Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C)C=O>[CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.[C:17]([O-:22])(=[O:23])[CH2:18][CH2:19][C:20]([O-:7])=[O:21]
Reactant: O=C1CCC(=O)O1
Agent: Nc1nc(O)c2ncn(COCCO)c2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C([O-])CCC(=O)[O-]

Procedure:
Acyclovir succinate is prepared by heating a solution of 0.2252 g of acyclovir (1 mmol) (Sigma), 0.200 g of succinic anhydride (2 mmoles) (Aldrich) and 0.14 mL of triethylamine in 15 mL of dry dimethylformamide at 60° C. in an oil bath for 21 hours. The solution was then cooled and the volatile constituents were evaporated in vacuo, and the residue was taken up in 8 mL of ice water and acidified to pH 2 with 2N HCl. A white precipitate was formed that was collected by filtration, thoroughly washed with ice water and dried in vacuo over P2O5 at 40° C. to yield 0.180 g (54 percent) of the product. The ester was then recrystallized from methanol and characterized by IR and 1H NMR spectroscopy.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#N)(=[O:4])[CH2:2][CH3:3].[OH-:13].[K+].[CH2:15]([OH:17])C>>[CH3:15][O:17][C:8](=[O:13])[C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH:6]=1
Reactant: [OH-]
Reactant: CCC(=O)c1cccc(C#N)c1
Reactant: CCO
Agent: [K+]
Product: CCC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
3-Propionyl-benzonitrile (0.61 g, 3.8 mmol) was refluxed in ethanol (5.3 mL) and KOH (0.48 g, 8.5 mmol) for 2 h. The ethanol was evaporated and the residue suspended in water (5 mL) and treated with 2N HCl (3.7 mL) to pH 1-2. The slurry was extracted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride, dried over sodium sulphate and evaporated. The residue was dissolved in methanol (3.5 mL) and treated with 97% sulfuric acid (0.26 mL). The mixture was stirred at room temperature for 16 h, then at 70° C. for 7.5 h and at 50° C. for 16 h. After evaporation of methanol, the residue was suspended in water and extracted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride, dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient) to yield 3-propionyl-benzoic acid methyl ester as an off-white solid (0.42 g, 56%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.C(#N)C.Cl.[CH3:26][O:27][NH:28][CH3:29].[OH-].[Na+]>O1CCOCC1.C(N(CC)CC)C>[CH3:26][O:27][N:28]([CH3:29])[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(CCc2ccc3ccccc3n2)cc1
Reactant: CNOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON(C)C(=O)c1ccc(CCc2ccc3ccccc3n2)cc1
Reaction time: 72 h
Yield: 84.3 %

Procedure:
To a solution of 4-(2-Quinolin-2-yl-ethyl)-benzoic acid (530 mg) in dioxane 5 ml/acetonitrile 5 ml was added triethylamine (0.60 ml) and O,N-Dimethyl-hydroxylamine hydrogen chloride (240 mg). After 72 h, the reaction mixture was poured into 1N sodium hydroxide solution and extracted with chloroform, dried magnesium sulfate, filtered and concentrated. Biotage MPLC chromatography eluting with 20-50% ethyl acetate provided the title compound (516 mg, 88%). MS: (M+H m/z=321.1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[N:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[CH2:12][CH2:11]3)=[O:14])[CH2:16][CH2:17]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=C(C1CCNCC1)N1CCN(c2ccncn2)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CCN(c2ccncn2)CC1
Yield: 26 %

Procedure:
4-[1-(4-Pyrimidinyl)piperazin-4-ylcarbonyl]piperidine (412 mg) was dissolved in dichloromethane (16 ml), cooled in an ice bath, stirred and treated dropwise with a mixture of 4-chlorophenylsulphonyl chloride (338 mg) and triethylamine (0.3 ml) in dichloromethane (16 ml). The reaction mixture was allowed to reach room temperature and stirred for 18 h before treating with saturated NaHCO3 solution. This mixture was extracted twice with dichloromethane. The combined organic extracts were washed twice with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to a yellow solid. The solid thus obtained was chromatographed through a 10 g silica "bond elut" prepacked column, eluting with 1% methanol, 1% ammonium hydroxide and 98% dichloromethane to obtain 1-(4-chlorophenylsulphonyl)-4-[1-(4-pyrimidinyl)piperazin-4-ylcarbonyl]piperidine (178 mg; 26% yield based on the amine), as a white solid, mp 125-128° C.;
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]=O)=[CH:10][C:5]=2[CH2:4][O:3]1.[N:14]1(C(OC(C)(C)C)=O)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[ClH:28].N1(CCC2C=CC3C(=O)OCC=3C=2)CCNCC1>>[ClH:28].[N:14]1([CH2:12][CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[C:2](=[O:1])[O:3][CH2:4][C:5]=3[CH:10]=2)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: Cl
Agent: O=C1OCc2cc(CCN3CCNCC3)ccc21
Product: O=C1OCc2cc(CCN3CCCNCC3)ccc21

Procedure:
5-[2-(1,4-Diazepan-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride was prepared from (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde and tert-butyl 1,4-diazepane-1-carboxylate in an analogous fashion to that described above for the synthesis of 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride (Method 1, steps C and D). MS: m/z 261 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][N:38]=1)[C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[CH3:15][C:4]1[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][N:38]=[C:30]([F:29])[CH:31]=2)[S:19][CH:20]=1
Reactant: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(N)n1
Reactant: O=C(O)c1ccnc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(NC(=O)c2ccnc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-amine (11-5, 200 mg, 0.60 mmol) in CH2Cl2 (2.0 mL) was added triethylamine (0.20 mL, 1.9 mmol) followed by 2-fluoroisonicotinic acid (107.7 mg, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (243.9 mg, 1.27 mmol) and hydroxybenzotriazole (172.0 mg, 1.27 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered, and dried under vacuum to give N-{4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-yl}-2-fluoroisonicotinamide (19, 68.4 mg) as yellow solids in 25% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.10 (s, 1 H), 8.47-8.50 (m, 2 H), 8.36-8.41 (m, 2 H), 7.96 (s, 1 H), 7.80 (s, 1 H), 7.41 (s, 2 H), 7.33 (s, 1 H), 2.13 (s, 6 H); ESI-MS: m/z 438.1 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:25]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][NH:26]1>>[O:30]=[S:25]1(=[O:31])[CH2:29][CH2:28][CH2:27][N:26]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nc2)CC1
Yield: 58 %

Procedure:
Using 6-[4-(6-bromopyridine-3-carbonyl)piperazin-1-yl]-5-methylnicotinonitrile (200 mg) described in Preparation Example 160 and isothiazolidine 1,1-dioxide (94 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (128 mg) was obtained.
Reaction SMILES: FC(F)(F)S(O[C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])(=O)=O.[NH2:15][C:16](C)([CH3:19])[CH2:17]O.C([O-])(O)=O.[Na+].CCOC(C)=O>C(Cl)Cl>[CH3:12][C@H:7]1[C:8](=[O:9])[O:10][CH2:11][C:16]([CH3:19])([CH3:17])[NH:15]1
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H]1NC(C)(C)COC1=O
Temperature: -40 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A solution of triflate 14 (5.00 g, 0.021 mol) in anhydrous CH2Cl2 (80 mL) under an N2 atmosphere, was cooled to −40° C. and was treated with a solution of 2-amino-2-methyl-1-propanol (2.5 folds, 4.68 g, 0.0525 mol) in anhydrous CH2Cl2 (10 mL). After stirring for 2 h at −40° C., the reaction mixture was warmed slowly to 0° C. then to room temperature and stirred overnight. The reaction mixture was treated with saturated aqueous NaHCO3 solution (100 mL). The organic phase was washed (water, brine), separated, and dried (Na2SO4). The aqueous layer was extracted with EtOAc (twice). The organic layer was separated, washed (water, brine) and dried (Na2SO4). The organic extracts were combined and concentrated to give a yellow oil. Column chromatography on silica gel using hexanes-EtOAc (1:2) to EtOAc gave 1.88 g (63%) of 15 as a light yellow oil: [α]23D −75° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 4.11 (s, 2H), 3.71 (q, 1H, J=6.8), 1.39 (d, 3H, J=6.8 Hz), 1.26 (s, 3H), 1.18 (s, 3H); 13C NMR (CDCl3) δ 229.2, 77.6, 49.5, 49.3, 27.2, 24.2, 18.4; LCMS (APCI) m/z 144.3 [(M+H)+, M=C7H13NO2]; Anal. (C7H13NO2) calcd: C, 58.72; H, 9.15; N, 9.78. found: C, 58.60; H, 9.35; N, 9.79. Note: 1H NMR data is similar with the data reported in the literature for the racemic compound (Koch, T. H.; Olesen, J. A.; DeNiro, J., J. Am. Chem. Soc. 1975, 97, (25), 7285-7288).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([C:36](=[O:38])[CH3:37])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4ccccc4)CC3)n1-2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ccccc3)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenyl-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.090 g, 0.22 mmol) and triethylamine (0.063 ml, 0.46 mmol) in dichloromethane (5 ml) was added acetyl chloride (0.017 ml, 0.24 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.082 g, 90%) as white solid. MS m/e: 421 (M+H+)
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:22][C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]2[N:11]=1)[CH3:2].CN(C=O)C.[H-].[Na+].[CH3:30][O:31][CH2:32]Cl>O>[CH3:30][O:31][CH2:32][N:22]1[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=[C:12]2[N:11]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[S:3][CH2:1][CH3:2]
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2[nH]1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1COC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (98 mg) and DMF (6 ml), 60% of sodium hydride (in oil) (29 mg) and chloromethyl methyl ether (25 μl) were sequentially added under ice-cooling. The mixture was heated room temperature, and stirred for 4 hours. Then, water was poured thereinto, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 72 mg of 3-methoxymethyl-2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 37).
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][C:25]([F:24])([F:37])[F:36])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Br)c3c2CC1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4OC(F)(F)F)c3c2CC1
Yield: 29.4 %

Procedure:
3-Benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (4.00 g, 10.8 mmol) was suspended in benzene (170 mL). 2-(Trifluoromethoxy)phenylboronic acid (4.48 g, 21.7 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.433 g, 0.617 mmol) and 2M Na2CO3 (17.6 mL) were added to the reaction mixture. Ar was bubbled through the reaction mixture for 20 min. The reaction mixture was heated at reflux for 11 h. After cooling, the reaction mixture was concentrated. The residue was combined with EtOAc (250 mL) and H2O (400 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product (7.95 g) was recrystallized from CH3OH to yield 3-benzoyl-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.43 g). The crude product from the mother liquors was chromatographed (SiO2 250 g, eluted with 2:1 toluene:EtOAc) to give 3-benzoyl-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (5.21 g). The yield of the reaction was 87%. IR (diffuse reflectance) 3266, 3227, 3187, 1615, 1574, 1498, 1483, 1464, 1428, 1382, 1354, 1334, 1323, 1288, 1253, 1221, 1202, 1167, 926, 790, 767, 750, 732, 704, 626 cm−1; MS (ESI+) for C26H21F3N2O2 m/z 450.9 (M+H)+; Anal. Calcd for C26H21F3N2O2: C, 69.32; H,4.70; N, 6.22; found: C, 69.25; H, 4.78; N, 6.25.
Reaction SMILES: N1C[CH:3]([CH2:5][N:6]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH:8]=[N:7]2)C1.S(=O)(=O)(O)O.[OH2:26].[CH3:27][OH:28]>>[F:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([C:9]3[CH:8]=[N:7][N:6]([CH2:5][C:3]([O:28][CH3:27])=[O:26])[CH:10]=3)=[CH:12][NH:13]2)=[CH:18][CH:17]=1
Reactant: O
Reactant: CO
Reactant: Fc1ccc2c(-c3cnn(CC4CNC4)c3)c[nH]c2c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cn1cc(-c2c[nH]c3cc(F)ccc23)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of 2-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)acetic acid (Example 6; 100 mg; 0.39 mmol) in MeOH (10 mL) was added concentrated sulfuric acid (0.02 mL; 0.39 mmol). The mixture was stirred at 85° C. overnight, cooled to r.t., poured into water, extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by preparative TLC (petroleum ether/EtOAc=1/1) to afford 33 mg (31%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].O1CCCC1.CO>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7](/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(=O)/C=C(\C)c1ccc(N)cc1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 93.4 %

Procedure:
Compound 19a (929 mg), iron powder (1.97 g), and ammonium chloride (436 mg) were added to a mixed solution of tetrahydrofuran (4 ml), methanol (4 ml), and water (4 ml). The obtained mixture was stirred at 70° C. for 3.5 hours. The mixture was allowed to cool and then filtered. The filtrate was separated with ethyl acetate and water. The organic layer was sequentially washed twice with water and once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (17%-33% ethyl acetate/n-hexane) to obtain Compound 19b (757 mg, 96%) as an orange solid. 1H-NMR (CDCl3) δ7.35 (2H, d, J=8.7 Hz), 6.65 (2H, d, J=8.7 Hz), 6.09 (1H, s), 4.19 (2H, q, J=7.1 Hz), 3.85 (2H, brs), 2.54 (3H, s), 1.30 (3H, t, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12]O)[CH3:9].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:8]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: CCN(CC)CCO
Reactant: Nc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCN(CC)CCNc1ccccc1
Yield: 75 %

Procedure:
93 parts of aniline, 180 parts of 2-diethylaminoethanol and 10 parts of triphenyl phosphite are heated for 20 hours at 210° C in a stirred autoclave. The autoclave is then let down and the water of reaction formed, the excess aniline and the unconverted aminoalcohol are distilled under reduced pressure. 144 parts of N-(β-diethylaminoethyl)-aniline, corresponding to a yield of 75% of theory, distil at a boiling point of 185° - 187° C/15 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:37]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH2:38]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:38][CH2:37][S:39]([CH3:42])(=[O:41])=[O:40])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: C=CS(C)(=O)=O
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCS(C)(=O)=O)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL), was added methyl vinyl sulfone (38 mg, 0.36 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to afford 5-Chloro-N2-(2-fluoro-5-methyl-4-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:15]([CH3:16])=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33].N>C1COCC1.CO>[CH3:1][C:2]1[C:15]([CH3:16])=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:32](=[O:33])[CH2:31][O:30][CH3:29])[CH:6]=1
Reactant: COCC(=O)Cl
Reactant: Cc1c(Oc2ccnc(N)c2)ccc([N+](=O)[O-])c1C
Agent: N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c(C)c2C)ccn1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a suspension of 4-(2,3-dimethyl-4-nitrophenoxy)pyridin-2-amine (110 mg, 0.424 mmol) in THF (3.0 mL) containing DIPEA (370 μL, 2.12 mmol) at 0° C. was added 2-methoxyacetyl chloride (155 μL, 1.70 mmol) in a single portion. The reaction mixture was warmed to RT for 1 hr and a solution of NH3 in MeOH (7M, 2.0 mL) was added and the resulting mixture maintained at RT for 16 hr and then evaporated in vacuo. The residue was partitioned between DCM (50 mL) and brine (40 mL) and the organic phase was seprated and dried (MgSO4) and was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 20-50% EtOAc in isohexane, gradient elution) to afford N-(4-(2,3-dimethyl-4-nitrophenoxy)pyridin-2-yl)-2-methoxyacetamide (94 mg, 67%) as an orange oil; Rt 2.14 min (Method 2); m/z 332 (M+H)+ (ES+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([F:26])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.ClC([O:30][C:31]1C=CC=CC=1)=O.Cl.[CH3:38][NH:39][CH3:40]>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[CH3:38][N:39]([CH3:40])[C:31](=[O:30])[NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([F:26])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)c(F)c2)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
To a solution of benzyl [4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]carbamate (163 mg, 0.461 mmol) in tetrahydrofuran (4.50 ml) was added triethylamine (0.128 ml, 0.918 mmol), and then phenyl chloroformate (0.0872 ml, 0.695 mmol) was added dropwise thereto, followed by stirring at room temperature for 10 min. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (2.0 ml), dimethylamine hydrochloride (188 mg, 2.31 mmol) and triethylamine (0.386 ml) were then added, followed by stirring at room temperature for 8 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with brine (30 ml×3), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=20:1) to provide the titled compound (165 mg, 47.5%) as pale yellow powder.