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1cc(N)c(O)cc1O
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
30 g of crude 4,6-dinitroresorcin were recrystallized in 1,500 g of ethanol to obtain 24.1 g of purified 4,6-dinitroresorcin. Next, 4.0 g of this purified 4,6-dinitroresorcin were added to methanol, and 0.0396 g of 5% palladium carbon (a 50% wet product) was then added thereto, followed by hydrogenation at 60° C. under an average hydrogen pressure of 0.8 MPaG. The reaction mass was poured into a 5% aqueous hydrochloric acid solution containing 6,000 ppm of stannous chloride, and then filtered to remove the catalyst. Afterward, analysis was carried out by HPLC, and it was confirmed that desired 4,6-diaminoresorcin was produced in a yield of 96.2 mol %. The solvent was removed from the filtrate by an evaporator to obtain the crystals of crude 4,6-dinitroresorcin. The crystals were dissolved in 21.3 g of water containing 0.32 g of stannous chloride, and 0.2 g of activated carbon was added to the solution. Thereafter, the solution was stirred for 30 minutes and then filtered to remove the activated carbon. When 16.0 g of 36% hydrochloric acid were gradually added dropwise to the filtrate, the gradual deposition of crystals was observed. The crystals were collected by filtration and then dried at 50° C. under reduced pressure to obtain 3.03 g (yield=46.4%) of 4,6-diaminoresorcin dihydrochloride.