Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[OH-].[Na+].[CH3:9][C:10]1[CH:19]=[CH:18][C:13]([CH2:14][N:15]=[N+:16]=[N-:17])=[CH:12][C:11]=1[C:20]([Cl:24])=[C:21]([Cl:23])[Cl:22]>C(O)C>[NH2:2][C:1]1[N:15]([CH2:14][C:13]2[CH:18]=[CH:19][C:10]([CH3:9])=[C:11]([C:20]([Cl:24])=[C:21]([Cl:23])[Cl:22])[CH:12]=2)[N:16]=[N:17][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: Cc1ccc(CN=[N+]=[N-])cc1C(Cl)=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(Cn2nnc(C(N)=O)c2N)cc1C(Cl)=C(Cl)Cl
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
To a hot (60° C.) solution of cyanoacetamide (1.09 g) in 30 ml of ethanol, 13 ml of a methanolic solution of NaOH (1N) was added and the resulting mixture was stirred at 60° C. for 20 minutes. At this point a solution of 4-methyl-3-(trichlorovinyl)benzyl azide (1.65 g) in 10 ml of ethanol was added and the reaction mixture stirred at 60° C. for an additional two hours. The precipitate was removed by filtration and rinsed with ethanol and ether. The filtrate was diluted with water (200 ml) and the resulting precipitate collected (1.56 g). The crude product was chromatographed on silica with 95:5 methylene chloride:methanol to give 889 mg of 5-amino-1-[4-methyl-3-(trichlorovinyl)benzyl]-1,2,3- triazole-4-carboxamide, m.p. 196°-197° C.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([CH3:7])[O:5][C:4](=[O:8])[C@@H:3]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:7][C@@H:6]1[O:5][C:4](=[O:8])[C@H:3]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:2]1[O:1][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: C[C@@H]1OC(=O)[C@H](CCc2ccccc2)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](O[C@H]1[C@H](C)OC(=O)[C@@H]1CCc1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of (3R,4R,5S)-4-hydroxy-5-methyl-3-phenethyldihydrofuran-2(3H)-one (800 mg, 3.63 mmol) in CH2Cl2 (20 mL) were added 2,6-dimethylpyridine (592 μl, 5.08 mmol) and triisopropylsilyl trifluoromethanesulfonate (1171 μl, 4.36 mmol) at 0° C., and the mixture was warmed to room temperature while stirring overnight. The reaction mixture was poured onto 50 mL saturated sodium bicarbonate solution and mixed thoroughly. The phases were separated, and the aqueous extracted with CH2Cl2 (2×25 mL). The combined CH2Cl2 extracts were dried and concentrated to a colorless oil which was purified by flash chromatography (SiO2, 0→50% EtOAc/hexanes) to give (3R,4R,5S)-5-methyl-3-phenethyl-4-((triisopropylsilyl)oxy)dihydro-furan-2(3H)-one (809 mg, 53%): 1H NMR (400 MHz, CDCl3) δ 7.33-7.25 (m, 2H), 7.25-7.17 (m, 3H), 3.98 (dd, J=5.9, 4.8 Hz, 1H), 4.34-4.24 (m, 1H), 2.99-2.88 (m, 1H), 2.88-2.76 (m, 1H), 2.61-2.51 (m, 1H), 2.04-1.94 (m, 2H), 1.43 (d, J=6.5 Hz, 3H), 1.09-0.99 (m, 21H); 13C NMR (101 MHz, CDCl3) δ 176.64, 140.98, 128.57, 128.51, 126.16, 82.10, 79.45, 49.17, 32.96, 31.14, 19.10, 18.00, 17.71; ESIMS m/z 378 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=[O:8])=O.N1C=CC=CC=1.[NH2:16][CH2:17][CH2:18][CH2:19][Si:20]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>C1CCCCC1>[CH3:9][C:3]1[C:4](=[O:6])[N:16]([CH2:17][CH2:18][CH2:19][Si:20]([O:27][CH2:28][CH3:29])([O:21][CH2:22][CH3:23])[O:24][CH2:25][CH3:26])[C:7](=[O:8])[C:2]=1[CH3:1]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: c1ccncc1
Solvent: C1CCCCC1
Product: CCO[Si](CCCN1C(=O)C(C)=C(C)C1=O)(OCC)OCC
Temperature: 25 °C
Yield: 42.9 %

Procedure:
To an appropriately sized reaction vessel equipped with a thermowell, Dean Stark trap connected to condenser with a nitrogen inlet, addition funnel, and mechanical stirrer. was charged 2.2 L of cyclohexane followed by dimethylmaleic anhydride (DMMA, 107.8 g, 0.85 mol) and pyridine (3.5 mL, 0.042 mol) with stirring. A slight endotherm was observed (20 to 14° C.) as the dimethylmaleic anhydride dissolved in the cyclohexane. The mixture was warmed to 25° C. and a turbid solution was observed. The addition funnel was charged with 3-aminopropyltriethoxysilane (189.2 g, 200 mL, 0.85 mol) which was added slowly over 15 minutes. An additional 300 mL cyclohexane was added to rinse in the 3-aminopropyltriethoxysilane and the addition funnel was replaced by a stopper. The mixture immediately exothermed to 24° C. and a white turbid solution was observed. The mixture was heated carefully (to avoid excessive foaming) over 30 minutes to reflux. A clear solution was observed at 40° C. and again turned to a white turbid solution at 70° C. The reaction mixture was refluxed for 1 h at 70° C. and aliquot was analyzed and indicated that the reaction was completed (88% product with 11% DMMA and no 3-aminopropyltriethoxysilane). The reaction mixture was cooled to room temperature and the cyclohexane layer decanted to a 5 L flask leaving the white polymeric residue (120 g). The cyclohexane layer was concentrated on the rotary evaporator at 60° C. bath temperature. The residue was transferred to a 500 mL RBF and dried under high vacuum for 2 h at 7° C. bath temperature to give 132 g of crude product as a viscous oil (crude purity 96.5% with 3.2% DMMA). The crude product was further purified via Kugelrohr distillation at 150-170° C. oven temperature under vacuum 0.15-0.2 torr to give 64.4 g (23% yield) of product with 99.7% purity by gas chromatography (GC) as a clear liquid. 1H NMR and mass were consistent with the desired structure. Pot residue was 60.6 g and total polymeric residue was 180.1 g (64%). Data: GC analysis performed on a DB-5MS Column, 25 meters, 0.32 mm ID, 0.52 μm film, heat from 75° C. to 200° C. @15° C./min, then 200° C. to 300° C. hold for 2 min @300° C., Injector temperature: 200° C., Detector temperature: 350° C., Retention time: 9.250 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([NH2:24])=[N:21]3)=[N:16][CH:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:25]([N:27]=[C:28]=[S:29])[CH3:26]>N1C=CC=CC=1>[CH2:25]([NH:27][C:28]([NH:24][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][C:14]([NH:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:15][N:16]=2)[N:21]=1)=[S:29])[CH3:26]
Reactant: COc1cc(Nc2cnc3ccc(N)nc3c2)cc(OC)c1OC
Reactant: CCN=C=S
Solvent: c1ccncc1
Product: CCNC(=S)Nc1ccc2ncc(Nc3cc(OC)c(OC)c(OC)c3)cc2n1
Temperature: 140 °C
Reaction time: 24 h
Yield: 50.3 %

Procedure:
In a sealed reactor, 88 mg (269 μmol, 1 eq) of N*7*-(3,4,5-trimethoxy-phenyl)-[1,5]naphthyridine-2,7-diamine and 48 μL (538 μmol, 2 eq) of ethyl isothiocyanate were introduced in 3 mL of pyridine. The mixture was stirred at 140° C. for 24 h. The mixture was allowed to reach rt and the solvent was removed under reduced pressure. The residue was purified by column chromatography using methylene chloride/ethanol: 96/4 as eluent. The solvent was evaporated to dryness to afford 56 mg of yellow powder with 51% yield.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[Cl:9][C:10]1[CH:15]=[C:14]([CH2:16]Cl)[CH:13]=[C:12]([F:18])[CH:11]=1.O>CN(C)C=O>[Cl:9][C:10]1[CH:15]=[C:14]([CH2:16][O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[CH:13]=[C:12]([F:18])[CH:11]=1
Reactant: Fc1cc(Cl)cc(CCl)c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(Cl)cc(COCC(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
Under argon stream, to a suspension of sodium hydride (601 mg, 60 wt. % oil dispersion) in dimethylformamide (13 ml) was added dropwise trifluoroethanol (1.08 ml) at 0° C., and the mixture was stirred for 15 minutes. To this reaction solution was added dropwise a solution of 1-chloro-3-fluoro-5-chloromethylbenzene (2.23 g) in dimethylformamide (9 ml), and then the mixture was stirred at room temperature for 1 hour. To this reaction mixture was added water, and the mixture was extracted with a mixed solvent of n-hexane/ethyl acetate=1/1. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 9/1) to give the titled compound (2.85 g).
Reaction SMILES: [C:1]12([CH2:15][CH:14]([NH:16][C:17](=[O:32])[NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][N:23]4C(OC)=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[OH-].[Na+].O>CO>[NH:23]1[C:24]2[C:20](=[C:19]([NH:18][C:17]([NH:16][CH:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:7][C:1]4([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:15]3)=[O:32])[CH:27]=[CH:26][CH:25]=2)[CH:21]=[N:22]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CC4(CCCCC4)Oc4ccccc43)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1cccc2[nH]ncc12)NC1CC2(CCCCC2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The product from Example 1C (4.06 mmol) was suspended in methanol (20 mL) and was treated with 5N methanolic NaOH (3.3 mL, 16.5 mmol). The mixture was stirred at room temperature for 45 min, then it was poured into H2O (100 mL). The precipitate that formed was collected by filtration and was air-dried to afford the title compound as an off-white solid, 794 mg (43%). 1H NMR (300 MHz, DMSO-d6) δ ppm 13.01 (br, 1H), 8.67 (s, 1H), 8.06 (s, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.23 (J=7.8 Hz, 1H), 7.16 (m, 1H), 7.08 (d, J=8.5 Hz, 1H), 6.90 (td; J=7.5, 1.0 Hz; 1H), 6.80 (dd; J=7.9, 1.0 Hz; 1H), 6.72 (d, J=8.1 Hz, 1H), 4.98 (m, 1H), 2.24 (m, 1H), 1.33-1.82 (m, 11H). MS (ESI+) m/z 377 (M+H).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[C:7]([C:11]([O:13]C)=O)[N:6]=1)=[O:4].[NH2:15][C:16]([CH3:21])([CH2:19][OH:20])[CH2:17][OH:18]>C(O)C>[OH:18][CH2:17][C:16]([NH:15][C:11]([C:7]1[CH:8]=[N:9][CH:10]=[C:5]([C:3]([NH:15][C:16]([CH3:21])([CH2:19][OH:20])[CH2:17][OH:18])=[O:4])[N:6]=1)=[O:13])([CH3:21])[CH2:19][OH:20]
Reactant: COC(=O)c1cncc(C(=O)OC)n1
Reactant: CC(N)(CO)CO
Solvent: CCO
Product: CC(CO)(CO)NC(=O)c1cncc(C(=O)NC(C)(CO)CO)n1
Temperature: 20 °C
Yield: 30.4 %

Procedure:
A solution of 500 mg of 2,6-dimethoxycarbonylpyrazine and 525 mg of 2-amino-2-methyl-1,3-propanediol in 5 cm3 of ethanol is heated at a temperature in the region of the reflux temperature for 3 hours. The reaction mixture is cooled to a temperature of 20° C. and the white solid formed is then filtered off and washed with twice 5 cm3 of ethanol. 260 mg of N,N′-bis(1,3-dihydroxy-2-methyl-2-propyl)pyrazine-2,6-dicarboxamide are thus obtained in the form of a white solid melting at 169° C. [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.34 (s, 6H: 2×CH3); 3.61 and 3.69 (2 dd, J=11 and 5.5 Hz, 8H: 4×CH2O); 4.88 (t, J=5.5 Hz, 4H: 4×OH); 8.16 (s, 2H: 2×CONH); 9.35 (s, 2H: ═CH at 3 and ═CH at 5)].
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[C:22](N1C=CN=C1)([N:24]1C=CN=[CH:25]1)=O.CNC>CN(C)C=O>[CH3:22][N:24]([CH3:25])[C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)[CH3:5])=[O:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Oc1ncn(-c2cccc(C(F)(F)F)c2)n1)C(=O)O
Agent: CNC
Solvent: CN(C)C=O
Product: CC(Oc1ncn(-c2cccc(C(F)(F)F)c2)n1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Three g of the compound of Example 24 was dissolved in 20 ml of dimethylformamide, and 3.4 g of carbonyldiimidazole was added to it. The mixture was stirred at ambient temperature for 20 minutes, and then 4 ml of 40% aqueous dimethylamine was added and the mixture was stirred at ambient temperature for 1 day. It was then poured into ice-water, and the solid was collected, dried and recrystallized from ethanol to obtain 1.5 g of the desired product, m.p. 126°-127°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[NH2:17]>>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([NH:17][C:16]1[CH:15]=[C:14]([Cl:13])[CH:20]=[C:19]([Cl:21])[CH:18]=1)=[O:7]
Reactant: O=C(O)c1cc(Br)cc(Br)c1O
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(Br)cc(Br)c1O
Yield: 44.2 %

Procedure:
Using 3,5-dibromosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([O:33][CH2:34][N:35]1[C:39](=[O:40])[CH:38]([CH3:41])[NH:37][C:36]1=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][CH2:34][N:35]1[C:39](=[O:40])[CH:38]([CH3:41])[N:37]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH:23]5[CH2:25][CH2:24]5)=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:36]1=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: CC1NC(=O)N(COCc2ccccc2)C1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(COCc4ccccc4)C(=O)C3C)nc2)CC1
Yield: 88.1 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (321 mg) described in Preparation Example 144 and 3-benzyloxymethyl-5-methylimidazolidine-2,4-dione (225 mg) described in Preparation Example 206 and by the reaction and treatment in the same manner as in Example 536, the title compound (391 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.N[C:21]1N=C(C2C=C(Br)C=CC=2O)C=[C:23](Cl)[N:22]=1.CN(C)CCCO>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH2:19][N:22]([CH3:23])[CH3:21])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Reactant: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Agent: CN(C)CCCO
Product: CN(C)CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Yield: 43 %

Procedure:
Following the method described in Example 135 for the synthesis of 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol and 3-dimethylamino-propan-1-ol provided 4-[5-bromo-2-(3-dimethylamino-propoxy)-phenyl]-6-chloro-pyrimidin-2-ylamine (43% yield).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[CH:12][N:11]=1.[CH:17]1([CH:20]=[O:21])[CH2:19][CH2:18]1>C1COCC1>[CH:17]1([CH:20]([C:15]2[C:10]([Cl:9])=[N:11][CH:12]=[N:13][C:14]=2[Cl:16])[OH:21])[CH2:19][CH2:18]1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=CC1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC(c1c(Cl)ncnc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
To a stirred solution of LDA (9.85 mL, 1.5 M, 15.8 mmol) in THF (20 mL) was added dropwise a solution of 4,6-dichloropyrimidine (2.00 g, 13.4 mmol) in THF (12 mL) at −78° C. After stirring for 1.5 hours, a solution of cyclopropanecarbaldehyde (1.05 g, 15.0 mmol) in THF (10 mL) was added dropwise. The solution was stirred at −78° C. for 1 hour and then quenched by addition of water (10 mL). The reaction mixture was allowed to warm to room temperature and partitioned between EtOAc and water. The organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes/EtOAc, 3:1) to give Cyclopropyl-(4,6-dichloro-pyrimidin-5-yl)-methanol (2.36 g, 80%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.70 (s, 1H), 4.56 (m, 1H), 2.63 (d, J=8.0 Hz, 1H), 1.70 (m, 1H), 0.76 (m, 1H), 0.55 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][CH2:34][CH2:35]Br>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:35][CH2:34][O:33][CH3:32])[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Reactant: COCCBr
Solvent: O
Solvent: CC#N
Product: COCCn1ccc2c(-c3ccc4c(c3C)CCCO4)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c21

Procedure:
The title compound was prepared in a manner similar to that described in example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 2-bromoethyl methyl ether and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29-7.36 (m, 1H) 6.97-7.12 (m, 1H) 6.69-6.82 (m, 1H) 5.71-5.81 (m, 1H) 5.18-5.49 (m, 1H) 4.82-4.90 (m, 1H) 4.72-4.79 (m, 1H) 4.57-4.67 (m, 1H) 4.16-4.28 (m, 2H) 3.75-3.85 (m, 2H) 3.69-3.72 (m, 3H) 3.51 (s, 2H) 3.34 (s, 3H) 2.63-2.76 (m, 2H) 2.06-2.16 (m, 2H) 1.93-2.06 (m, 3H) 1.01-1.21 (m, 9H); LCMS (m/z) ES+=483 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:12](=[O:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([O:9]CC)=O.[H-].[Na+].[C:24]([O:33][CH2:34][CH3:35])(=[O:32])/[CH:25]=[CH:26]\[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C=O>[CH2:34]([O:33][C:24]([CH:25]1[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:7](=[O:9])[C:6](=[C:2]2[S:1][CH:5]=[CH:4][S:3]2)[C:12](=[O:21])[N:13]1[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)C(C(=O)NCc1ccccc1)=C1SC=CS1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1C(=O)C(=C2SC=CS2)C(=O)N(Cc2ccccc2)C1C(=O)OCC
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-(1,3-dithiol-2-ylidene)-2-(N-benzylcarbamoyl)acetate (1.0 g) and dimethylformamide (25 ml) is added dropwise to a suspension of sodium hydride (63% dispersion in oil, 144 mg) in dimethylformamide (10 ml). Said addition is carried out under ice-cooling. The mixture is stirred at the same temperature for 30 minutes. A solution of diethyl maleate (0.6 ml) in dimethylformamide (10 ml) is added dropwise thereto. The mixture is stirred at room temperature overnight. The mixture is poured into water, and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The mixture is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=1:2) to give 1-benzyl-5-(1,3-dithiol-2-ylidene)-4,6-dioxopiperidine-2,3-dicarboxylic acid diethyl ester (196 mg) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.Cl.[CH3:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH3:43])[N:4]=1
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Reactant: CC(C)(C)CN
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(NCC(C)(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A solution of Example C2 (0.100 g, 0.238 mmol) in DCM (5 mL) was treated with mCPBA (0.059 g, 0.238 mmol), stirred at RT for 2 h, treated with 2,2-dimethylpropan-1-amine hydrochloride (0.410 g, 3.32 mmol) and TEA (0.464 mL, 3.33 mmol) and stirred at RT for 5 days. The mixture was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-N-neopentylpyrimidin-2-amine (81 mg, 74%). MS (ESI) m/z: 460.3 (M+H+).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([S:18](Cl)(=[O:20])=[O:19])[C:11]2[N:12]=[CH:13][CH:14]=[N:15][C:16]=2[CH:17]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([S:18]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:19])=[O:20])[C:11]2[N:12]=[CH:13][CH:14]=[N:15][C:16]=2[CH:17]=1
Reactant: NC1CCCC1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc2nccnc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(NC1CCCC1)c1cc(Cl)cc2nccnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of cyclopentyl amine (0.134 mg, 1.6 mmol) in pyridine (5 ml) was added a solution of 7-chloroquinoxaline-5-sulfonyl chloride (0.26 g, 0.748 mmol, crude) in DCM (5 mL) at 0° C. The reaction was stirred at room temperature for 15 minutes before being partitioned between brine and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification on silica gel (rf=0.38 in 1:1 hexanes/ethyl acetate) afforded 7-chloro-N-cyclopentylquinoxaline-5-sulfonamide as an off-white powder.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[C:7](=[S:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1.[OH-].[Na+]>>[CH2:1]([S:13][C:7]1[C:6]([F:5])=[CH:11][NH:10][C:9](=[O:12])[N:8]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: O=c1[nH]cc(F)c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: C=CCSc1nc(=O)[nH]cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
Allyl bromide (0.013 mol) was added to a solution of 5-fluoro-4-thiouracil (0.01 mols), 8.73 mols NaOH (25 mls) and the reaction mixture stirred at room temperature for 5 hrs. The reaction mixture was then extracted with chloroform (2×5 ml), before the aqueous solution was acidified with HCl when the titled compound was precipitated; yield 40%, m.p. 150°-152° C. (water). (Found: C, 44.87; H, 3.84. Calc. for C7H7SFN2O; C, 45.15; H, 3.80).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:17]#[N:18].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:21]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=4[F:13])[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: N#Cc1ccc(N2CCNCC2)c(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(F)c1
Temperature: 77.5 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, step 1, 0.857 g), 3-fluoro-4-(piperazin-1-yl)benzonitrile (1.039 g), triethylamine (0.75 mL), and THF (6 mL) is stirred for 3 h at 75-80° C. The mixture is then concentrated under reduced pressure and the residue is partitioned between dichloromethane and saturated sodium bicarbonate. The combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96). The appropriate fractions are combined and concentrated. Ethyl ether is added to the residue and the resulting solid is collected, washed with additional ethyl ether, and dried under reduced pressure to give 1.25 g of the title compound. A portion of this material is recrystallized from ethyl acetate; mp 132-133° C. ; IR (mineral oil) 1255, 1513, 1246, 801, 1504 cm-1 ; 1H NMR (CDCl3) δ2.74, 3.26, 3.77, 6.90, 7.13, 7.25, 7.34, 7.53, 8.13.