Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(/N=[CH:6]/[C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:15])CCC.S(=O)(=O)(O)[OH:17]>O.C(OCC)(=O)C>[Cl:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:7]=1[CH:6]=[O:17]
Reactant: O=S(=O)(O)O
Reactant: CCCC/N=C/c1c(Cl)cccc1CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cccc(Cl)c1C=O
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 19.7 g (88.1 mmol) butyl-[1-(2-chloro-6-ethyl-phenyl)-meth-(E)-ylidene]-amine in 70 ml water at 0° C. was added dropwise 18.9 ml concentrated sulphuric acid. The mixture was then heated at reflux for 90 min before being cooled to room temperature and diluted with ethyl acetate. The mixture was then washed sequentially with water, saturated aqueous sodium bicarbonate solution, and saturated brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane 1:30) to afford 11.4 g (77%) of the title compound as a yellow oil. 1H-NMR (CDCl3): 1.22 (3H, t, CH3), 2.97 (2H, q, CH2), 7.20 (1H, d, ArH), 7.30 (1H, d, ArH), 7.39 (1H, dd, ArH), 10.65 (1H, s, CHO).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:42])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]4[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]4)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:41]=[S:37]1(=[O:40])[CH2:38][CH2:39][N:34]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:25]([C:22]3[CH:23]=[CH:24][C:19]([C:10]4[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=4[O:14][C:15]([F:18])([F:16])[F:17])=[CH:20][CH:21]=3)=[O:42])=[CH:32][CH:31]=2)[CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)cc2)c1
Yield: 89.5 %

Procedure:
{4′-[4-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylcarbamoyl]-6-trifluoromethoxy-biphenyl-3-yl}-carbamic acid tert-butyl ester (140 mg) was stirred in 1:1 trifluoroacetic acid:dichloromethane (6 ml) at 20 C for 1 h. The mixture was then basified and extracted with ethyl acetate. The dried extracts were then evaporated giving a dark gum (105 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19]>CN(C)C=O>[CH2:7]([S:10][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[CH2:8][CH3:9]
Reactant: O=C(c1cccs1)c1ccccc1Cl
Reactant: CCCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1ccccc1C(=O)c1cccs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cloudy solution of 400 mL of dry dimethylformamide containing 224 g or potassium-t-butoxide, cooled to 0° under a nitrogen atmosphere, was added 18 mL of n-propanethiol dropwise at such a rate to maintain the temperature below 5° C. The resulting mixure was stirred for 5 minutes and then a solution of 44 g of the product of Example 1 dissolved in 100 mL of dimethylformamide was added. The reaction mixture was stirred for 24 hours at room temperature, poured into 2 L of ice-water and extracted with methylene chloride. The organic layer was separated, washed with 1N NaOH (aq), water, and dried (MgSO4). Filtration, followed by concentration of the filtrate in vacuo gave a dark residue which after column chromatography on silica (methylene chloride as eluant) provided 40 g of the subject compound as a red oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:35]([O:37][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:36]>>[CH3:40][C:39]([CH3:42])([CH3:41])[CH2:38][O:37][C:35]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:36]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)COC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2,2-dimethyl-propyl ester was prepared according to General Procedure E by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoro-acetate salt (Intermediate 27) with 2,2-dimethylpropyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 0.93 (s, 9H), 1.98-2.01 (m, 4H), 3.00-3.10 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.70-3.80 (m, 2H), 4.14-4.17 (m, 2H), 5.03-5.09 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.37 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=488.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:47])[N:29]([CH:44]([CH3:46])[CH3:45])[CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:47])[N:29]([CH:44]([CH3:45])[CH3:46])[CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[N:27]=2)[CH2:20]1
Reactant: CC(C)N(CC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N(CC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 82.8 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[N-isopropyl-N-(p-nitrobenzyloxycarbonylmethyl)carbamoyl]-1,3-thiazol-2-yl}azetidine (1.81 g, 2.69 mmol) (obtained as described in Reference Example 48(4)) in anhydrous tetrahydrofuran (90 ml) were added acetic acid (0.18 ml, 3.23 mmol) and a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (3.23 ml, 3.23 mmol) in an ice bath. The mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:ethyl acetate (1:1) as the eluant to afford 3-hydroxy-1-{4-[N-isopropyl-N-(p-nitrobenzyloxycarbonylmethyl)carbamoyl]-1,3-thiazol-2-yl}azetidine (968 mg, yield 83%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([NH:14]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:34])[CH:4]([NH2:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1
Reactant: COC(=O)C(COc1ccc(Br)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
The compound obtained in step b above (22b) (2.21 g, 4.10 mmol) was stirred in TFA (8 mL) and CH2Cl2 (10 mL) at 0° C.→rt for 1 h, the solvent was removed under vacuum. MeOH (10 mL) was added and then NaHCO3 (344 mg, 4.10), the mixture was stirred at room temperature for 4 h and then concentrated. The residue was dissolved in CH2Cl2 and washed with brine, dried and concentrated to give crude title compound (1.07 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[C:14]([O:18][C:19](=[O:30])[NH:20][CH:21]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:22]=O)([CH3:17])([CH3:16])[CH3:15].O>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:22][CH:21]([NH:20][C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:30])[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)NC(C=O)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=CC(NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of trimethyl phosphonoacetate (19 mL, 0.11 mol) in THF (200 mL) was added 60% NaH (3.1 g, 0.08 mol) in portions. The ice bath was removed and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then cooled to 0° C. before a solution of (1-cyclohexyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (9 g, 37 mmol) in THF (200 mL) was added. The reaction mixture was stirred at room temperature for another 20 min. Water (100 mL) was added, and then most of the THF was evaporated. The product was extracted with EtOAc (400 mL), and the organic layer was washed with aqueous NaCl solution and then dried with MgSO4. Evaporation yielded a residue which was purified by column chromatography (1:1 heptane:EtOAc) to yield 4-tert-butoxycarbonylamino-4-cyclohexyl-but-2-enoic acid methyl ester as a white solid.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)(O)[O-].[Na+].Br[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>CN(C)C=O.O>[CH3:19][C:18]([CH3:20])=[CH:17][CH2:16][CH2:15][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC(C)=CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of 2-nitroimidazole (3.0 g, 27 mmol) in dry dimethylformamide (25 mL), was added anhydrous sodium bicarbonate (4.2 g, 50 mmol) followed by 5-bromo-2-methyl-2-pentene (5.0 g, 30.67 mmol). The reaction mixture was heated at 60-70° C. with stirring under nitrogen for 16 hours. Solvent dimethylformamide and the unreacted bromide were removed under reduced pressure (<1 mm) at 50-60° C. to yield a paste which was dissolved in water (50 mL) and extracted with ethyl acetate (5×50 mL). The combined organic extracts were dried and concentrated to give a brown oil which was recrystallized from petroleum ether (b.p. 40-60° C.) to yield a yellow solid. Yield: 4.8 g, m.p. 51-52° C. 1H NMR (CDCl3) δ1.55 (s, 3H, CH3), 1.75 (s, 3H, CH3), 2.7 (q, 2H, olefinic CH2), 4.5 (t, 2H, N—CH2), 5.2 (t, 1H, olefinic H), 7.1 (s, 1H, imidazole H), 7.2 (s, 1H, imidazole H). M.S. [M+H]+ 196, [M+NH4]+ 213.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5](N)=[O:6].[OH-:22].[Na+]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:22])=[O:6]
Reactant: NC(=O)c1cc(N)c(Oc2ccccc2)c(S(N)(=O)=O)c1
Reactant: [OH-]
Agent: [Na+]
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzamide (1 g) and 1N sodium hydroxide (20 ml) was refluxed for 1 hour. After cooling, the 3-amino-4-phenoxy-5-sulphamyl-benzoic acid was precipitated from the reaction mixture by addition of 4N hydrochloric acid until pH 2.5. After several recrystallizations from aqueous ethanol and drying, the compound was obtained with a melting point of 252°-253° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH:25]([O:28][CH3:29])[O:26][CH3:27])[CH:17]=1.O>CC(N(C)C)=O>[CH3:29][O:28][CH:25]([O:26][CH3:27])[C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23])[O:8][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
3-Amino-phenol (0.050 mol) was dissolved in DMA (100 ml). K2CO3 (0.050 mol) was added. 4-Chloro-2-dimethoxymethyl-1-nitro-benzene (0.050 mol) was added and the reaction mixture was stirred overnight at 100° C., then for 2 hours at 120° C. The reaction mixture was poured out into water and this mixture was extracted with diisopropyl ether. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2:CH3OH 100:0 (to remove starting material) up to 70:30). The desired fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[C:21]1([NH:20][S:9]([C:8]2[CH:13]=[CH:14][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:11])=[O:10])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Acetylsulfanilyl chloride 1 (55 g, 236 mmol) was added in portion to a stirring, 0° C. suspension of sodium acetate (48.4 g, 590 mmol) and aniline 2 (22 mL, 236 mmol) in ethanol (300 mL). The reaction mixture was stirred at room temperature overnight and then poured into ice-cold water (1.5 L) with vigorous stirring. After stirring for 1 h, the white solid that gradually precipitated was collected by filtration. The filter cake was washed with ice-cold water, dried under vacuum, and recrystallized from hot ethanol to give N-[4-[(phenylamino)sulfonyl]phenyl]acetamide (3) (also called 137-19 or LED137) (41 g, 60%) as a white solid, mp 209-210° C. 1H NMR (CD3OD, 400 MHz) δ 7.64 (br s, 4H), 7.18 (t, J=7.6 Hz, 2H), 7.06-7.00 (m, 3H), 2.10 (s, 3H).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[CH3:22])=O.O.[NH2:24][NH2:25]>CN(C1C=CN=CC=1)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:3]3[C:2](=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=3)[NH:25][N:24]=2)=[C:15]([CH3:22])[CH:16]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(C)c1
Yield: 41.3 %

Procedure:
Prepared as in Example 104 from [2-fluoro-3-(trifluoromethyl)phenyl](4-methoxy-2-methylphenyl)methanone (1.34 g, 4.90 mmol), hydrazine hydrate (1.61 mL, 51.7 mmol) and DMAP (0.632 g, 5.17 mmol) to give the product (0.620 g) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>CCO.O>[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:23])=[O:3])=[CH:6][CH:7]=1)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
(Scheme 3, Compound I) To a solution of 4-decanoylamino-benzoic acid ethyl ester (2.0 g, 6.6 mmol) in EtOH (30 mL) was added NaOH (10 N, 6 mL, 60 mmol). The resulting mixture was stirred at rt for 3 hours, diluted with H2O (30 mL), acidified to pH˜1.0 using HCl (6N). The precipitates were filtered off by filter paper, washed by H2O and hexanes. This compound was obtained as a white solid. (1.8 g, 6.5 mmol, 98% yield). 1H NMR (DMSO-d6) δ 9.91 (br. s, 1H), 7.76 (d, 2H, J=8.7 Hz), 6.50 (d, 2H, J=8.7 Hz), 2.29 (t, 2H, J=7.5 Hz), 1.57 (m, 2H), 1.25 (m, 12H), 0.85 (t, 3H, J=6.9 Hz). Mass Spec: 278.21 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:4][C:5]([NH:8][C:9]2[C:22]([O:23][CH3:24])=[CH:21][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][OH:20])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.C(Cl)Cl.C(N(CC)CC)C.[C:48](Cl)(=[O:51])[CH2:49][CH3:50]>>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32](=[O:34])(=[O:33])[N:35]([CH3:36])[CH3:37])=[N:4][C:5]([NH:8][C:9]2[C:22]([O:23][CH3:24])=[CH:21][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][C:48](=[O:51])[CH2:49][CH3:50])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CCO)CC2
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OCCN1CCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)c(OC)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-hydroxy-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide (80.0 mg, 0.146 mmol) was stirred in Methylene chloride (1.60 mL, 25.0 mmol) with Triethylamine (30.6 μL, 0.219 mmol) at room temperature. Propanoyl chloride (12.7 μL, 0.146 mmol) was then added quickly under nitrogen. The reaction was complete after stirring over night. The reaction mixture was washed with bicarb and extracted with XS DCM. The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on an ISCO flash system (0-10% MeOH:DCM). The desired fractions were concentrated and the product was obtained as a foam from a small amount of DCM (35 mg, 40%). mp: 40° C. softened, 60-70 glass, MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.57 (t, 1H), 7.51 (s, 1H), 7.25 (m, 1H), 6.67 (s, 1H), 4.25 (t, J=6 Hz, 2H), 3.89 (s, 3H), 2.87 (m, 2H), 2.83 (t, J=6 Hz, 2H), 2.76-2.72 (m, 12H), 2.36 (t, J=7.5 Hz, 2H), 1.17 (t, J=7.5, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[C:22]3[N:29]([CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)[CH:28]=[CH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:32][CH2:31][CH2:30][N:29]1[C:22]2[C:21]([NH:20][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:18])([F:19])[F:17])[CH:10]=4)=[C:2]([CH3:1])[CH:3]=3)=[N:26][CH:25]=[N:24][C:23]=2[CH:27]=[CH:28]1
Reactant: Cc1cc(Nc2ncnc3ccn(CCNC(=O)OC(C)(C)C)c23)ccc1Oc1cccc(OC(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2ncnc3ccn(CCN)c23)ccc1Oc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
tert-Butyl {2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (523 mg) was dissolved in dichloromethane (6.4 mL), trifluoroacetic acid (4.8 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), and washed with aqueous sodium hydrogen carbonate (40 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (420 mg) as a white powder.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[C:4]1=[O:17].[C:18]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[ClH:1].[CH:18]1([NH:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[C:9]=3[O:13][CH3:14])[C:4]2=[O:17])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc2c(c1OC)CCC(N)C2=O
Reactant: O=C1CCCC1
Agent: Cl
Product: COc1ccc2c(c1OC)CCC(NC1CCCC1)C2=O

Procedure:
In a manner similar to that of Reference Example 3, 10 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride is reacted with 300 volume parts of cyclopentanone. The procedure yields 10.2 parts of 2-cyclopentylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride as colorless crystals melting at 158°-167° C (decomposition).
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:22]1([CH2:25][C:26]([NH2:34])([CH3:33])[C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][C:26]([NH:34][C:12]([C:9]2[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:18])([F:20])[F:19])[C:6]([C:2]3([F:1])[CH2:5][O:4][CH2:3]3)=[CH:11][N:10]=2)=[O:13])([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH3:33])[CH2:24][CH2:23]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(F)COC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (Example 142b) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 66e) as starting materials and isolated (31 mg, 26%); MS (ESI, m/z): 473.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C=O)C.[Cl:15]N1C(=O)CCC1=O>C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([Cl:15])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1cccnc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-3-ethylpyridine (Wonda Science, CAS[42753-67-3]; 12.2 g, 0.1 mol) is dissolved by stirring in 500 ml of ethyl acetate with 10 ml DMF. A thermometer is placed in the solution to monitor temperature. N-Chlorosuccinimide (13.3 g, 0.1 mol) is added in several portions to keep the solution at room temperature. The solution becomes dark in color and is stirred at room temperature overnight. The supernatant is decanted from the dark solids that formed and transferred to a separatory funnel. The organic solution is washed with 500 ml saturated aqueous sodium bisulfite and then 500 ml brine. The organic layer is dried with MgSO4 and concentrated on a rotovap. The dark brown crude product is chromatographed on 500 g of flash silica-gel eluting with 35% EtOAc/Hexanes. Concentration of the appropriate fractions on a rotovap gives a light-tan oil. The oil is dissolved in hexanes and decolorized with activated carbon. The solvent is cooled to −20° C. and the solid which forms is isolated by filtration to give the product as a flaky off-white solid. (MP 67-68° C.).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:14])C.[Cs+]>CN(C)C=O>[Cl:11][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([OH:14])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)ccnc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
2,4-dichloro-3-nitro-pyridine (4.01 g, 20.8 mmol) and cesium acetate (8.0 g, 41.6 mmol) were dissolved in anhydrous N,N-dimethyl formamide (104 ml) under nitrogen atmosphere, and the reaction mixture was heated to 800 and stirred for 18 hours. The reaction mixture was cooled to room temperature the reaction was quenched by adding water. The organic layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain pale-yellow solid (1.69 g, 47%).