Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.Br[CH2:38][CH2:39][OH:40]>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH2:38][CH2:39][OH:40])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: OCCBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCN(CCO)C[C@H]1F

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-3-fluoro-1-(2-hydroxyethyl)piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 273) and 2-bromoethanol following General Procedure S.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.[N:35]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][N:38]3[CH2:39][CH2:40][N:35]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][CH2:37]3)=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc2ccc(C=O)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 25 °C
Reaction time: 46 h
Yield: 61.9 %

Procedure:
To the suspension of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine-6-carbaldehyde (0.0300 g, 0.0638 mmol), tert-Butyl 1-piperazinecarboxylate (20.8 mg, 0.112 mmol) and Acetic acid (11 mg, 0.18 mmol) in dry Methylene chloride (2.0 mL, 31 mmol) was added Sodium triacetoxyborohydride (27.0 mg, 0.128 mmol). The mixture was stirred at r.t. for 46 hours. The mixture was washed with water (2×2 mL) and brine, dried over Na2SO4, filtered and the filtrate was chromatographed in an 8 g AnaLogix column using MeOH/DCM (0/100 to 5/95) to give a solid product (0.0253 g, 61.9% yield). LCMS: (FA) ES+ 641. 1H NMR (400 MHz, d-chroloform) δ 9.91 (s, 1H), 8.28 (s, 1H), 7.94-7.97 (m, 2H), 7.58-7.60 (m, 1H), 7.34-7.46 (m, 4H), 5.47-5.51 (m, 1H), 4.05-4.13 (m, 1H), 3.70-3.76 (m, 1H), 3.58 (s, 2H), 3.42 (s, br, 4H), 2.81 (s, 3H), 2.45 (s, br, 4H), 2.00-2.17 (m, 3H), 1.65-1.72 (m, 3H), 1.46 (s, 9H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[C:27]([NH2:29])[N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.C(N(C(C)C)C(C)C)C>CCCCO>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[N:28]=[C:27]([NH2:29])[N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
Into a 25-mL round-bottom flask was placed a solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (238 mg, 1.00 mmol, 1.00 equiv) in n-BuOH (8 mL), 6-chloro-9H-purin-2-amine (155 mg, 0.91 mmol, 0.91 equiv, 98%) and N-ethyl-N-isopropylpropan-2-amine (390 mg, 2.96 mmol, 2.95 equiv, 98%). The resulting solution was stirred overnight at 130° C. and concentrated under vacuum. The residue was eluted onto a C18 column (water/acetonitrile) to afford 0.150 g (40%) of 149 as a white solid. LC-MS (ES, m/z): 371 [M+H]+. H-NMR (300 MHz, CD3OD, ppm): δ 7.71 (d, 2H), 7.51 (s, 5H), 7.29 (m, 2H), 7.10 (d, 1H), 5.67 (s, 1H), 1.69 (d, 3H)
Reaction SMILES: OO.NC(N)=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:20][C:21]1[CH:34]=[CH:33][C:32]2[O:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[N+:35]([O-:37])=[O:36])[C:24](=[O:38])[C:23]=2[CH:22]=1>C(Cl)Cl>[Br:20][C:21]1[CH:34]=[CH:33][C:32]2[O:31][C:30]3[C:25](=[N+:26]([O-:5])[CH:27]=[CH:28][C:29]=3[N+:35]([O-:37])=[O:36])[C:24](=[O:38])[C:23]=2[CH:22]=1
Reactant: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])ccnc12
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])cc[n+]([O-])c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of urea hydrogen peroxide (58.6 mg, 0.623 mmol) in 5 mL of CH2Cl2 at 0° C. was added dropwise trifluoroacetic anhydride (87 μL, 0.623 mmol). After stirring for 5 min at 0° C., a solution of 8-bromo-4-nitro-10H-chromeno[3,2-b]pyridin-10-one (80 mg, 0.249 mmol) in CH2Cl2 (5 mL) was added and the resulting reaction was stirred at rt for 1.5 h. The mixture was carefully quenched with saturated NaHCO3 and extracted with ethyl acetate (5×5 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. Purification of the crude residue by column chromatography (CH2Cl2 to CH2Cl2/EA=10:1 to 5:1) gave 8-bromo-4-nitro-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide as an light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH2:23])[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[N:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CN)n1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2ccc(F)cc2)n1
Yield: 48.1 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 12-(d) except for using tert-butyl[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate (7.00 g, 20.7 mmol) obtained in Reference Example 12-(c), and using 4-fluorobenzenesulfonyl chloride (4.00 g, 20.6 mmol) in place of 3-pyridylsulfonyl chloride to afford the title compound (4.91 g) as a white solid. (Yield: 48%)
Reaction SMILES: [CH3:1][C:2]1([NH:5][C:6]2[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]([NH2:16])=[O:15])=[CH:8][N:7]=2)[CH2:4][CH2:3]1.C1(C2[O:25]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1([NH:5][C:6]2[N:11]=[C:10]([S:12]([CH3:13])=[O:25])[C:9]([C:14]([NH2:16])=[O:15])=[CH:8][N:7]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1nc(NC2(C)CC2)ncc1C(N)=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(NC2(C)CC2)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a stirring solution of 2-(1-methylcyclopropylamino)-4-(methylthio)-pyrimidine-5-carboxamide (305 mg, 1.280 mmol) in chloroform (25.6 mL) was added portionwise 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (502 mg, 1.920 mmol). The resulting pale yellow solution was stirred at ambient temperature overnight. The reaction solution was concentrated under reduced pressure to give crude product as a white solid. Ethyl acetate (10 mL) was added and the slurry was stirred at room temperature for 1 h, filtered, washed with ethyl acetate, and dried in a vacuum oven for a few hours to afford 2-(1-methylcyclopropylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (242 mg, 0.952 mmol, 74.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35-8.90 (m, 2H), 7.88-8.14 (m, 1H), 7.28-7.59 (m, 1H), 2.74 (s, 3H), 1.32-1.46 (m, 3H), 0.68-0.84 (m, 2H), 0.50-0.70 (m, 2H). MS (ESI) m/z 255.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1C=CC=CC=1>[N+:17]([C:13]1[CH:12]=[C:11]([C:10]2[S:32][C:6]([C:5]3[CH:21]=[CH:22][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)[CH:16]=[CH:15][CH:14]=1)([O-:19])=[O:18]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(C(=O)NNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Solvent: c1ccccc1
Product: Cc1ccc(-c2nnc(-c3cccc([N+](=O)[O-])c3)s2)cc1
Temperature: 60 °C

Procedure:
A mixture of 1-[(4-methyl)benzoyl]-2-(3-nitrobenzoyl)hydrazine (1.40 g, 4.68 mmol) and Lawesson's Reagent (0.95 g, 2.34 mmol) in benzene (25 ml) is slowly heated to 60° C. After 3 hours the solution is concentrated, quenched with 35 ml of water and heated to reflux for 12 hours. The mixture is then cooled to room temperature and the precpitate is collected by filtration. The precipitate is then taken up in chloroform (100 ml) and the insoluble portion is removed by filtration. The filtrate is then dried over MgSO4 and concentrated to yield 2-(3′-nitrophenyl)-5-(p-tolyl)-1,3,4-thiadiazole as a pale yellow solid. (0.67 g, 48%). 1H NMR (CDCl3): δ 2.45 (s, 3H), 7.35 (d, 2H), 7.73 (t, 1H), 7.92 (d, 2H), 8.38 (t, 2H), 8.81 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:22][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([F:23])[CH:25]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.036 g, 0.1 mmol), 3-fluoro-benzoyl chloride (14.6 μL, 0.12 mmol) and triethylamine (18.1 μL, 0.13 mmol)) in methylene chloride (2 mL) was stirred at room temperature overnight and concentrated to give a crude product that was subjected to a purification by prep HPLC. The corresponding fractions were collected and lyophilized to give a TFA-salt of Compound 455 as a tan solid in 85.4% yield. LCMS m/z (%)=487 (M+H 79Br, 97), 489 (M+H 81Br, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.42 (s, 1H), 9.71 (bs, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.83-7.73 (m, 3H), 7.66 (s, 1H), 7.63-7.57 (m, 1H), 7.46 (t, J=8.7 Hz, 1H), 7.30 (d, J=9.1 Hz, 1H), 4.45-4.21 (m, 2H), 3.68 (s, 3H), 3.51-3.42 (m, 2H and water), 3.43-3.20 (m, 2H), 2.93-2.60 (m, 2H), 1.97-1.68 (m, 4H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:29]=[CH:28][C:15]([C:16]([O:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(Cl)(=O)C(Cl)=O.[C:36]1([CH:43]=[CH:42][CH:41]=[C:39](O)[CH:38]=1)[OH:37].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:11][C:12]1[CH:29]=[CH:28][C:15]([C:16]([O:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([O:25][C:39]3[CH:41]=[CH:42][CH:43]=[C:36]([OH:37])[CH:38]=3)=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Reactant: Oc1cccc(O)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)Oc3cccc(O)c3)cc2)cc1

Procedure:
Compound 16 (2.05 g, 5.2 mmol) was suspended in toluene (100 mL), and refluxed with oxalyl chloride (2.0 mL, 23.2 mmol) for five hours. Volatile components were removed, and the white solid was taken in CH2Cl2 (50 mL) and added dropwise while stirring to a solution containing resorcinol (1.23 g, 11.2 mmol), triethylamine (5.4 mL, 39 mmol), and DMAP (0.06 g, 0.52 mmol). Following stirring at room temperature for 12 hours, the mixture was then refluxed for twenty four hours. The solvent was removed under reduced pressure, and the residue purified by column chromatography (CH2Cl2:EtOH, 10:0.03, and then CH2Cl2:EtOH, 10:0.3). The product was then recrystallized from ethanol. Yield (1.6 g, 64%). 1H NMR: δH (CDCl3; 300 MHz): 0.92 (3 H, t, 3J=6.9 Hz, CH3), 1.23-1.60 (14 H, m, CH2), 1.86 (2 H, m, O—CH2—CH2), 4.07 (2 H, t, 3J=6.5 Hz, O—CH2), 6.15 (1 H, bs, OH), 6.69 (2 H, m, Ar—H), 6.78 (1 H, d, 3J=8.3 Hz, Ar—H), 7.01 (2 H, d, 3J=8.9 Hz, Ar—H), 7.25 (1 H, t, 3J=8.5 Hz, Ar—H), 7.38 (2 H, d, 3J=8.8 Hz, Ar—H), 8.18 (2 H, d,3J=8.9 Hz, Ar—H), 8.27 (2 H, d, 3J=8.8 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 14.5, 23.1, 26.4, 29.5, 29.7, 29.8, 30.0, 32.3, 68.8, 109.8, 113.8, 113.9, 114.9, 121.2, 122.6, 127.2, 130.5, 132.3, 132.9, 152.0, 155.8, 157.4, 164.3, 165.0, 165.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[NH2:18].C([O-])(=O)C.[Na+]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(N)cc1OC
Reactant: Cc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(Nc2nc(C)nc3ccccc23)cc1OC

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (178.6 mg, 1.0 mmol), 3,4-dimethoxy-aniline (153 mg, 1.0 mmol) and sodium acetate (98.4 mg, 1.2 mmol) similar to example 20 to give 295 mg (100%) of off white solids. 1H NMR (CDCl3): 7.85-7.70 (m, 4H), 7.51-7.46 (m, 1H), 7.38 (brs, 1H), 7.16 (dd, J=2.1 Hz, J=8.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 3.95 (s, 3H)), 3.91 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: [P:1]([O-:9])([O-:8])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].[OH-].[Na+:11].[CH2:12]([CH:14]1[O:16][CH2:15]1)[Cl:13]>>[P:1]([O-:9])([O:8][CH2:15][CH:14]([OH:16])[CH2:12][Cl:13])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].[Na+:11]
Reactant: CCCCOP(=O)([O-])[O-]
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: CCCCOP(=O)([O-])OCC(O)CCl
Temperature: 70 °C
Reaction time: 20 h
Yield: 86.5 %

Procedure:
20 g (0.13 moles) of monobutyl phosphate having a purity of 99% (AV1=360.6, AV2=721.3) was charged into a reactor, to which 129 ml of 1N sodium hydroxide aqueous solution was added and agitated at 70° C. to obtain uniform solution, at which the acid value of the reaction system was 46.7. While keeping the reaction system at 70° C., 59.2 g (0.64 moles) of epichlorohydrin was gradually dropped, followed by agitation at the temperature for 20 hours. The acid value of the reaction system was approximately zero, revealing that the conversion rate of the phosphoric monoester was almost 100%. The resulting product was collected by HPLC and the solvent was distilled off under reduced pressure to obtain 30.2 g (yield 86.5%) of sodium butyl 2-hydroxy-3-chloropropyl phosphate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:32])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23](OC(=O)C)[CH:24]=[CH2:25])=[C:17]([CH3:30])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:31]=1.[C:33]1([P:39]2(=[O:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:32])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]=[CH:24][CH2:25][N:42]4[CH2:41][CH2:40][P:39](=[O:45])([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:44][CH2:43]4)=[C:17]([CH3:30])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:31]=1
Reactant: O=P1(c2ccccc2)CCNCC1
Reactant: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Product: Cc1c(C=CCN2CCP(=O)(c3ccccc3)CC2)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12

Procedure:
2-(2,6-Dichloro-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ5-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one was prepared following the procedure of Example 1 form acetic acid 1-[2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester and 4-phenyl-[1,4]azaphosphinane 4-oxide. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.38 (br s, 1H), 10.71 (br s, 1H), 7.90-7.60 (m, 9H), 7.56 (t, 1H, J=7.8 Hz), 7.22 (br d, 1H, J=15.3 Hz), 7.70-6.40 (br m, 1H), 4.23 (s, 3H), 4.18 (br m, 2H), 4.00-4.15 (br m, 4H), 2.60-2.40 (br n, 4H), 2.39 (s, 1H); ESMS (m/z): found, 606 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([OH:14])=O)=[O:7].[CH:24]1([NH2:28])[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:28][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:10]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCC1
Reactant: COc1ccc(C(=O)Nc2cc(C(=O)O)ccc2C)cc1OC
Product: COc1ccc(C(=O)Nc2cc(C(=O)NC3CCC3)ccc2C)cc1OC

Procedure:
Using an analogous procedure to that described in Example 8, 3-(3,4-dimethoxybenzamido)-4-methylbenzoic acid was reacted with cyclobutylamine to give the title compound; Mass Spectrum: M+H+ 369.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:3][CH2:4]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f57) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][NH2:22])=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1.[CH:24](OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]3[O:20][CH:24]=[N:22][N:21]=3)=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)ccc1Nc1c(-c2nnco2)cc2[nH]cnc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20b (0.048 g, 0.144 mmol) is suspended in 3 mL absolute EtOH and HC(OEt)3 (0.60 mL, 3.54 mmol) is added followed by catalytic pTsOH.H2O. The reaction mixture is heated to reflux under N2. After 2 hours, the reaction mixture is cooled to room temperature and concentrated under reduced pressure. Purification by flash column chromatography (97:3 ethyl acetate:MeOH) provides 36 mg (73%) desired product as a light yellow solid. LC/MS ESI (+) m/z 344, 346 (M+ Cl pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ13.10 (bs, 1H), 9.39 (s, 1H), 8.49 (s, 1H), 8.10 (bs, 1H), 7.78 (bs, 1H), 7.20 (d, 1H), 7.00 (dd, 1H), 6.41 (bs, 1H), 2.18 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]\[C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CN(C)C=O.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1ncc(/C=C\c2ccc([N+](=O)[O-])cc2)s1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(CCc2ccc(N)cc2)s1
Yield: 26.7 %

Procedure:
A mixture of N-{5-[(Z)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (1 g) and 10% palladium carbon (1.04 g) in ethyl acetate (100 ml) and N,N-dimethylformamide (20 ml) was stirred under 4 atm hydrogen at ambient temperature for 4 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform/methanol (30:1→20:1) as an eluent, and triturated with ethyl ether to give N-{5-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (240.9 mg) as an off-white solid.
Reaction SMILES: [CH3:1][NH2:2].CO.[CH:5]([C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)=O.[BH4-].[Na+]>O>[CH3:1][NH:2][CH2:5][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: N#Cc1c(C=O)[nH]c2ccccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1[nH]c2ccccc2c1C#N
Temperature: 0 °C
Reaction time: 5 h
Yield: 75.3 %

Procedure:
Methylamine (6.2 mL, 49.4 mmol, 33% in EtOH) was added to a MeOH (50 mL) solution of 2-formyl-1H-indole-3-carbonitrile (2.80 g, 16.5 mmol) at 0° C. Upon stirring for 5 h at 0° C., NaBH4 (740 mg, 19.8 mmol) was added to the solution and the stirring was continued for 16 h. The mixture was diluted with water, extracted with methylene chloride; the organic layer was dried and evaporated. The crude residue was subjected to chromatography (1-5% MeOH in methylene chloride). The desired fractions were collected and concentrated; the residue was recrystallized from a methylene chloride/hexane mixture to afford the title compound (2.30 g, 75%). 1H NMR (300 MHz, DMSO-d6, δ): 7.54 (m, 1H), 7.48 (m 1H), 7.21 (m, 2H), 3.93 (s, 2H), 2.31 (s, 3H). MS (ESI): m/e 186 (M+H)+.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[O:14])C(=O)[NH:10]2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=1.Cl>[OH-].[Na+]>[Cl:3][C:4]1[CH:12]=[C:11]([NH2:10])[C:7](=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=1)[C:8]([OH:14])=[O:1]
Reactant: O=C1Nc2cc(Cl)cc([N+](=O)[O-])c2C1=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Cl)cc([N+](=O)[O-])c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
4 ml of a 30% hydrogen peroxide solution are added dropwise at room temperature to 3.8 g (16.7 mmol) of 6-chloro-4-nitro-indoline-2,3-dione in 60 ml of sodium hydroxide solution. The mixture is stirred for 2 hours at room temperature, acidified to pH 2 to 3 with 4N hydro-chloric acid, filtered and dried. 3.18 g (87.8% of theory) of 4-chloro-6-nitro-anthranilic acid having a melting point of 202°-205° are obtained.