Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[Cl:24][C:25](OC(Cl)(Cl)Cl)=[O:26]>C1COCC1>[O:12]=[C:9]1[N:8]([C:25]([Cl:24])=[O:26])[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cl)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of (R)-(−)-4-phenyl-2-oxazolidinone in THF (200 mL) at 0° C. was slowly added a 2.5 M solution of butyllithium in hexane (19 mL, 0.03 mol). The mixture was stirred at 0° C. for 30 min and then cooled to −78° C. Trichloromethyl chloroformate (7.8 mL, 0.03 mol) was added quickly in one portion and the reaction solution was stirred at −78° C. for 30 min. The resulting mixture was allowed to warm to room temperature, and was subsequently concentrated in vacuo. The resulting residue was taken up in CH2Cl2 (200 mL) and filtered, and the filtrate was concentrated in vacuo to afford the title compound as an off-white solid (4.5 g, 65%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:5][C:6]1[CH:7]=[C:8]2[C:14]([C:17](=[O:18])[CH2:16][Cl:15])=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1c[nH]c2ncc(Br)cc12
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a suspension of AlCl3 (3.38 g, 25.38 mmol) in dichloromethane (100 mL) was added 5-Bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5.07 mmol). After stirring for 30 min, chloroacetyl chloride (2.84 g, 25.38 mmol) was added and the reaction mixture was stirred for 2 hours at room temperature. On completion, solvents were evaporated and quenched with aq. NaHCO3 solution at 0° C. Resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and filtered through a plug of silica gel. Solvent was evaporated to dryness to give 1-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-chloro-ethanone (1.3 g, 93% yield).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20](O)=[O:21])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:27])=O.CN(C)C=O.Cl>ClCCl>[C:1]1([N:7]([C:14]2[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([Cl:27])=[O:21])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
A 50 mL round bottom flask equipped with a magnetic stirrer and a nitrogen inlet-outlet was charged with 4-(N,N-diphenylamino)cinnamic acid (1.0 g, 3.2 mmol) in 15 mL dichloromethane. Thionyl chloride (0.35 mL, 4.8 mmol) was added followed by 12.4 □L N,N-dimethylformamide. Hydrogen chloride gas evolution began immediately and then ceased within one hour of stirring. The solution was stirred for 3 h and then concentrated on a rotary evaporator. The product was transferred to a high vacuum line and residual solvent was removed under vacuum. The product was obtained as a brown solid and stored under nitrogen without any further purification.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:17]([NH:19][C:20]1([C:29]#[N:30])[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]1)=[O:18]>>[C:29]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]1)#[N:30]
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared starting from 3-chloro-benzo[d]isothiazole 1,1-dioxide and 2-amino -N-(-4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamide bis hydrochloride salt according to the procedure from Example 10, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to acetonitrile. MS, m/z 486=M+1.
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.Cl>C1COCC1.C(OCC)(=O)C>[OH:18][C:19]1([C:6]2[NH:5][CH:9]=[CH:8][N:7]=2)[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1
Reactant: CCOC(OCC)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ncc[nH]2)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
A mixture of imidazole (25.6 g, 0.4 mol), triethyl orthoformate (236.8 g, 1.6 mol) and p-toluenesulfonic acid (2 g) was heated at 130° C. overnight with no condenser so ethanol can boil off. The excess orthoformate was removed by rotary evaporation and the residue was purified by vacuum distillation to give 1-(diethoxymethyl)-1H-imidazole (46.7 g). To a solution of the resulting protected imidazole (46.7 g) in anhydrous THF (350 mL) under N2 cooled at −40° C., was added n-butyllithium (2.5 M in hexane, 110 mL) at such a rate that the temperature did not rise above −35° C. After complete addition, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (18.25 g, 91.5 mmol) in anhydrous THF (70 mL) under N2 was added dropwise over 10 minutes keeping the temperature below −40° C. The reaction was stirred at 40° C. for 2 hours then 350 mL of 0.1 N HCl added and stirred for 15 minutes, ethyl acetate (350 mL) added and stirred for 5 minutes. The organic layer was separated and aqueous extracted with ethyl acetate (350 mL). The combined organic layers were washed with saturated NaHCO3, brine, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with 10% methanol in ethyl acetate with 0.5% ammonia hydroxide to give tert-butyl 4-hydroxy-4-(1H-imidazol-2-yl)piperidine-1-carboxylate (10.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>>[Br:15][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nccc(C)n2)cc1
Product: Cc1ccnc(-c2ccc(CBr)cc2)n1

Procedure:
Reaction of this 2-(4-methylphenyl)-4-methylpyrimidine with N-bromosuccinimide, as described in Example 15, affords 2-(4-bromomethylphenyl)-4-methylpyrimidine with a melting point of 104°-106° C. after recrystallisation from ligroin. A mixture of 105 g of 2-(4-bromomethylphenyl)-4-methylpyrimidine and 265 g of triethylphosphite is slowly heated, with stirring, to 150° C., while simultaneously distilling off ethyl bromide, and then stirred for 5 hours at this temperature. After distilling off excess triethylphosphite, the phosphate is obtained in a yield of 125 g in the form of a light brown viscous oil.
Reaction SMILES: ClCCl.[C:4]1([CH2:22][OH:23])[S:5][CH:6]=[C:7]2[C:13]=1[C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[S:10][C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=1>C(OCC)C>[C:4]1([CH:22]=[O:23])[S:5][CH:6]=[C:7]2[C:13]=1[C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[S:10][C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=1
Reactant: OCc1scc2c1-c1ccccc1Sc1ccccc1-2
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1scc2c1-c1ccccc1Sc1ccccc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a dichloromethane solution of the alcohol 15 (3.0 mmoles in 40 ml) dipyridine-chromium-(VI)-oxide (pyridinyl dichromate, PDC, 0.006 mole) was added. The reaction mixture was stirred at room temperature for 18 hours. Diethyl ether (50 ml) was added to the reaction mixture and the thus diluted reaction mixture was purified on a Florisil column to give a yellow crystal product.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10](=[O:19])[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:18].N1C=CC=CC=1.Cl>ClCCl>[CH3:8][O:9][C:10](=[O:19])[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1c(C)cccc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(C)cccc1NC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.4 %

Procedure:
Add isopropyl chloroformate (19.8 mL, 19.8 mmol, 1.0 M in toluene) dropwise to a solution of 2-Amino-6-methyl-benzoic acid methyl ester (3.27 g, 19.8 mmol) and pyridine (4.0 mL, 50 mmol) in dichloromethane (39 mL) at 0° C. under an atmosphere of nitrogen and stir at room temperature for 14 h. Add 1M HCl and separate the layers. Extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (3.80 g, 76%): 1H NMR (CDCl3) δ 1.29 (d, J=6.5 Hz, 6H), 2.43 (s, 3H), 3.94 (s, 3H), 5.00 (septuplet, J=6.5 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 7.32 (t, J=8.1 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 8.86 (brs, 1H). MS (ES+): 252 (M+H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[CH3:14][O:15][NH:16][CH3:17].[CH2:18]([O:25][C:26]([N:28]1[CH2:32][C@H:31]([O:33][Si:34]([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@@H:29]1[C:51]([OH:53])=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:47]([Si:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[O:33][C@H:31]1[CH2:32][N:28]([C:26]([O:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:27])[C@@H:29]([C:51](=[O:53])[N:16]([O:15][CH3:14])[CH3:17])[CH2:30]1)([CH3:48])([CH3:49])[CH3:50]
Reactant: CNOC
Reactant: CC(C)(C)[Si](O[C@@H]1C[C@H](C(=O)O)N(C(=O)OCc2ccccc2)C1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)[C@H]1C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.50 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 761 mg of O,N-dimethylhydroxylamine hydrochloride were added in order to a pyridine (30 ml) solution of 2.62 g of (2R,4R)-4-(tert-butyl-diphenyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester obtained in (step 1), and the reaction liquid was stirred overnight at room temperature. The solvent of the reaction liquid was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound.
Reaction SMILES: [CH:1]1[C:6](Br)=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][OH:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.O>[N:14]1[CH:19]=[CH:18][C:17]([C:6]2[CH:5]=[C:4]3[C:3](=[CH:2][CH:1]=2)[NH:10][CH:9]=[C:8]3[CH2:11][CH2:12][OH:13])=[CH:16][CH:15]=1
Reactant: OCCc1c[nH]c2ccc(Br)cc12
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1c[nH]c2ccc(-c3ccncc3)cc12

Procedure:
5-Bromotryptophol (1.05 g, 4.39 mmol; see Table 1 and 2) and pyridine-4-boronic acid (10 mg, 6.59 mmol) were suspended in tetrahydrofuran (65 ml), and Na2CO3 solution (4.65 g, 43.9 mmol) in 44 ml of H2O) were added. Bistriphenylphosphinepalladium dichloride (456.2 mg, 0.65 mmol) was then added. The reaction mixture, which was clear when hot, was boiled at 65° C. for 14 h, while stirring. The course of the reaction was monitored by TLC. For working up, the reaction solution was filtered. The filtrate comprised two phases. The organic phase was separated off. The solvent was distilled off on a rotary evaporator. The viscous residue was purified by flash chromatography [silica gel 60 (45 g); eluent: EtOAc (800 ml)].
Reaction SMILES: [CH3:1][O:2][C:3]1([O:18][CH3:19])[C:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:6](=[O:17])[CH:5]=[CH:4]1.[OH:20]O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1([O:18][CH3:19])[C:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:6](=[O:17])[CH:5]2[CH:4]1[O:20]2
Reactant: OO
Reactant: COC1(OC)C=CC(=O)C=C1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC1(OC)C(NC(=O)OC(C)(C)C)=CC(=O)C2OC21
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Compound 3 (3.4 g, 12.7 mol) in tetrahydrofuran (93 mL) was cooled in an ice bath. To the stirring solution, in drop-wise fashion, was added hydrogen peroxide (30% aq., 22 mL) and aqueous sodium hydroxide (1M, 61 mL) in tandem using 2 separate addition funnels and utilizing a Claisen adapter. The reaction mixture was stirred for 30 minutes in the ice bath and then for 5 hours at room temperature. The flask was cooled in an ice bath and the peroxide was carefully quenched with manganese dioxide. After filtration of the mixture over a small bed of silica gel followed by rinsing of the silica gel with ethyl acetate, the mixture was washed with brine. The organics were then dried over anhydrous magnesium sulfate, filtered, and evaporated. The resulting oil was treated with pentane to precipitate an off white solid after solvent evaporation yielding 2 g (56%) of compound (4). 1H NMR indicated 20% starting material in the mixture, which was easily removed in the next step (treatment with TFA). The 1H NMR of the product was consistent with that reported in the literature (Synthesis 1998, 775).
Reaction SMILES: C(OC([N:8]1[CH2:18][CH:17]2[N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:10]([CH2:11][C:12]3[NH:13][N:14]=[CH:15][C:16]=32)[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:19]2[CH:10]3[CH2:9][NH:8][CH2:18][CH:17]2[C:16]2[CH:15]=[N:14][NH:13][C:12]=2[CH2:11]3)(=[O:21])=[O:22])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CNCC1c1cn[nH]c1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12-(4-Chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid tert-butyl ester (207 mg, 0.471 mmol) was covered with HCl in dioxane (4 N, 2 mL). The reaction mixture was stirred at room temperature for 2 h after which it was concentrated under vacuum and purified by preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene as a white solid. Retention time (min)=1.125, method [1], MS(ESI) 339.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.2 Hz, 2H), 7.30-7.25 (m, 3H), 5.09 (s, 1H), 4.35-4.14 (m, 1H), 3.25-3.18 (m, 2H), 2.98 (d, J=13.7 Hz, 1H), 2.77 (dd, J=17.0, 7.1 Hz, 2H), 2.55 (d, J=17.0 Hz, 1H)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][NH:25]4)=[CH:21][C:20]=3[O:28][CH3:29])[NH:15][C:14]3=[N:30][CH:31]=[CH:32][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5].C1N=[CH:36][N:35]([C:38](N2C=NC=C2)=[O:39])[CH:34]=1.CN>C1COCC1.CCOC(C)=O>[NH2:6][C:4]([C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:11][C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:27]=[C:26]3[C:22]([CH2:23][CH2:24][N:25]3[C:38]([N:35]([CH3:36])[CH3:34])=[O:39])=[CH:21][C:20]=2[O:28][CH3:29])[NH:15][C:14]2=[N:30][CH:31]=[CH:32][C:13]=12)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)NCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)N(C)C)CC2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
A mixture of of 2-fluoro-6-[(2-{[5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (67 mg, 0.15 mmol) and CDI (30 mg, 0.18 mmol) in THF (4 mL) was stirred for 15 min, then treated with a solution of methylamine (2M in THF, 4 mL, 8 mmol) and was heated for 2 days in a sealed vessel at 80° C. More methylamine (2M in THF, 5 mL) was added and the reaction mixture was heated for 22 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (50 mL), washed with a saturated Na2CO3 solution (50 mL), water (50 mL) and a saturated NaCl solution (50 mL). The aqueous layers were back extracted with EtOAc (50 mL). The organic layers were combined and concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 6-[(4-{[2-(aminocarbonyl)-3-fluorophenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-N,N-dimethyl-5-(methyloxy)-2,3-dihydro-1H -indole-1-carboxamide as a yellow solid (43 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83 (s, 6H), 2.94 (t, J=8.06 Hz, 2H), 3.73-3.86 (m, 5H), 6.18-6.28 (m, 1H), 6.84-6.95 (m, 2H), 6.97 (s, 1H), 7.31-7.42 (m, 1H), 7.47 (s, 1H), 7.82 (s, 1H), 8.01 (s, 1H), 8.07 (s, 1H), 8.41 (d, J=8.24 Hz, 1H), 10.47 (s, 1H), 11.21 (s, 1H); ESIMS (M+H)+=505.15.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
76.5 mg of solid brown 3-{4-[3-(4-fluoro-3-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-fluoro-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1>C(Cl)(Cl)Cl>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[CH:4]=[C:3]5[O:2][CH2:1][O:13][C:12]5=[CH:11][C:10]4=[N:9][CH:8]=3)[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1cc(I)c(C(=O)N(CCN(C)C)c2ccnc3cc4c(cc23)OCO4)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)n(CCN(C)C)c3c4cc5c(cc4ncc3c2cc1OC)OCO5
Yield: 41 %

Procedure:
Prepared from N-(6,7-Methylenedioxyquinolin-4-yl)-N—(N,N-dimethylaminoethyl)-2-iodo-4,5-dimethoxybenzamide; (41% yield); reaction time 25 min; mp 283-285° C. (dec.); IR (CHCl3) 1653; 1H NMR (CDCl3) δ 2.33 (s, 6H), 3.04 (t, 2H, J=7.2), 4.07 (s, 3H), 4.14 (s, 3H), 4.64 (t, 2H, J=7.2), 6.18 (s, 2H), 7.47 (s, 1H), 7.68 (s, 1H), 7.89 (s, 2H), 9.37 (s, 1H); 13C NMR (CDCl3) δ 45.9, 49.2, 56.3, 56.3, 57.9, 101.2, 102.0, 102.3, 107.1, 108.8, 111.7, 114.8, 119.3, 127.6, 140.9, 143.5, 147.3, 147.7, 149.9, 150.3, 154.2, 164.1; HRMS calcd for C23H23N3O5H, 422.1716; found 422.1710.
Reaction SMILES: C1(S([N:10]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]2[C:19]([O:21][CH3:22])=[O:20])(=O)=O)C=CC=CC=1.C[O-].[Na+].Cl>CO>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:13]=[CH:14][NH:10][C:11]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1c(C(F)(F)F)ccn1S(=O)(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1[nH]ccc1C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of the product prepared in Step A (704 mg, 1.9 mmol, 1 eq) in methanol (10 mL) was added a solution of NaOMe in MeOH (2.46 mL of a 25% solution, 10.6 mmol, 5.6 eq). After 1 hr, 1 N HCl was added, the aqueous was extracted with diethyl ether, washed with brine, dried over MgSO4 and concentrated to yield methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][CH:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: CC(NC(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(NC(=O)c1ccc(N)cc1)c1ccccc1

Procedure:
A solution of 5 g (0.018 mole) of 4-nitro-N(alpha-methylbenzyl)-benzamide (#3) in 200-ml of absolute ethanol was added to a Paar hydrogenation bottle. To the solution was added a 0.4 g sample of 5% palladium on charcoal and the bottle placed on a Paar low-pressure hydrogenation apparatus. The mixture was shaken at room temperature in the presence of 45 p.s.i. of hydrogen for 2.5 hours. The catalyst was then removed by filtration through celite and the ethanol evaporated to yield the desired compound, 4-amino-N-(alpha-methylbenzyl)-benzamide (#4). Recrystallization from benzene produced the compound in pure form.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C@H:18]([OH:27])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:12]=2)[CH:7]=1.[CH3:29][NH2:30]>CO>[CH3:29][NH:30][C:3](=[O:2])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C@H:18]([OH:27])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2cc(OC[C@H](O)CCc3cccnc3)ccc2c1
Reactant: CN
Solvent: CO
Product: CNC(=O)COc1ccc2cc(OC[C@H](O)CCc3cccnc3)ccc2c1

Procedure:
A solution of 6-((2R)-2-hydroxy-4-(3-pyridyl)-1-butoxy)naphthalen-2-yloxyacetic acid methyl ester (0.215 g) in methanol (10 ml) was saturated with methylamine gas. After 16 hours the crystalline product was collected by filtration and dried under vacuum to give the title compound as a solid (0.10 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][C@H:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[N:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27]>CN1C(=O)CCC1.CCOC(C)=O>[O:29]=[C:28]1[NH:26][N:27]=[C:1]([C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([NH:13][C@H:14]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]4)[N:12]=2)[N:9]=[CH:8][CH:7]=[CH:6]3)[NH:2]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3cccnc23)C1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccnc23)C1
Temperature: 175 °C
Yield: 32.5 %

Procedure:
To (S)-tert-butyl 3-((6-cyano-1,7-naphthyridin-8-yl)amino)pyrrolidine-1-carboxylate (210 mg, 0.619 mmol) in NMP (1.5 mL) was added ethyl hydrazinecarboxylate (258 mg, 2.475 mmol). The reaction mixture was heated at 175° C. for 2 days and was then cooled, diluted with EtOAc, and washed with aqueous NH4Cl. The organic phase was dried and concentrated. The crude product was purified by preparative HPLC eluting with a gradient of 35-60% ACN in water (acid mode) to give the title compound (80 mg, 33%).