Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:6]=O)(=[O:3])[CH3:2].[OH-].[K+]>O1CCCC1.CO>[C:8]1([C:5]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:4][C:1](=[O:3])[CH:2]=[CH:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)CC(C=O)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C=CC(c2ccccc2)(c2ccccc2)C1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 3-acetyl-2,2-diphenylpropionaldehyde (48.9 g) in a mixture of tetrahydrofuran (55 ml) and methanol (30 ml) was added 10% aqueous solution of potassium hydroxide (15 ml) at room temperature. The solution was stirred for 2 hours and evaporated in vacuo. To the residue was added brine and extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (5:1) as an eluent to give 4,4-diphenyl-2-cyclopenten-1-one (39.76 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.C1COCC1>[F:21][C:22]([F:24])([F:23])[C:10]([CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:20])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C(COCc1ccccc1)COCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OC(COCc1ccccc1)(COCc1ccccc1)C(F)(F)F
Temperature: 0 °C
Yield: 99.3 %

Procedure:
A mixture of 1,3-dibenzyloxy-2-propanone (2 g) and (trifluoromethyl)trimethylsilane (2.56 ml, 2.3 equivalents) in dichloromethane (20 ml) was stirred and cooled to 0° C. A solution of 1M tetrabutylammonium fluoride in THF (4 ml) was added dropwise over 3 minutes. Initial addition of a few drops gave an exotherm of 10° C. Throughout the addition the batch temperature was maintained below 10° C. After completing the addition the dark brown mixture was stirred at +5° C. for 5 minutes when HPLC analysis indicated the reaction to be complete. The reaction mixture was stirred for an additional 5 minutes and then washed with 1M aqueous hydrochloric acid (15 ml), saturated sodium bicarbonate (15 ml) and 1% w/v aqueous sodium chloride solution (2×15 ml). The organic extract was concentrated in vacuo to give 2.5 g of the desired product as dark oil in 99.3% yield. The NMR spectrum of the product was concordant with a reference sample.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:14](=O)[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][S:11](=[O:25])(=[O:24])[CH2:10]2)=[CH:4][CH:3]=1.[C:26]1([NH:32][NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:33]=[C:14]3[C:13](=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[CH2:12][S:11](=[O:25])(=[O:24])[CH2:10][CH:9]23)=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: O=C1C(=Cc2ccc(Cl)cc2)CS(=O)(=O)CC1=Cc1ccc(Cl)cc1
Solvent: CO
Product: O=S1(=O)CC(=Cc2ccc(Cl)cc2)C2=NN(c3ccccc3)C(c3ccc(Cl)cc3)C2C1
Yield: 65.1 %

Procedure:
A mixture of 2.0g of tetrahydro-3,5-bis-[(4-chlorophenyl)methylene]-4H-thiopyran-4-one-1,1-dioxide and 0.6g of phenyl hydrazine in 100ml of methanol is heated at reflux temperature for 2 hours and then cooled. The precipitate is collected by filtration and recrystallized from acetone/hexane to give 1.6g of the title compound, melting point 246.5°-249°C.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[CH:29][C:30]([F:39])=[C:31]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[CH:28]=[CH:29][C:30]([F:39])=[C:31]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:32]=3)[CH2:25][CH2:26]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)ccc1F

Procedure:
Example 65 was prepared from diphenylacetyl chloride and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 8.33–8.18 (m, 1H), 7.49–7.10 (m, 12H), 7.10–6.93 (m, 1H), 6.90–6.76 (br, 1H), 4.87 (s, 1H), 3.44–3.28 (m, 2H), 3.06–2.89 (m, 2H), 2.56–2.40 (m, 3H), 2.40–2.31 (m, 2H), 2.13–1.93 m, 2H), 1.86–1.52 (m, 8H), 1.01 (t, 3H, J=7.6 Hz) ESMS m/e: 516.6 (M+H)+; Anal. Calc. For (HCl salt) C32H39ClFN3O2.0.25CHCl3.1.00H2O: C, 64.49; H, 6.93; N, 6.99. Found: C, 64.23; H, 7.21; N, 6.99.
Reaction SMILES: O[CH2:2][C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([CH2:12][CH2:13][CH3:14])[S:9]2)[C@@H:5]([OH:15])[C@@H:4]1[OH:16].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>N1C=CC=CC=1.C(Cl)Cl>[N:28]([CH2:2][C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([CH2:12][CH2:13][CH3:14])[S:9]2)[C@@H:5]([OH:15])[C@@H:4]1[OH:16])=[N+:29]=[N-:30]
Reactant: CCCC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CN=[N+]=[N-])O[C@@H]2S1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
(3aR,5R,6S,7R,7aR)-5-(hydroxymethyl)-2-propyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (200 mg, 0.81 mmol) was dissolved in pyridine (2 mL) and CH2Cl2 (2 mL) and cooled to 0° C. Tosyl chloride (230 mg, 1.2 mmol) was then added and the solution allowed to warm to room temperature over 1 h. The mixture was diluted with CH2Cl2 (10 mL) and washed with water (2×5 mL), dried (MgSO4), filtered and concentrated. The resultant colourless residue (280 mg) was taken up in DMF (3 mL) and NaN3 (158 mg, 2.4 mmol) was added. The resultant mixture was stirred at 55° C. for 2 days. Concentration of the mixture gave a residue which was taken up in CH2Cl2 (20 mL) and washed with water (2×5 mL), dried (MgSO4), filtered and concentrated. Flash chromatography of the residue on silica gel (MeOH:EtOAc, 1:9) gave 180 mg (82% yield) of (3aR,5R,6S,7R,7aR)-5-(azidomethyl)-2-propyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (50) as a colourless oil. 1H NMR (500 MHz, methanol-d4): δ 0.98 (t, 3H, J=7.3 Hz), 1.63-1.67 (m, 2H), 2.46-2.50 (m, 2H), 3.33 (m, 1H), 3.54 (dd, 1H, J=4.3, 9.5 Hz), 3.44 (dd, 1H, 2.3, 12.0 Hz), 3.55 (dd, 1H, J=6.2, 12.0 Hz), 4.06 (dd, 1H, J=4.4, 4.6 Hz), 4.29 (m, 1H, J=4.3 Hz), 6.31 (d, 1H, J=6.9 Hz).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[C:12]1([C:18]2[CH2:23][C:22](=[C:24]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[CH:21]=[CH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccnc(-c2ccccc2)c1
Solvent: CCO
Product: O=C1C(=C2C=CN=C(c3ccccc3)C2)C(=O)c2ccccc21
Temperature: 200 °C
Reaction time: 14 h
Yield: 36.3 %

Procedure:
Under exclusion of air, a mixture of phthalic anhydride (4.38 g, 29.5 mmol) and 2-phenyl-4-picoline (5.0 g, 29.5 mmol) was heated to 200° C. The reaction melt was stirred at 200° C. for 14 h until a yellow precipitate was formed. The reaction was cooled to 100° C. and ethanol (300 mL) was added. The resultant brown mass was refluxed in ethanol for 1 h and sonicated in a water bath to break up the compound. The precipitate was filtered and triturated in ethanol (100 mL) to give the title compound as a yellow solid (3.2 g, 10.7 mmol, 36% yield). 1H-NMR (DMSO-d6) 12.06 (broad s, 1H), 9.04 (d, J=1.3, 1H), 8.68 (dd, J=6.7, 1.3, 1H), 8.17 (d, J=6.7, 1H), 7.79 (dd, J=8.0, 5.2, 2H), 7.61 to 7.64 (m, 3H), 7.45 to 7.53 (m, 4H); MS ES 300 (M+H)+, calc. 299; TLC (1:2:8 v/v methanol-acetone-dichloromethane) Rf=0.32.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:24]O.[OH-].[Na+].Cl>C(O)C>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]([NH2:17])=[O:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1cccc(OCc2cccc(C#N)c2)c1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(O)c1cccc(OCc2cccc(C(N)=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3[[3-(1-hydroxyhexyl)phenoxy]methyl]benzonitrile (5.0 g.), 30% hydrogen peroxide (6.6 ml), ethanol (9 ml) and 6N sodium hydroxide (0.7 ml) was stirred at room temperature for one hour. The reaction was then heated to 50° C. for three hours. The solution was neutralized with 5% aqueous hydrochloric acid and extracted with chloroform. The organic extract was dried (MgSO4) and concentrated to a solid. The solid was recrystallized from ethyl acetate giving 3.4 g (63%) yield) of solid, m.p. 97°-98° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:32])[N:5]([C:9]([NH:11][CH:12]2[CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:30][CH3:31])=[C:18]([S:22]([NH:25][C:26]([NH:28][CH3:29])=S)(=[O:24])=[O:23])[CH:19]=3)[O:14][CH2:13]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].[OH:33]O>[OH-].[Na+]>[CH2:1]([C:3]1[C:4](=[O:32])[N:5]([C:9]([NH:11][CH:12]2[CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:30][CH3:31])=[C:18]([S:22]([NH:25][C:26]([NH:28][CH3:29])=[O:33])(=[O:23])=[O:24])[CH:19]=3)[O:14][CH2:13]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCC1=C(C)CN(C(=O)NC2COc3cc(OC)c(S(=O)(=O)NC(=S)NC)cc3C2)C1=O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Product: CCC1=C(C)CN(C(=O)NC2COc3cc(OC)c(S(=O)(=O)NC(=O)NC)cc3C2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1 g of 3-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-6-(methylaminothiocarbonylaminosulfonyl)-7-methoxychroman (Example 22) was suspended or dissolved in 20 ml of cold 0.5N sodium hydroxide solution. 1 ml of 37% strength hydrogen peroxide solution was added in the cold (-4° to 0° C.). The mixture was stirred at 0° C. for 1.5 hours. The crude product was precipitated by addition of 2N HCl and then purified over silica gel (eluting agent methylene chloride/glacial acetic acid 9:1). The product had a melting point of 245°-246° C.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]([CH3:24])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+:13]=[N-:14]>>[ClH:1].[CH3:24][C:16](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][N:12]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:14]=[N:13]1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCc2c[nH]c(N)n2)nn1
Yield: 43.3 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.062 g, 0.362) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.075 g, 0.434 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine hydrochloride (0.054 g, 43%) of a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 8.39 (s, 1H), δ 7.12-7.07 (m, 5H), δ 6.54 (s, 1H), δ 6.36 (s, 1H), δ 5.09 (s, 2H), δ 3.01 (t, 2H), δ 2.76 (t, 2H), δ 1.60 (s, 3H) ppm; 13C; 147.7, 143.1, 136.3, 132.7, 129.9, 128.9, 128.6, 128.5, 128.2, 127.4, 127.1, 124.9, 109.9, 61.2, 23.0, 22.3, 14.7 ppm; HRMS (ESI) calcd for C16H20N6(M+) 308.1749. found 308.1742.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:34]1[N:38]([CH3:39])[N:37]=[CH:36][C:35]=1[CH3:40].NN.Cl>CO.C1COCC1.CO>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][C:35]=2[CH3:40])[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a solution of 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (196 mg, 0.34 mmol) in MeOH/THF (2 mL/0.5 mL) was added hydrazine (0.5 mL, 15.9 mmol). After stirring overnight at RT, the reaction mixture was concentrated, and purified on silica (50% MeOH in CHCl3 (0.5% NH4OH) to give a free base of the tile compound, which was dissolved in MeOH (2 mL), and treated with HCl (aq, 37%). After stirring overnight, the reaction solution was concentrated to give the title compound (107 mg, 51%) as a di-HCl salt: LC-MS (ES) m/z=457 (M+H)+. 1H NMR (d4-MeOD, 400 MHz) δ ppm 7.96 (s, 1H), 7.90 (m, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.53 (t, J=7.3 Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 4.66 (m, 1H), 3.91 (s, 3H), 3.33-3.14 (m, 4H), and 2.10 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:57]([C:59]1[CH:60]=[C:61]([N:65]2[CH2:69][CH2:68][CH:67]([C:70](O)=[O:71])[C:66]2=[O:73])[CH:62]=[CH:63][CH:64]=1)[CH3:58]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:70]([CH:67]1[CH2:68][CH2:69][N:65]([C:61]2[CH:62]=[CH:63][CH:64]=[C:59]([CH2:57][CH3:58])[CH:60]=2)[C:66]1=[O:73])=[O:71]
Reactant: CCc1cccc(N2CCC(C(=O)O)C2=O)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)c1
Yield: 33.6 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.099 g; 0.428 mmol), PyBOP (0.335 g; 0.643 mmol), N,N-diisopropylethylamine (0.222 mL; 1.29 mmol) and 1-(3-ethylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.428 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.059 g (33%) of the title compound as a white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][CH:17]=2.I[CH3:32]>C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([CH:23]([CH3:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][CH:17]=2
Reactant: CI
Reactant: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cnc2ccc(C(C)C(=O)OC(C)(C)C)cc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a flame-dry 100 ml 3-neck round-bottomed flask was added lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (5 ml, 5 mmol) and THF (20 mL). The mixture was cooled to −78° C. followed by adding tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (0.88 g, 3 mmol) in THF (10 mL) dropwise via addition funnel. After stirring at −78° C. for 30 min, iodomethane (0.4 ml, 6 mmol) was added. The reaction mixture was stirred for 30 min at −78° C. then allowed to warm to rt and stir for 1 h. The mixture was then quenched with sat. NH4Cl (3 mL). Solvent was removed. The residue was partitioned between EtOAc/water. The organic layer was washed with brine, dried over MgSO4 and removed solvent. The crude material was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2, solvent system: hexane:acetone-90%:10%, Flow=30 mL/min) to afford a final product as yellowish liquid. MS m/z: 288.4 (M+H). Calc'd. for C17H21NO3—287.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12]/[CH:13]=[CH:14]/[B:15]([OH:17])[OH:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:19]([C:22](O)([CH3:24])[CH3:23])([CH3:21])[CH3:20].S([O-])([O-])(=O)=O.[Mg+2]>CCOCC>[CH3:20][C:19]1([CH3:21])[C:22]([CH3:24])([CH3:23])[O:16][B:15](/[CH:14]=[CH:13]/[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:17]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=C(NC/C=C/B(O)O)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC1(C)OB(/C=C/CNC(=O)OCc2ccccc2)OC1(C)C
Reaction time: 48 h
Yield: 49.7 %

Procedure:
A mixture of (E)-(3-(((benzyloxy)carbonyl)amino)prop-1-en-1-yl)boronic acid (2.38 g, 10.14 mmol), pinacol (1.418 g, 12 mmol), and magnesium sulfate (2 g, 16.62 mmol) in ether (25 mL) was stirred for 2 days. The mixture was filtered and concentrated. The crude material was purified by silica gel chromatography using 0-30% EtOAc/hexane as the eluent to give (E)-benzyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)carbamate as a clear oil (1.6 g, 50%). LCMS: Rt=3.66 min, 77%, (M+H)+=318, (M−H)−=316.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([NH2:20])[C:3]=1[N+:21]([O-])=O>O1CCCC1.C(O)(=O)C.[Zn]>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:15]=2)[N:5]=[C:4]([NH2:20])[C:3]=1[NH2:21]
Reactant: Cc1nc(NCc2ccc(C(F)(F)F)cc2)nc(N)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)nc(N)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.1 %

Procedure:
To a vigorously stirred solution of 6-methyl-5-nitro-N*2*-(4-trifluoromethylbenzyl)-pyrimidine-2,4-diamine (450 mg, 1.376 mmol) in tetrahydrofuran (20 ml) and acetic acid (5 ml) on cold water bath, zinc powder (particle size<10 micron, 5 g) was added by portions in 2 min. Water bath was removed and more zinc powder (2 g) were added. The suspension was stirred at ambient temperature for 60 min and quenched with 10% aqueous sodium carbonate to pH>8. The obtained suspension was extracted with ethyl acetate (10 times). The combined organic solution was filtered via plug of silica gel (10 g) and eluted with 20% in ethyl acetate to give 430 mg of pale yellow oil after evaporation. The product solidified after drying in vacuo. Yield 100%. It was used in the next step without further purification. LC-MS (m/z) 298.1 (MH+); tR=1.68. 1H NMR (500 MHz, DMSO-d6): 2.02 (s, 3H), 3.1-3.8 (br, NH2+H2O), 4.43 (d, 2H), 5.88 (br, 2H), 6.26 (t, 1H, NH), 7.48 (d, 2H), 7.62 (d, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:14]1[N:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C>CS(C)=O>[NH2:20][C:18]1[N:19]=[C:14]([N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([N:3]([CH2:1][CH3:2])[CH3:12])=[O:5])[CH2:7]2)[CH:15]=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22]
Reactant: CCN(C)C(=O)[C@@H]1CCCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 80 °C
Yield: 49.3 %

Procedure:
To a solution of (R)—N-ethyl-N-methylpiperidine-3-carboxamide (600 mg, 4.1 mmol) in dimethylsulfoxide (6 mL) were added 6-chloro-3-nitropyridin-2-amine (0.58 g, 3.3 mmol) and triethylamine (1.2 mL, 8.3 mmol) at room temperature. The reaction mixture was heated to 80° C. for 18 h. The reaction mixture was poured into ice water, extracted with ethyl acetate and concentrated under reduced pressure. The crude material was purified via column chromatography (10% ethyl acetate in petroleum ether) to afford (R)-1-(6-amino-5-nitropyridin-2-yl)-N-ethyl-N-methylpiperidine-3-carboxamide (500 mg, 28.4%). MS (ES+) (M+H) 308.31.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)C.[OH-].[Na+].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:2]([O:9][NH:10][C:25]([NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C=Nc1ccccc1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(NOCc1ccccc1)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Under a nitrogen atmosphere, a flask was charged sequentially with O-benzylhydroxylamine hydrochloride (37.5 g, 0.23 mole), water (40 mL) and diethyl ether (400 mL). The resulting mixture was cooled to 0° C. and a solution of sodium hydroxide (9.4 g, 0.23 mole) in water (40 mL) was added dropwise. After 0.5 hour, phenyl isocyanate (25.5 mL, 0.23 mole) was added. A white precipitate formed. The reaction was maintained at ambient temperature for 2 hours. The precipitate was isolated by filtration, washed with water and dried to provide 46.2 g of 1-benzyloxy-3-phenyl urea as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:37])[CH2:26]C(NC2C=CC(F)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15]CCN2CCOCC2)C=1.[CH2:38]([O:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.COCCOCCOC>O>[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]([NH:50][C:13]2[N:12]=[CH:11][N:15]=[C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25](=[O:37])[CH3:26])=[CH:3][C:2]=3[F:1])[CH:14]=2)=[CH:51][CH:52]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1)Nc1ccc(F)cc1
Solvent: O
Solvent: COCCOCCOC
Product: CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Temperature: 160 °C
Yield: 45 %

Procedure:
A mixture of N-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)acetamide (Compound B of Example 13, 281 mg, 1.00 mmol), 4-benzyloxyaniline (Aldrich, 398 mg, 2.00 mmol), and 2-methoxyethyl ether (2 mL) was heated at 160° C. for 45 min. The cooled mixture was treated with H2O (50 mL) and extracted with EtOAc (100 mL). The EtOAc extract was washed with brine (3×25 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (200 mg, 22%) as a purple solid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.43 (s, 1H), 8.23 (s, 1H), 7.72 (dd, 1H, J=12.5, 2.0 Hz), 7.44-7.42 (m, 4H), 7.38 (dd, 2H, J=8.0, 6.9 Hz), 7.33-7.23 (m, 3H), 6.98 (d, 2H, J=9.0 Hz), 6.07 (s, 1H), 5.07 (s, 2H), 2.05 (s, 3H); MS (ESI+) m/z 445.13 (M+H)+.