Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:19]([N:36]([C@@H:42]1[C@H:46]([OH:47])[C@@H:45]([CH2:48][OH:49])[O:44][C@H:43]1[N:50]1[CH:57]=[CH:56][C:54](=[O:55])[NH:53][C:51]1=[O:52])[C:37](=[O:41])[CH2:38][CH2:39][NH2:40])([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>N1C=CC=CC=1>[C:1]([C@@:46]1([OH:47])[C@@H:45]([CH:48]([C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[OH:49])[O:44][C@@H:43]([N:50]2[CH:57]=[CH:56][C:54](=[O:55])[NH:53][C:51]2=[O:52])[C@@H:42]1[N:36]([C:19]([O:21][CH2:22][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20])[C:37](=[O:41])[CH2:38][CH2:39][NH2:40])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCCC(=O)N(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)C(O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](N(C(=O)CCN)C(=O)OCC2c3ccccc3-c3ccccc32)[C@@]1(O)C(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Palmitoyl chloride (1.55 mL, 1.8 mmol) was added to a solution of nucleoside 28 in abs pyridine and the reaction mixture was stirred overnight at room temperature. The solution was then quenched with MeOH, evaporated to dryness, dissolved in dichloromethane and washed with saturated aq sodium bicarbonate and brine. The organic phase was dried oversodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica (EtOAc-Hexanes 1:1) affording 0.5 g of 29 (yield, 65%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([S:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[CH2:13]/[C:12]/1=[CH:30]\[C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[N:32]=1)(=O)C.[ClH:43].C(#N)C>CO>[ClH:43].[ClH:43].[CH:20]1([C:18](=[O:19])[CH:17]([N:14]2[CH2:15][CH2:16][CH:11]([SH:10])/[C:12](=[CH:30]/[C:31]3[CH:35]=[CH:34][N:33]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[N:32]=3)/[CH2:13]2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH2:22][CH2:21]1
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(Cc2ccccn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: O=C(C1CC1)C(c1ccccc1F)N1CCC(S)/C(=C/c2ccn(Cc3ccccn3)n2)C1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Potassium carbonate (39 mg) was added to a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[(2-pyridyl)methyl]-1H-pyrazol-3-yl}methylidene)piperidine (140 mg) in methanol (5 ml). After stirring for 0.5 hour, 1N hydrochloric acid (3 ml) was added to the mixture. The mixture was filtered using a membrane filter. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 25/75, v/v) to afford the title compound (120 mg, yield: 80%) as a yellow amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.CCOCC.C(=O)(O)[O-].[K+]>O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:15]2[C:16]([N+:20]([O-:22])=[O:21])=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCCN(c2nc(Cl)ncc2[N+](=O)[O-])C1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 3.16 g (0.02 mole) of piperidine-3-carboxylic acid ethyl ester, 3.71 g (0.019 mole) of 2,4-dichloro-5-nitro-pyrimidine and 60 mL of ether at 5 degrees, was added a solution of 4 g (0.04 mole) of potassium bicarbonate in 40 mL of water was added over 25 minutes. The mixture was stirred for an additional 1 hour, then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-88:12) to give 3.99 g of (rac)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-piperidine-3-carboxylic acid ethyl ester (IV-67).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[N:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][C:30](OCC)=[O:31])=[CH:22][CH:21]=1.[Li+].CC([N-]C(C)C)C>CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[C:5]([CH:6]=[C:29]([CH2:28][CH2:27][CH2:26][C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[C:30](=[O:31])[N:10]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(C=O)c(Nc2cccc([N+](=O)[O-])c2)n1
Reactant: CCOC(=O)CCCCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Product: Cc1ccc2cc(CCCc3ccncc3)c(=O)n(-c3cccc([N+](=O)[O-])c3)c2n1

Procedure:
The procedure of Example 1 was repeated using 6-methyl-2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 1), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq.) and LDA (1.5 eq.) to obtain 7-methyl-1-(3-nitrophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 165 to 166° C./AcOEt, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]12[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:25]C(=O)O[C:21]2=[O:22].N12CCN(CC1)CC2.CO>CN(C)C=O>[C:21]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:22])[C:20]1[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:25]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccccc1N
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
A mixture of octadecanol (270 grams, 1.0 mol; obtained from Sigma-Aldrich Co.), isatoic anhydride (244 grams, 1.5 mol; obtained from Sigma-Aldrich Co.), and 1,4-diazabicyclo[2.2.2]octane (56 grams, 0.50 mol; obtained from Sigma-Aldrich Co.), in 1,000 milliliters of dimethylformamide was stirred and heated to 100° C. in a 4 liter beaker. Vigorous gas evolution occurred. After 10 minutes, the resultant dark solution was heated to 150° C. for 15 minutes. The reaction mixture was then cooled to 50° C. and vigorously stirred while 3,000 milliliters of methanol was added. The resultant suspension was stirred for 0.5 hour, followed by vacuum filtration. The solid thus obtained was washed in the filter funnel with 4×300 milliliter portions of methanol and was then dried in air to give the product stearyl anthranilate as white powder (330.5 grams, 85 percent yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:27])[CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)=[O:31].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:28][O:29][C:30](=[O:31])[C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([O:26][C:23]2[CH:22]=[CH:21][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:27])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:25][CH:24]=2)[CH:37]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2)c1

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 346, step 1) was reacted with 3-methoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=516.4 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([OH:19])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:30]=[CH:31][C:32]=1[NH2:33].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:28][C:27]=2[Cl:26])=[O:19])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1ccc(NC(=O)c2cn(Cc3ccccc3)c3ccccc23)c(Cl)c1
Temperature: -15 °C
Yield: 98.4 %

Procedure:
To a solution of 1-benzylindole-3-carboxylic acid (201.3 mg, 0.801 mmol) in methylene chloride (4.0 ml) was added oxalyl chloride (103.1 μl, 1.202 mmol) under stirring at −15° C. The reaction mixture was stirred at room temperature for 2.5 hours and then, distilled under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride (4.0 ml) and to the resulting solution were added a solution of methyl 3-chloro-4-aminophenylacetate (167.9 mg, 0.841 mmol) in methylene chloride (4.0 ml) and triethylamine (0.35 ml, 2.523 mmol) under stirring at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was diluted with chloroform, washed with 1N HCl, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby methyl 4-((1-benzyl-3-indolylcarbonyl)amino)-3-chlorophenylacetate (341.3 mg, 98%) was obtained. The compound was provided for the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=2)[N:8]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[S:26][CH2:27][CH3:28])[N:6]=1>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:7]2[N:6]=[C:5]([NH:3][CH2:1][CH3:2])[C:14]3[C:9](=[CH:10][C:11]([C:15]([F:17])([F:16])[F:18])=[CH:12][CH:13]=3)[N:8]=2)=[C:20]([S:26][CH2:27][CH3:28])[CH:21]=1
Reactant: CCN
Reactant: CCSc1cc(Cl)ccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Solvent: C1CCOC1
Product: CCNc1nc(-c2ccc(Cl)cc2SCC)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.5 ml of ethylamine (a 70% aqueous solution) was added to a mixture of 600 mg of 4-chloro-2-(4-chloro-2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline and 10 ml of THF, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to obtain 606 mg of 2-(4-chloro-2-ethylsulfanylphenyl)-4-ethylamino-7-trifluoro methylquinazoline (Compound of Present Invention 15).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[Br:24][Si](C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])[CH:16]([Br:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Br
Reactant: CC(C)(C)c1cc(C(O)c2ccccc2)cc(C(C)(C)C)c1O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(C(Br)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
To a solution of 31.2 g (0.1 mole) of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-α-phenylbenzenemethanol (Example 16) in 350 mL of CCl4 is added 34.8 (0.227 mole) of bromotrimethylsilane. After 40 minutes at room temperature the reaction mixture is evaporated to dryness on a rotary evaporator with the water bath temperature at 35° C. The brown oil residue is used immediately without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=O.[BH3-]C#N.[Na+]>CO>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][NH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: O=Cc1cccs1
Reactant: COC(=O)CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCNCc1cccs1
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a stirring 25 mL MeOH solution of 1.40 g (10 mmol) of methyl β-alaninate hydrochloride and 1.34 g (12 mmol) of thiophene carboxaldehyde was added 1.26 g (20 mmol) of NaCNBH3. After 1 hour, 25 mL of saturated KHCO3 was added to the reaction. The reaction mixture was then filtered, and the resulting filtrate was extracted with 50 mL of DCM. The organic layer was treated as described above in Example 7, and the residue was chromatographed to yield 0.60 g (30%) of product. Analysis calculated for C9H13NO2S (M.W. 199.27): C, 54.25; H, 6.58; N, 7.03. Found: C, 54.02; H, 6.63; N, 6.77.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9]/[C:8](=[CH:12]\N(C)C)/[C:7]1=O)[CH3:2].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:40][C:41]([NH2:43])=[NH:42])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]1[C:7]2[N:43]=[C:41]([NH:40][C:30]3[CH:31]=[CH:32][C:33]([N:34]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]4)=[C:28]([O:27][CH3:26])[CH:29]=3)[N:42]=[CH:12][C:8]=2[CH2:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC/C(=C\N(C)C)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)CC1CCCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from crude {3-[1-dimethylamino-meth-(E)-ylidene]-2-oxo-cyclohexyl}-acetic acid ethyl ester (108 mg, 0.33 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (111 mg, 0.30 mmol) using in analogous manner the procedure described in example 45b). Obtained as yellow crystals (83 mg, 66%). MS ISP (m/e): 422.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.60 (s, 1H), 8.25 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.27 (d, 1H), 7.20 (d, 1H), 7.02 (s, 1H), 4.06 (q, 2H), 3.79 (s, 3H), 3.10 (m, 2H), 2.60-2.70 (m, 3H), 2.14 (s, 3H), 2.02 (m, 1H), 1.86 (m, 1H), 1.65 (m, 2H), 1.15 (t, 3H).
Reaction SMILES: [O:1]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:16]Cl>C(O)(=O)C>[I:16][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: ClI
Reactant: c1ccc(OCOc2ccccc2)cc1
Solvent: CC(=O)O
Product: Ic1ccc(OCOc2ccccc2)cc1
Yield: 67 %

Procedure:
4-(Phenoxy)methoxybenzene (7.40 g, 36.9 mmol) was dissolved in acetic acid and treated with iodine monochloride (7.50 g, 46.2 mmol) at 50° C. for 4 hours. The mixture was then concentrated and the residue taken up in methylene chloride. The solution was washed with 10% sodium sulfite solution, dried with magnesium sulfate, filtered and concentrated to a yellow solid. This was triturated with hexane, collected and dried to give 8.06 g of the title compound as a pale pink solid. GS-MS (m/z, EI): 326 [M]+.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].[CH3:17]O>>[CH3:17][O:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CO
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93 %

Procedure:
Methyl 2-hydroxy-3-nitrobenzoate (2.85 g, 13.50 mmol) was dissolved in hot methanol (10 mL) at 75° C. to make clear solution and 1N aq. sodium hydroxide (28.3 mL, 28.3 mmol) was added dropwise. The mixture was heated under reflux for 15 minutes and then cooled to room temperature, concentrated to remove the methanol and then cooled in an ice bath. The solution was acidified via the dropwise addition of 1M (aq.) HCl until the pH was ˜1, resulting in the product precipitating out of solution. The solid was collected by filtration, rinsed with water, and dried on the filter to afford the product 2-methoxy-3-nitrobenzoic acid (2.48 g, 12.58 mmol, 93% yield) as a white solid. HPLC (Method N) RT=1.57 minutes.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7]O)[NH2:6].C(N(CC)CC)C.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[C:17]([N@@:6]1[CH2:7][CH:5]1[C:4]([O:3][CH3:2])=[O:9])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)[C@H](N)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1C[N@]1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
200 g of D-serine methyl ester hydrochloride was added to 1.8 L of chloroform, and the reaction solution was cooled to 0° C., to which 448 mL of triethylamine was then slowly added. 358.4 g of trityl chloride was slowly added to the reaction mixture which was then stirred for 1 hour. The reaction mixture was warmed to room temperature, and 1 L of chloroform was added thereto, followed by washing with 2.5 L of water. The organic layer was dried over magnesium sulfate and cooled to 0° C., to which 484 mL of triethylamine and 15.7 g of 4-methylaminopyridine were then sequentially and slowly added. The reaction mixture was stirred for 5 min and 139 mL of methane sulfonyl chloride was slowly added thereto. The reaction mixture was warmed to room temperature, stirred for another 4 hours and then refluxed for 12 hours. The reaction mixture was cooled to room temperature, and washed with 4 L of water and then 3 L of brine. The organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. 3 L of ethanol was added to the resulting residue which was then stirred. The resulting solids were filtered to afford 329 g of the title compound.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:22]=[CH:21][C:20]([C:23](=O)/[CH:24]=[CH:25]/[N:26](C)C)=[CH:19][CH:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.O.[NH2:31]N>CO>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:18]=[CH:19][C:20]([C:23]5[NH:31][N:26]=[CH:25][CH:24]=5)=[CH:21][N:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CN(C)/C=C/C(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Reactant: NN
Solvent: CO
Solvent: O
Product: c1cc(-c2ccc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)nc2)[nH]n1

Procedure:
A mixture of (2E)-1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-3-(dimethylamino)-2-propen-1-one (D53) (195 mg, 0.5 mmol) and hydrazine hydrate (0.4 ml) in methanol (3 ml) was heated at reflux for 24 hours. The reaction mixture was cooled and applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title compound (E215). MS (ES+) m/e 361 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:35])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[CH:25][C:26](=[O:33])[N:27]([CH2:29][C:30]([OH:32])=O)[CH:28]=5)[C:20]([CH3:34])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[N:36]#[C:37][NH2:38].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH:38]([C:30](=[O:32])[CH2:29][N:27]1[C:26](=[O:33])[CH:25]=[CH:24][C:23]([C:21]2[N:22]=[C:17]([NH:16][C:14]([C:11]3([C:9]4[CH:8]=[CH:7][C:5]5[O:6][C:2]([F:35])([F:1])[O:3][C:4]=5[CH:10]=4)[CH2:13][CH2:12]3)=[O:15])[CH:18]=[CH:19][C:20]=2[CH3:34])=[CH:28]1)[C:37]#[N:36]
Reactant: N#CN
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CC(=O)NC#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To 2-(5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)acetic acid (0.13 g, 0.27 mmol), cyanamide (27 μL, 0.32 mmol), and triethylamine (75 μL, 0.54 mmol) in N,N-dimethylformamide (3 mL) was added 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.12 g, 0.33 mmol) and the reaction mixture was stirred at room temperature for 1 hour. At this point the reaction mixture was filtered and purified by reverse-phase HPLC. The resulting trifluoroacetic acid salt was dissolved in dichloromethane and washed with a saturated sodium bicarbonate solution and 1N Hydrochloric acid. The organics were dried over sodium sulfate and evaporated to dryness to give the product (45 mg, 31%). ESI-MS m/z calc. 507.14. found 508.4 (M+1)+ Retention time 1.63 minutes.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:14]=2)[CH2:9]1)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[N:19]1([CH2:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][CH:8]([NH2:7])[CH2:17][CH2:16]3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(CN3CCCCC3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCc2cc(CN3CCCCC3)ccc2C1
Temperature: 25 °C

Procedure:
(6-Piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (0.113 g, 0.327 mmol) was suspended in CH2Cl2 (2.5 mL) then TFA was added (2.5 mL). The reaction was stirred at RT until complete consumption of starting material was observed by HPLC analysis (2 h). The reaction mixture was concentrated in vacuo to afford the crude title compound as the bis-TFA salt, which was used without further purification. MS (APCI pos) 245 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.C1(C2NN=C(NC3C=CN=C([C:33]4[S:37][C:36]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:35][CH:34]=4)N=3)C=2)CC1>>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:7][C:2]([C:33]2[S:37][C:36]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:35][CH:34]=2)=[N:3][CH:4]=1
Reactant: Clc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: NS(=O)(=O)c1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)s1
Product: NS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1

Procedure:
Using 2-bromo-5-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine as starting material, following same procedure as described in Compound 50, the HCl salt of 5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 42) was prepared (92.7 mg, 33.4%). LC-MS (m/z)=397.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.78-0.79 (m, 2H), 1.00-1.02 (m, 2H), 1.97-1.99 (m, 1H), 6.42 (s, 1H), 7.59 (d, J=4.4 Hz, 1H), 7.78 (d, J=3.6 Hz, 1H), 7.84 (s, 2H), 8.50 (s, 1H), 9.65 (s, 1H).