Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[O:11].Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:10]([NH:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:11])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: COc1ccccc1N=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
2-Methoxyphenyl isocyanate (0.4 g, 2.6 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and triethylamine (0.3 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After stirring for 10 minutes at 5° C., the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL) for 30 minutes. The solid was collected and slurried with hot methanol (15 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(2-methoxy-phenyl)-urea (0.7 g, 80%) as a white solid: mp 214-216° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 3.83 (s, 3H, OCH3), 4.73 (d, J=5.7 Hz, 2H, CH2), 5.13-5.20 (dd, J=5.3 and 12.5 Hz, 1H, CH), 6.79-6.98 (m, 3H, Ar), 7.49 (t, H=5.7 Hz, 1H, NH), 7.77-7.89 (m, 3H, Ar), 8.04-8.08 (dd, J=1.4 and 7.3 Hz, 1H, Ar), 8.19 (s, 1H, NH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 48.86, 55.64, 110.59, 118.07, 120.42, 121.22, 121.88, 127.16, 129.20, 131.61, 133.65, 134.77, 140.112, 147.40, 155.24, 167.00, 167.50, 169.83, 172.76; Anal. calcd. for C22H20N4O6+0.66H2O: C, 58.94; H, 4.79; N, 12.50. Found: C, 59.24; H, 4.86; N, 12.74.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[CH3:16][C:17]1[N:18]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=2)[CH:19]=[CH:20][N:21]=1>>[C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:26][C:25]3[CH:24]=[CH:23][C:22]([N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH3:16])=[CH:29][CH:28]=3)[CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2cccc(O)c2)CCOCC1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C#N)CCOCC3)c2)cc1
Yield: 38 %

Procedure:
4-Cyano-4-(3-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran was reacted with 4-(2-methylimidazol-1-yl)benzylchloride to give the titled compound in 38% yield as colorless needles according to the procedure described in Example 2H.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2cccnc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1cccnc1
Temperature: 5 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-yl)propan-2-ol (1 g, 2.81 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in an ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers, which were separated by HPLC. 1H NMR (DMSO, TFA salt) δ (ppm): 8.90 (s, 1H), 8.60 (d, 1H), 8.10 (d, 1H), 7.50 (m, 2H), 7.22 (d, 2H), 7.10 (d, 1H), 3.6 (m, 2H), 2.70 (m, 4H), 2.45 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=[O:12])(=O)(O)[OH:9]>>[CH:5]1[CH:6]=[C:1]([OH:7])[C:2]([S:8]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)(=[O:12])=[O:9])=[CH:3][CH:4]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(c1ccc(O)cc1)c1ccccc1O

Procedure:
The mixture containing 4,4′-dihydroxydiphenylsulfone, 2,4′-dihydroxydiphenylsulfone, phenolsulfonic acid and phenol which is obtained by adding phenol and sulfuric acid to the filtrate formed by filtration of 2,4′-dihydroxydiphenylsulfone, followed by the dehydration of the resultant mixture, can be treated in the same manner as that in the treatments of the mixture containing 4,4′-dihydroxydiphenylsulfone, 2,4′-dihydroxydiphenylsulfone, phenolsulfonic acid and phenol which is obtained by the dehydration of phenol and sulfuric acid. 4,4′-Dihydroxydiphenylsulfone is separated by crystallization to obtain a mixture having a content of 2,4′-dihydroxydiphenylsulfone greater than the content of 4,4′-dihydroxydiphenylsulfone. 2,4′-Dihydroxydiphenylsulfone is crystallized by adjusting the composition of the mixture so that the ratio of the amounts by weight of phenol to water is in the range of 10:90 to 90:10; and the formed crystals are separated by filtration. The filtrate formed above by the filtration and containing phenol and phenolsulfonic acid can be used repeatedly as the raw material for producing dihydroxydiphenylsulfone by the dehydration of phenol and sulfuric acid and/or phenolsulfonic acid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH:25]([C:28]1[C:33](B(O)O)=[CH:32][N:31]=[CH:30][N:29]=1)([CH3:27])[CH3:26]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:33]4[C:28]([CH:25]([CH3:27])[CH3:26])=[N:29][CH:30]=[N:31][CH:32]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CC(C)c1ncncc1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: CC(C)c1ncncc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 14.9 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 4-isopropylpyrimidine-5-boronic acid (available from Combi-Blocks Inc.; 66 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(4-isopropyl-pyrimidin-5-yl)-benzoic acid (14 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ 13.30 (br s, 1H), 9.14 (s, 1H), 8.62 (d, J=1.7 Hz, 1H), 8.50 (d, J=2.4 Hz, 2H), 8.29-8.36 (m, 2H), 8.10 (dd, J=8.4, 2.0 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.1 Hz, 5H), 2.75-2.85 (m, 1H), 1.03-1.19 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[S:18]([C:21]1[CH:22]=[C:23]([C:27]2[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=3)[N:28]=2)[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19]>ClCCl>[CH3:37][C:36]1([CH3:38])[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=2)[N:28]=[C:27]1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:22]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Nc3ccccc3)c1)=N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a stirred solution of aniline (50 mg, 0.52 mmol) and N,N-diisopropylethylamine (122 mg, 0.86 mmol) in dichloromethane (4 mL) was added methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (170 mg, 0.43 mmol) in dichloromethane (2 mL). The mixture was stirred for 18 h at room temperature and purified on preparative Thin layer chromatography to afford 170 mg of methyl 3,3-dimethyl-2-(3-(N-phenylsulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate, which was used directly.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(OC)c(CNC3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1

Procedure:
Boronic acid 4 (329 mg, 1.00 mmol) is coupled to 4-bromoanisole (125 μL, 1.00 mmol) using Method B to give the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(C)(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.038 g, 44%). MP: 85-93° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.45 (s, 1H), 8.08-8.06 (m, 1H), 7.72 (s, 1H), 7.45 (s, 1H), 7.36-7.31 (m, 1H), 7.30-7.25 (m, 2H), 6.57 (s, 1H), 6.14-6.06 (m, 1H), 3.82 (s, 3H), 3.41-3.33 (m, 2H), 2.89-2.76 (m, 6H), 2.75-2.70 (m, 2H), 2.57-2.50 (m, 2H), 1.69 (t, 3H, J=18.7 Hz), 1.13-1.06 (m, 3H). MS: 563.18 (MH)+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.[C:16](O)(=[O:18])[CH3:17]>>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:16](=[O:18])[CH3:17])=[N:10][CH:11]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(Br)cn1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Br)cn1
Yield: 41.4 %

Procedure:
Triethylamine (17.7 mL, 75 mmol) is added to a mixture of 2-amino-5-bromopyridine (5.0 g, 29 mmol) and acetic acid (7.1 mL, 75 mmol). The solution is heated to reflux for 48 hours. After this time, the solution is concentrated. The reside is dissolved in water and the pH is adjusted to 10 with 1N NaOH. The solids are collected by filtration. The crude product is recrystallized from boiling water to give the title compound (2.6 g 12.0 mmol) as a white solid. 1H NMR (300 MHz, CDCl3) δ10.62 (1H, bs), 8.42 (s, 1H), 8.01 (m, 2H), 2.05 (s, 3H).
Reaction SMILES: [C:1]([N:4](C(=O)C)[C:5]1[NH:6][C:7](=[O:14])[C:8]2[NH:9][CH:10]=[N:11][C:12]=2[N:13]=1)(=[O:3])[CH3:2]>O.CO>[C:1]([NH:4][C:5]1[NH:6][C:7](=[O:14])[C:8]2[NH:9][CH:10]=[N:11][C:12]=2[N:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)c1nc2nc[nH]c2c(=O)[nH]1
Solvent: O
Solvent: CO
Product: CC(=O)Nc1nc2nc[nH]c2c(=O)[nH]1

Procedure:
Diacetylguanine (3 g) was refluxed in a mixture of water (5 ml) and methanol (50 ml) for 4 hours. The solvents were then removed under reduced pressure, the residue washed with cold methanol, and dried under vacuum, to give N-acetylguanine, a compound of Formula (1a).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=C(C)C)=[N:6][C:5]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4]1)[CH3:2].I([O-])(=O)(=O)=[O:18].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[CH2:1]([N:3]1[C:7]([CH:8]=[O:18])=[N:6][C:5]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4]1)[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCn1nc(N2CCCC2)nc1C=C(C)C
Agent: O=[Os](=O)(=O)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCn1nc(N2CCCC2)nc1C=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A mixture of 1-ethyl-5-(2-methylprop-1-enyl)-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole (441 mg, 2.00 mmol, Eq: 1.00), osmium(VIII) oxide (382 mg, 382 μl, 60.1 μmol, Eq: 0.03), sodium periodate (1.71 g, 8.01 mmol, Eq: 4) and benzyltriethylammonium chloride (182 mg, 801 μmol, Eq: 0.4) in dioxane (21 ml) and water (6.3 ml) was stirred for 2 hours at 120° C. The mixture was diluted with ethyl acetate and washed with 2× water and brine. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 2-Ethyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazole-3-carbaldehyde (268 mg/69.2%) as a dark green viscous oil. MS: m/e=195.4 (M+H+)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][O:25][C@H:24]1[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][S:2]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C@H:24]1[C@H:23]([O:22][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:28][CH2:27][CH2:26][O:25]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCCCCCCCO
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.51 ml of methanesulfonyl chloride dissolved in 5 ml of benzene was added dropwise to a solution of 2.067 g of dl-7-(trans-3-hexadecyloxytetrahydropyran-2-ylmethoxy)-1-heptanol (prepared as described in Preparation 55) and 1.83 ml of triethylamine dissolved in 15 ml of benzene, whilst ice-cooling. The reaction mixture was stirred at room temperature for 15 minutes, after which it was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 2.406 g of crude dl-7-(trans-3-hexadecyloxytetrahydropyran-2-ylmethoxy)heptyl methanesulfonate as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([CH2:21]Cl)[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:23][NH:24][CH3:25]>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([CH2:21][N:24]([CH3:25])[CH3:23])[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNC
Reactant: ClCc1nnc2ccc3nc(Cl)c(-c4ccccc4)nc3n12
Product: CN(C)Cc1nnc2ccc3nc(Cl)c(-c4ccccc4)nc3n12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-chloro-9-(chloromethyl)-2-phenyl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazine (10-2) (840 mg, 0.254 mmol) and dimethylamine (2M in THF, 5 mL, 10 mmol) was stirred at room temperature for 2 hours. The solvent was evaporated to give 1-(3-chloro-2-phenyl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazin-9-yl)-N,N-dimethylmethanamine (10-3).
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1.C1C(=O)N([I:26])C(=O)C1>O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([I:26])=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc2ccc(Cl)nn2c1I
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a CHCl3 (20 mL) solution of N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (320.4 mg, 1521 μmol) was added n-iodosuccinimide (167.4 μl, 1673 μmol) as a solid in a single portion. The solution was maintained at rt for 20 min, then poured into water. The resulting mixture was extracted with CH2Cl2 (1×50 mL). The layers were separated and the organic layer was washed with saturated aqueous Na2S2O3 (1×20 mL) and brine (1×10 mL). The organic layer was dried (Na2SO4) and concentrated for purification by MPLC (CombiFlash® Companion®, Teledyne Isco, Lincoln, Nebr.). The residue was taken up in minimal CH2Cl2/MeOH and absorbed onto a 25 g silica loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (80 g) (Teledyne Isco, Lincoln, Nebr.) using a gradient of 1% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2 to afford N-(6-chloro-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (427.0 mg, 83.41% yield) as a grey solid. LCMS (ESI positive ionization) m/z: 337.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4](F)[C:3]=1[NH2:10].S(=O)(O)[O-].[Na+].[CH3:16]N(C)C(=O)C>C(OCC)(=O)C>[N:10]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:16]=1
Reactant: CC(=O)N(C)C
Reactant: Nc1cc(F)cc(F)c1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: c1ccc2[nH]cnc2c1
Temperature: 120 °C

Procedure:
Aldehyde 1e (2.05 g, 4.28 mmol), 1,2-diamino-3,5-difluorobenzene (617 mg, 4.28 mmol) and sodium bisulfite (891 mg, 8.57 mmol) were dissolved in N,N-dimethylacetamide (43 mL) and heated in a 120° C. oilbath for 21 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and washed with half-saturated aqueous sodium chloride solution (75 mL, a 1:1 mixture of deionized water and saturated aqueous sodium chloride solution). The aqueous layer was back-extracted with ethyl acetate (2×100 mL). All the organic extracts were combined, dried over magnesium sulfate, and concentrated to a brown tar (3.39 g). This crude material was purified by silica gel chromatography (eluting with a gradient of 70% to 100% ethyl acetate in hexanes), to give benzoimidazole product 1f (2.11 g, 81%) as a tan foam: 1H NMR (CD3OD) δ 8.46 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.46 (dd, J=1.3, 8.6 Hz, 1H), 7.13 (m, 1H), 6.84 (m, 1H), 5.99 (dd, J=2.3, 9.9 Hz, 1H), 4.60 (s, 2H), 4.01 (m, 1H), 3.86 (m, 1H), 3.32 (m, 2H, obscured by solvent peak) 2.67 (m, 1H), 2.28 (s, 3H), 2.18 (m, 2H), 1.89 (m, 1H), 1.73 (m, 2H), 1.47 (s, 9H), 1.13 (t, J=7.1 Hz, 1H). Anal. (C33H36F2N6O3.0.4 H2O) C, H, N, F.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C:7](=[O:16])[N:8]2[C:12]=1[CH2:11][CH2:10][C@H:9]2[C:13](O)=[O:14])(=[O:3])[CH3:2].[C:28]([O:32][C:33](=[O:45])[NH:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1)=[NH:36])([CH3:31])([CH3:30])[CH3:29].C1CN([P+](ON2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:21]([O:20][C:18](=[O:19])[NH:17][C:6]1[C:7](=[O:16])[N:8]2[C:12](=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)[CH2:11][CH2:10][C@H:9]2[C:13](=[O:14])[NH:44][CH2:43][C:40]1[CH:41]=[CH:42][C:37]([C:35]([NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:45])=[NH:36])=[CH:38][CH:39]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CN)cc1
Reactant: CC(=O)c1cc(NC(=O)OCc2ccccc2)c(=O)n2c1CC[C@H]2C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(NC(=O)OCc2ccccc2)c(=O)n2c1CC[C@H]2C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 48.7 %

Procedure:
The acid (43 mg, 0.116 mmol) obtained from Step D was placed in a flask with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid tert-butyl ester (32 mg, 0.128 mmol), PyAOP (76 mg, 0.145 mmol) and dissolved in 2 mL DMF. DIEA (61 μL, 0.348 mmol) was added and the reaction allowed to stir for 2 h. The reaction was diluted with EtOAc and 5% NaHCO3 was added and stirred for 10 min. The phases were separated and the aqueous phase extracted 2× with EtOAc, dried with sodium sulfate and concentrated. Purified by HPLC and lyopholized to give the product as a white solid (34 mg, 41% yield). 1HNMR (300 MHz, CDCl3) δ 1.614 (s, 9H) 2.3 (m, 1H) 2.5 (s, 3H) 2.6 (m, 1H) 3.4–3.6 (m, 2H) 3.6–3.8 (m, 2H) 5.2 (m, 1H) 5.25 (s, 2H) 7.4 (m, 9H) 7.6 (m, 2H) 7.8 (m, 2H).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][N:12]=2)=[CH:7][C:6]=1[CH3:21].Cl>C1COCC1.CCOC(C)=O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][N:12]=2)=[CH:7][C:6]=1[CH3:21]
Reactant: CCOC(=O)c1cc(-c2ccc(OCOC)c(C)c2)no1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccc(O)c(C)c2)no1
Yield: 70.5 %

Procedure:
A solution of ethyl 3-[4-(methoxymethoxy)-3-methylphenyl]-5-isoxazolecarboxylate (725 mg, 2.49 mmol) and aqueous 4 N HCl solution (6 mL) in THF (10 mL) was stirred at 25° C. for 16 h. The reaction mixture was diluted with EtOAc and successively washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (434 mg, 70% yield) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1.[C:16]([O-:19])([O-])=[O:17].[K+].[K+]>CC(C)=O.O>[C:3]([O:19][C:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1)=[O:17])([CH3:7])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: c1ccc2c(C3CCCNC3)c[nH]c2c1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(c2c[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the 3-piperidin-3-yl-1H-indole obtained in Example 29 in acetone/water (1:1) at 0° C. is treated with di-tert-dicarbonate (4.1 g, 18.7 mmol) and K2CO3 (11.75 g, 85 mmol), stirred for 2 hours while warming to room temperature, and concentrated in vacuo. The resultant aqueous mixture is extracted with ethyl acetate. The extracts are combined, dried over Na2SO4 and concentrated in vacuo. The resultant residue is purified by column chromatography (silica gel, 1% NH4OH in MeOH:CHCl3, 0:100 to 10:90 as eluent) to afford the title product, 1.25 g, identified by HPLC and mass spectral analyses.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:8])([CH3:7])[C:4]#[C:5][CH3:6].[N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([O:24][CH2:25][CH3:26])[C:21](O)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([O:24][CH2:25][CH3:26])[C:21]([NH:2][C:3]([CH3:8])([C:4]#[C:5][CH3:6])[CH3:7])=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC#CC(C)(C)N
Reactant: CCOC(Oc1ccc2ncccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(C)(C)NC(=O)C(OCC)Oc1ccc2ncccc2c1
Yield: 88.7 %

Procedure:
Triethylamine (0.3 ml) was added to a stirred solution of 4-amino-4-methylpent-2-yne hydrochloride (0.054 g) in N,N-dimethylformamide (2 ml) giving a white suspension. 2-(6-Quinolinoxy)-2-(ethoxy)acetic acid (0.1 g) was added followed by N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride (0.077 g) and a catalytic amount of 1-hydroxybenzotriazole (0.005 g), and the white suspension was stirred at ambient temperature for 18 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with water, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulphate and evaporated under reduced pressure to give a yellow oil (0.117 g). The oil was purified by flash chromatography (silica gel; ethyl acetate/hexane, 1:1 by volume) to give the required product (0.096 g) as a colourless oil.