Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.C(=O)(O)[O-].[Na+]>CCO>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(-c3ccccc3)cn2c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A stirred mixture of 2-amino-5-picoline (0.56 g, 5.22 mmol) and 2-bromoacetophenone (1.0 g, 5.02 mmol) in EtOH (50 ml) was heated under reflux for 2 h. The reaction mixture was left to cool to room temperature and then sodium bicarbonate (0.76 g, 9.04 mmol) was added and the reaction mixture was heated under reflux for 15 h. The solvent was then removed under reduced pressure and the residue was dissolved in EtOAc (70 ml) and washed with water (40 ml). The organic phase was dried (Na2SO4) and the solvent was removed under reduced pressure to give an orange solid. This solid was purified by flash chromatography (1:1 Hexane/EtOAc) to give the title compound (0.753 g, 70%) as a pale orange solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](SC)[N:10]=2)[C:3]1([CH3:20])[CH3:19].Cl.[NH2:22][CH2:23][CH2:24][CH:25]1[C:33]2[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=2)[NH:27][C:26]1=[O:35].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:34][C:30]1[CH:29]=[C:28]2[C:33]([CH:25]([CH2:24][CH2:23][NH:22][C:11]3[N:10]=[C:9]([NH:8][C@@H:4]4[CH2:5][CH2:6][CH2:7][C@@H:2]([OH:1])[C:3]4([CH3:20])[CH3:19])[C:14]([C:15]#[N:16])=[CH:13][N:12]=3)[C:26](=[O:35])[NH:27]2)=[CH:32][CH:31]=1
Reactant: NCCC1C(=O)Nc2cc(F)ccc21
Reactant: CSc1ncc(C#N)c(N[C@@H]2CCC[C@@H](O)C2(C)C)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC1(C)[C@H](O)CCC[C@H]1Nc1nc(NCCC2C(=O)Nc3cc(F)ccc32)ncc1C#N
Temperature: 90 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
A mixture of 4-(((1R,3R)-3-hydroxy-2,2-dimethylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (92 mg, crude), 3-(2-aminoethyl)-6-fluoroindolin-2-one hydrochloride (95 mg, 0.41 mmol) and DIEA (122 mg, 0.94 mmol) in DMA (2 mL) was stirred at 90° C. for 1 h. The solvent was evaporated and the residue was purified by standard methods to afford the title compound (36.7 mg, 0.083 mmol, 29% yield for two steps). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.05 (s, 1H), 7.34-7.29 (m, 1H), 6.79-6.69 (m, 1H), 6.69-6.61 (m, 1H), 4.67-4.59 (m, 1H), 3.60-3.44 (m, 4H), 2.29-2.08 (m, 2H), 1.93-1.67 (m, 3H), 1.67-1.49 (m, 3H), 1.02-0.97 (m, 6H). MS (ESI) m/z 439.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=[C:21]([C:23]([OH:25])=O)[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:49]=[CH:48][C:40]([CH2:41][N:42]2[CH:46]=[C:45]([NH2:47])[CH:44]=[N:43]2)=[CH:39][CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[CH:20]=[C:21]([C:23](=[O:25])[NH:47][C:45]2[CH:44]=[N:43][N:42]([CH2:41][C:40]3[CH:48]=[CH:49][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)[CH:46]=2)[CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)O)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Reactant: COc1ccc(Cn2cc(N)cn2)cc1
Product: COc1ccc(Cn2cc(NC(=O)c3cc(-c4cc5ccccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1

Procedure:
The title compound was prepared according to the experimental used in Example 1, Step 4 using intermediate (1c) and 1-(4-methoxy-benzyl)-1H-pyrazol-4-ylamine. After the usual aqueous work up, the resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—50% ethyl acetate/hexane. This afforded the title compound as a pink solid, 180 mg, 50%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](/[C:8](=[N:27]/[NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)(=[O:19])=[O:20])[CH:22]=2)/[CH3:9])[CH:7]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1F
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1F
Temperature: 120 °C
Yield: 19 %

Procedure:
1-(5-chloro-2-fluorophenyl)ethanone (20 mg, 0.116 mmol) and 3-(morpholinosulfonyl)benzohydrazide (33.1 mg, 0.116 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-fluorophenyl)ethylidene)-3-(morpholinosulfonyl)benzohydrazide (10 mg, 0.022 mmol, 19.22% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.26 (m, 1H), 8.09 (m, 1H), 7.80 (d, 1H, J=7.6 Hz), 7.58 (t, 1H, J=7.6 Hz), 7.37 (m, 1H), 7.21 (m, 1H), 6.95 (m, 1H), 3.61 (m, 4H), 2.90 (m, 4H), 2.29 (s, 3H). Mass [M+H]+: 440.1
Reaction SMILES: [N+:1]([C:4]1[C:13]([Br:14])=[C:12]([Br:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[C:13]([Br:14])=[C:12]([Br:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2
Reactant: O=c1[nH]c2cc(Br)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1c(Br)c(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 90 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
To a stirred mixture of 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (327 mg, 0.89 mMol) in ethanol (10 mL) was added SnCl2.2H2O (1.0 g, 4.45 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 4 h. The mixture was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (2×1 mL), to get 227 mg (76%) of crude title product (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 193 mg of pure title product as bright yellow needles; mp: 324°-6° C. (dec.), changed color from 270° C. IR (KBr, cm-1): 3456; 3281; 1700; 1643. NMR (1H, DMSO-d6): d 5.844 (s, 2H); 6.732 (s, 1H); 11.257 (s, 1H); 11.810 (s, 1H). Purity: >96.96% by HPLC. HRMS: calcd for C8H8N3O2Br2 (M+) m/z 332.8747; found: 332.8754. Potency relative to DCK: 341%.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH3:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[O:31])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([C:27]3[CH:28]=[C:29]([C:30](=[O:31])[NH:32][C:33]4[S:34][CH:35]=[CH:36][N:37]=4)[CH:38]=[CH:39][C:26]=3[CH3:25])=[N:3][CH:4]=2)[CH2:17][CH2:18]1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.53 min, MH+ 527. NMR: δH [2H6]-DMSO 12.73,(1H, b), 11.70,(1H, b), 9.26,(1H, d), 8.43, (1H, dd), 8.33,(1H, d), 8.25,(1H, s), 8.10,(1H, d), 7.93,(1H, d), 7.58,(1H, d), 7.54,(1H, d), 7.36,(1H, t), 7.30,(2H, m), 7.12,(1H, t), 3.78,(2H, s), 2.67–2.25,(11H, b), 2.14,(3H, s).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:10]([Cl:9])[CH:11]=2)=[CH:3][N:4]=1
Reactant: Nc1ncc(Br)nn1
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cnc(N)nn2)cc1Cl
Temperature: 82 °C
Yield: 55.7 %

Procedure:
To a mixture of 6-bromo-1,2,4-triazin-3-amine (Step 1, 1.0 g, 5.7 mmol) and [3-chloro-4-(methoxycarbonyl)phenyl]boronic acid (1.5 g, 6.8 mmol) (VMR, Cat. #100013-404) in 1,4-dioxane (22 mL) was added a solution of potassium phosphate (2.4 g, 11 mmol) in water (5.1 mL). The mixture was degassed by purging nitrogen for 10 min. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) and again was degassed with nitrogen. The mixture was stirred and heated at 82° C. (an oil bath) for 1 h. The mixture was cooled to r.t., diluted with water, stirred for 30 min, and a grey solid formed. The solid was isolated by filtration, rinsed several times with water, and dried in air. The solid was then triturated sequentially with hexanes, dichloromethane-hexanes (1:1), and hexanes to afford the desired product (840 mg, 55.54%). LCMS (M+H)+: m/z=264.9/267.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=O)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH2:17][NH2:18].CC(O)=O>C(O)C>[Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[N:17][NH2:18])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(c1c(Cl)cnc2[nH]ccc12)C1CCC1
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Product: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCC1
Yield: 47.3 %

Procedure:
A mixture of (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanone (0.2 g, 0.85 mmol), anhydrous hydrazine (0.13 mL, 4.26 mmol) and AcOH (0.008 mL, 0.142 mmol) in ethanol (10 mL) was heated at reflux for about 20 h. During this time, water was distilled from the reaction mixture via the use of a Dean-Stark trap. The volatiles were removed under reduced pressure and the residue was partitioned between water (10 mL) and EtOAc (20 mL). The organic phase was dried over anhydrous MgSO4, filtered, and the solvent evaporated under reduced pressure. The crude material was purified by chromatography over silica gel using a 10 to 50% gradient of EtOAc in heptane as the eluent to provide 5-chloro-4-(cyclobutyl(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine as an off-white solid (0.10 g, 49%): LC/MS (Table 2, Method o) Rt=2.22 min; m/z: 249 and 251 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:14]=2[O:21]C)=[C:11]2[C:6]([C:7]([F:23])=[CH:8][CH:9]=[CH:10]2)=[N:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.C1CCCCC=1>>[CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[OH:21])=[C:11]2[C:6]([C:7]([F:23])=[CH:8][CH:9]=[CH:10]2)=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc2c(F)cccc2c1-c1ccc(OC)cc1OC
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: C=CCn1nc2c(F)cccc2c1-c1ccc(O)cc1O
Yield: 40.5 %

Procedure:
Prepared according to Method D step C from 2-allyl-3-(2,4-dimethoxyphenyl)-7-fluoro-2H-indazole (0.057 g, 0.2 mmol), boron tribromide (0.150 mL, 1.6 mmol) and 1.0 mL of cyclohexene to give the product (0.023 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][C@@H:9]1[C@@H:22]([OH:34])[C@@H:23]([NH2:33])[CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CC[O:39][CH2:38][CH2:37]1.ClCCl>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][C@@H:9]1[C@@H:22]([OH:34])[C@@H:23]([NH:33][C:38](=[O:39])[CH3:37])[CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCOCC1
Reactant: COc1cccc(O[C@@H]2C[C@H]([C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)N(C(=O)OC(C)(C)C)C2)c1
Solvent: ClCCl
Product: COc1cccc(O[C@@H]2C[C@H]([C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(C)=O)N(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
Add to an ice cold solution of (2R,4R)-2-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-4-(3-methoxy-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.24 g, 0.51 mmol) and 4-methylmorpholine (0.061 mL, 0.556 mmol) in dichloromethane (15 mL) 1-acetylimidazole (0.061 g, 0.556 mmol). Warm to room temperature and stir 18 h. Concentrate and dissolve in ethyl acetate and wash with 1N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate) and purify (silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures) to give the title compound as a foam (0.18 g, 69%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[CH2:6]([OH:11])[CH2:7][CH2:8][CH2:9]O>C1C=CC=CC=1>[C:1]([O:5][CH2:9][CH2:8][CH2:7][CH2:6][O:11][C:1](=[O:4])[C:2]#[CH:3])(=[O:4])[C:2]#[CH:3]
Reactant: OCCCCO
Reactant: C#CC(=O)O
Solvent: c1ccccc1
Product: C#CC(=O)OCCCCOC(=O)C#C

Procedure:
The 1,4-butanediol dipropiolate was prepared as follows. A solution of 27.5 g. (0.393 mole) of propiolic acid in 75 ml of benzene was reacted with 16.07 g. (0.179 mole) of 1,4-butanediol in the presence of 1.5 g. paratoluenesulfonic acid as a catalyst. The reaction mixture was stirred and heated to reflux under nitrogen until 6.44 g. of water was azeotroped over into a Dean-Stark trap. The reaction mixture was washed with 10% sodium carbonate aqueous solution until the pH value of the mixture was basic, then washed with deionized water several times and dried over sodium carbonate. The solvent was removed on a Rotavapor and 1,4-butanediol dipropiolate was obtained in 90% yield as white crystals with a melting point of 59° C. The structure of 1,4-butanediol dipropiolate is as follows:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH3:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25].O>CC(C)=O>[CH2:17]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH:25][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH3:16]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: CCOCCOCCCN
Solvent: CC(C)=O
Solvent: O
Product: CCOCCOCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Yield: 87.3 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 3-[(2-ethoxy)ethoxy]-1-propylamine (4.41 g, 0.030 mol) was heated at 140° C. for 5 hours. The reaction mixture was dissolved in acetone (20 mL) and the solution poured into water (120 mL). The solid that formed was collected by filtration and dried under ambient conditions to give 3.0 g (87%) of material. Recrystallization from isooctane gave 2.45 g of the product; mp 65°-66° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=5)[C:24]([O:26]C)=[O:25])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>CO.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=5)[C:24]([OH:26])=[O:25])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.2 %

Procedure:
To a solution of example 53 (0.190 g, 0.480 mmol) in methanol (2.7 ml), lithium hydroxide (0.201 g, 4.80 mmol) in water (0.75 ml) was added and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as brown solid (0.070 g, 38%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.39 (s, 1H), 8.87 (d, J=2.6 Hz, 1H), 8.77 (s, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.39 (m, 2H), 8.16 (d, J=8.7 Hz, 1H), 8.07 (m, 3H). 7.85 (dd, J=8.7, 1.5 Hz, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.52 (dd, J=8.3, 4.1 Hz, 1H), 6.22 (s, 2H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N[C:24]1C=CC=CC=1>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[CH:24]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1ccccc1
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccccc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using aniline instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.03 (s, 3H), 2.19 (s, 3H), 4.48 (d, J=5.8 Hz, 2H), 6.88 (t, J=7.5 Hz, 1H), 6.95 (bs, 1H), 7.11 (bs, 2H), 7.20 (t, J=6.2 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.52 (bs, 2H), 7.69 (t, J=6.9 Hz, 1H), 7.90 (s, 1H), 8.51 (d, J=4.3 Hz, 1H); MS (ESI) m/z 306.1 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH:21]=2)=[CH:4][C:5](=[O:19])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([OH:13])=O)[CH:7]=1.FC1C(C2C=CC(N3N=CC=N3)=CC=2)=CC(=O)N(CC[C@@](C)(S(C)(=O)=O)C([NH:44][O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)=O)C=1>>[F:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH:21]=2)=[CH:4][C:5](=[O:19])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([NH:44][O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)=[O:13])[CH:7]=1
Reactant: C[C@@](CCn1cc(F)c(-c2cccc(Oc3nccs3)c2)cc1=O)(C(=O)O)S(C)(=O)=O
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Product: C[C@@](CCn1cc(F)c(-c2cccc(Oc3nccs3)c2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Yield: 65.8 %

Procedure:
The title compound (115 mg, 65.8%) was prepared as an off-white solid from (2R)-4-{5-fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoic acid (144 mg, 0.31 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 26, Step D. MS (LCMS) m/z 566.2 (M−1).
Reaction SMILES: C([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=O)C.[ClH:16]>O>[ClH:16].[OH:7][CH:6]1[O:8][C@H:9]([CH2:14][OH:15])[C@@H:10]([OH:13])[C@H:11]([OH:12])[C@H:5]1[NH2:4]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: O
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 70 °C
Yield: 161.2 %

Procedure:
The apparatus for this test consisted of a 1 liter round bottom vessel heated with a heating mantel. The ingredients, 150 grams of water, 21 g of 98% N-acetylglucosamine and 238 grams of 36.7% hydrochloric acid, were mixed together and added to the reaction vessel. The stirred reaction mix was heated up to 70° C. and mixed for 3 hours at which time the mixture was transferred to a beaker and cooled to 20° C. Few crystals were present. The mixture was transferred back into the reaction vessel and 10 grams of N-acetylglucosamine added. The reactor was reheated to 70° C. and reacted for 3 hours, cooled to 4° C. overnight. The crystals present were filtered and washed with ethanol, vacuum dried and assayed (20 g of glucosamine hydrochloride at 99.9%). The filtrate was transferred back into the reaction vessel and 10 g of N-acetylglucosamine were added. The reactor was again heated to 70° C., reacted for 3 hours, cooled overnight to 4° C., filtered, ethanol washed, vacuum dried and assayed (16.1 g of glucosamine hydrochloride at 99.6%). The filtrate was again returned to the reactor, 41.5 grams added and the reaction cycle repeated. Thirty-three grams of glucosamine hydrochloride resulted from the 4th cycle with an assay of 99.5%. The total yield was 86% with all the glucosamine hydrochloride produced 99+ in assay and white in color. This material did not need recrystallization.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Yield: 79.3 %

Procedure:
To a solution of the product of step (iv) (100 g, 0.45 mol) in DMF (350 mL) was added TEA (129 mL, 0.91 mol) and 3-aminopyridine (42.3 g, 0.45 mol). HATU (174 g, 0.45 mol) was added to the solution portionwise. The suspension was filtered, washed with water and dried under a reduced pressure to afford the subtitle compound (v) as a yellow solid (105 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=O)[C:5]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[N:6][CH:7]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[N:15]([OH:17])[C:9]([C:10]([F:13])([F:12])[F:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)cc1[N+](=O)[O-])C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: On1c(C(F)(F)F)nc2ncc(Cl)cc21

Procedure:
5-Chloro-3-nitro-2-(trifluoroacetamido)pyridine (2.0 grams) was hydrogenated with two moles of hydrogen in ethanol containing 0.5 gram of 5 percent palladium on carbon. The resulting reaction mixture was filtered and evaporated to separate the desired 6-chloro-1-hydroxy-2-(trifluoromethyl)-1H-imidazo-(4,5-b)pyridine compound which, after recrystallization from benzene melted at 268°-70°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.I[CH2:21][CH2:22][CH3:23].[H-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[CH2:21]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:10]=2[CH3:12])[C:6]([CH:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)=[CH:7]1)[CH2:22][CH3:23]
Reactant: COc1cc(C)c2[nH]cc(C3CCN(C)CC3)c2c1
Reactant: CCCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCn1cc(C2CCN(C)CC2)c2cc(OC)cc(C)c21
Yield: 72.2 %

Procedure:
By a method similar to Preparation 26, using 5-methoxy-7-methyl-3-(1-methylpiperidin-4-yl)-1H-indole (5.81 mmole, 1.50 g), iodopropane (5.81 mmole, 0.987 g, 0.566 mL) in THF (100 mL), potassium hydride (5.81 mmole, 0.665 g), and 18-crown-6 (0.58 mmole, 0.153 g) afforded 1.26 g (72%) of the title compound: mass spectrum (ion spray): m/z=301 (M+1);. Calculated for C19H28N2O-0.3H2O: C, 74.61; H, 9.43; N, 9.16. Found: C, 74.37; H, 9.03; N, 9.01.