Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([NH2:15])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C>>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]#[N:15])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1Nc1cccc([N+](=O)[O-])c1

Procedure:
3,85 g (15 mMol) of 2-(3-Nitrophenylamino)benzoic acid amide in 30 ml (0,325 Mol) phosphorooxychloride were treated with 4,32 ml (31 mMol) triethylamine which is added dropwise, whereby the reaction mixture warms up. After thirty minutes the excess of phosphorooxychloride is distilled off, the residue is treated with water and the solid product is filtered off.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[C:13](=[CH:17][CH:18]=1)[C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:22](NC1C=C(C(O)=O)C(=CC=1)C(O)=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCC.CC(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCCCCC.CC(C)CCCCCCCCCCCCCNC1C=C(C(O)=O)C(=CC=1)C(O)=O.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCCCCCCCCC>>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[C:13](=[CH:17][CH:18]=1)[C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCNc1ccc(C(=O)O)c(C(=O)O)c1
Reactant: CCCCCCCCNc1ccc(C(=O)O)c(C(=O)O)c1
Agent: CC(C)CCCCCCCCCCCCCNc1ccc(C(=O)O)c(C(=O)O)c1
Agent: CCCCCCCCCCC(C)Nc1ccc(C(=O)O)c(C(=O)O)c1
Agent: CCCCCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(C(=O)O)c1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(C(=O)O)c1

Procedure:
Similarly, the diethyl 4-alkylaminophthalates described in Example 11 give, respectively, 4-octylaminophthalic acid, 4-nonylaminophthalic acid, 4-decylaminophthalic acid, 4-undecylaminophthalic acid, 4-(methylundecyl)aminophthalic acid, 4-dodecylaminophthalic acid, 4-tridecylaminophthalic acid, 4-tetradecylaminophthalic acid, 4-pentadecylaminophthalic acid, 4-(14-methylpentadecyl)aminophthalic acid, 4-hepadecylaminophthalic acid, 4-octadecylaminophthalic acid, and 4-nonadecylaminophthalic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I>O>[Cl:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([I:15])=[CH:4][CH:3]=1
Reactant: Oc1cccc(Cl)n1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1nc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 6-chloropyridin-2-ol (3.00 g, 23.2 mmol) and sodium carbonate (4.88 g, 46.4 mmol) in water (60 mL) was added iodine (5.84 g, 23.0 mmol), and the mixture was stirred at room temperature overnight. The resulting solid was collected by filtration, 1N hydrochloric acid was added to the obtained solid, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and to the obtained residue were added diisopropyl ether and hexane, and the resulting solid was collected by filtration to give the title compound (1.04 g, yield 18%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[H][H]>CO.[Pd]>[NH2:13][C:3]1[C:2]([NH2:1])=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: COc1cc(N)c([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(N)c(C(=O)O)c1
Yield: 51.2 %

Procedure:
3-amino-5-methoxy-2-nitrobenzoic acid (85; 1.6 g, 7.5 mmol) was dissolved in methanol (100 mL) and 10% Pd/C (300 mg) was added. The resulting reaction mixture was stirred under 1 atm of hydrogen at room temperature for 18 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 2,3-diamino-5-methoxybenzoic acid 86 (0.7 g).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=O)(C)(C)C.[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:29][CH:30]=1.O.CCN(CC)CC>C1COCC1>[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:29][CH:30]=1.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)O)CCC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCN(CC2(C(=O)O)CCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.5 %

Procedure:
In a 500 mL, 3-necked round bottom flask under N2, a mixture of 1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclobutane carboxylic acid (30 g, 92 mmol, Step 6) in THF (150 mL) was stirred at room temperature for 10 min. To this suspension, a solution of p-TsOH H2O (52.4 g, 276 mmol) in THF (150 mL) was added at room temperature. After stirring at that temp for 10 min, the resulting solution was heated under reflux condition for 3 hrs. After cooling down to room temperature, Et3N (28.1 mL, 202 mmol) was added very slowly during the period of 1 h with seeding. The white precipitate was formed during the addition of Et3N. The resulting white suspension was stirred at room temperature for 6 h and it was filtered and the obtained solid was washed with THF (100 mL×2), dried at 50° C. for 5 h to give 35 g (96%) of the titled compound as white powder
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)=[O:5])[CH3:2].O[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: Oc1cccnc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(F)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccnc2)NS(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (250 mg) was reacted with 3-hydroxypyridine to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide (112.6 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=O)=[CH:4][N:3]=1.[ClH:11].[NH2:12][OH:13]>CO>[ClH:11].[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=[N:12][OH:13])=[CH:4][N:3]=1
Reactant: Cc1ncc(C=O)c(N)n1
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1ncc(C=NO)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a mixture of 27.4 g of 2-methyl-4-amino-5-formylpyrimidine and 1000 ml of methanol was added, while stirring at room temperature, dropwise gradually 25 ml of an aqueous solution containing 15.2 g of hydroxylamine hydrochloride. The reaction was allowed to proceed for further 3 hours at room temperature, which was then concentrated to dryness under reduced pressure. The concentrate was recrystallized from ethanol to give 25.6 g of 2-methyl-4-amino-5-pyrimidine aldoxime hydrochloride. The resulting mother liquor was concentrated to dryness under reduced pressure, followed by subjecting the concentrate to crystallization from a mixture of methanol/ether (1:1 V/V) to give 10.8 g of 2-methyl-4-amino-5-pyrimidine aldoxime hydrochloride. The total yield was 96.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([C:21]2[CH:32]=[CH:31][C:24]3[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=3[CH:22]=2)[O:18][C:17]1=[O:33].[CH:37]1([N:43]=[C:44]=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(O)(C)C>ClCCl>[CH:37]1([NH:43][C:44]([NH:1][C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][C@@H:19]([C:21]4[CH:32]=[CH:31][C:24]5[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=5[CH:22]=4)[O:18][C:17]3=[O:33])[CH:3]=2)=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C=NC1CCCCC1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)NC5CCCCC5)c4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
A solution of (5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.209 g) in dichloromethane (4 ml) was treated with cyclohexyl isocyanate (0.075 g) and the mixture stirred under nitrogen at 20° C. for 3 h. At this point further cyclohexyl isocyanate (0.150 g) was added, and the reaction mixture stirred for a further 65 h. Isopropanol (15 ml) was added to quench excess isocyanate, and the mixture stirred for 3 h. The solvents were removed in vacuo to give a residue which was purified by Biotage. Elution with 6:4 EtOAc/cyclohexane followed by solvent evaporation in vacuo gave the title compound (0.212 g). LCMS RT=3.77 min, ES+ve 624 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C.[Cl-].[Na+].O.[Fe]>[Br:17][C:3]1[C:2]([OH:1])=[C:9]([O:10][CH3:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: BrBr
Reactant: COc1ccc(C=O)cc1O
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C=O)c(Br)c1O
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
3-Hydroxy-4-methoxy-benzaldehyde (20.0 g, 131.4 mmoles) and sodium acetate (23.7 g, 289.2 mmoles) are suspended in acetic acid (650 mL). Iron powder (513.8 mg, 9.2 mmoles) is added and the resulting suspension is cooled to approximately 15° C. A solution of bromine (23.1 g, 144.6 mmoles) in acetic acid (130 mL) is slowly (over 1 hour) dropped into the reaction mixture, keeping temperature at approximately 15° C. The reaction is left at room temperature for 30 minutes. The crude is poured in 780 mL of brine; the desired compound is filtered-off from the mother liquor and washed, sequentially, with brine and water. The product is dried under vacuum overnight to afford a white solid (26.6 g), which is used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.[H][H]>O1CCCC1.[Ni]>[CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12]
Reactant: [H][H]
Reactant: CSCCOc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CSCCOc1ccccc1N

Procedure:
33.9 g of he oil obtained under (a) are hydrogenated in 100 ml of absolute tetrahydrofuran, with the addition of 13.6 g of Raney nickel, under normal pressure (hydrogen absorption=10.6 liters). After the catalyst has been filtered off, the filtrate is concentrated by evaporation, and then purified by means of chromatography (silica gel; hexane/ethyl acetate as eluant).
Reaction SMILES: [CH2:1]([O:3]C=C)[CH3:2].[Li]C(C)(C)C.I[C:12]1[CH:13]=[CH:14][C:15]([NH2:22])=[C:16]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[OH-].[Na+]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCCCCC>[C:1]([C:12]1[CH:13]=[CH:14][C:15]([NH2:22])=[C:16]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: C=COCC
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1ccc(N)c(S(N)(=O)=O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a solution of ethylvinylether (5.8 ml, 60 mmol) in dry THF (50 ml) at −78° C. was added t-BuLi (1.7 M in pentane, 25 ml, 40 mmol) and the yellow mixture was stirred for 1 h at −78° C. The cooling bath was removed and the mixture was warmed slowly to 0° C. and stirred for another 30 min. The mixture was recooled to −78° C. and a solution of ZnCl2 (2M in THF, 20 ml, 40 mmol) was added slowly and the cooling bath was removed and varmed to 20° C. 5-Iodo-2-aminobenzenesulfonamide (see compound 37) (1.8 g, 6 mmol) and Pd(PPh3)4 (0.2 g, 3 mol %) was added and the mixture was refluxed for 6 h. The THF was evaporated and the residue was boiled in 1 M hydrochloric acid (30 ml) and MeOH (30 ml) for 30 min. EDTA (14.6 g, 50 mmol) was added and made slightly basic (pH≈8–9) with 1 M NaOH followed by extraction with EtOAc (3×150 ml), drying (Na2SO4) and evaporation of the solvent gave a brown solid. Trituration with n-hexane gave 0.95 g (74%) of 5-acetyl-2-aminobenzenesulfonamide as off-white powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 224–226° C. (decomp).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:12])([CH2:8][CH2:9][CH2:10][OH:11])[CH:6]([CH3:13])[CH2:5][CH2:4][NH:3]1.[CH3:14][C:15]([CH3:17])=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:1][CH:2]1[C:7]([CH3:12])([CH2:8][CH2:9][CH2:10][OH:11])[CH:6]([CH3:13])[CH2:5][CH2:4][N:3]1[CH:15]([CH3:17])[CH3:14]
Reactant: CC1CCNC(C)C1(C)CCCO
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(C)C(C)(CCCO)C1C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 2,3,4-trimethyl-3-piperidinepropanol (13.0 g, 70 mmol), acetone (400 mL), methanol (300 mL), sodium cyanoborohydride (4.4 g, 70 mmol), 3A molecular sieves (30 g) and acetic acid (4.0 mL, 70 mmol) was stirred under a nitrogen atmosphere for 2 hours. The pH was readjusted to a pH of 5 by the addition of 1.5 mL of additional acetic acid and the reaction mixture was stirred for 24 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water (200 mL) and acetone (20 mL) and was acidified with concentrated hydrochloric acid. The mixture was basified with 10% NAOH and extracted with ether (4×300 mL) . The ether extracts were combined, washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by a Kugelrohr distillation at 0.1 mm Hg and 100-110° C. to afford 15.7 g (99%) of 2,3. 4-trimethyl-l- (1-methylethyl)-3-piperidinepropanol as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C12CC(CC1)CC2C(O)=O.C([NH-])C1C=CC=CC=1>>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: O=C(O)C1CC2CCC1C2
Agent: [NH-]Cc1ccccc1
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 164.4 %

Procedure:
Using the procedure described in Example 5, treatment of L-proline-L-isoleucine benzylamide (100 mg, 0.32 mmol) with 2-norbornyl α-chloromethyl ketone (82 mg, 0.48 mmol, 1.5 eq; prepared from 2-norbornanecarboxylic acid by the method described in Example 1) provided 69 mg of L-isoleucine, N-[1-(2-bicyclo[2.2.1]hept-2-yl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Procedure CC: To a stirring solution of 4-bromo-2-fluorobenzoic acid (11.0 mmol) and oxalyl chloride (2.0 mmol) in dichloromethane (0.10M), add 2 drops of dimethylformamide as a catalyst. Stir at room temperature for 3 hours. After this time, concentrate the reaction in vacuo. Assume total conversion to the acid chloride.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:35][C:36]([O:38]C)=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[CH:35][C:36]([OH:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccccc1Oc1ccccc1
Yield: 54.5 %

Procedure:
A mixture of 2-phenoxybenzaldehyde (2.12 g; 10.70 mmol) and methyl (triphenylphos-phoranylidene)acetate (4.01 g; 11.76 mmol) in 60 mL of THF was refluxed overnight. The reaction was cooled, diluted with ethyl acetate (50 mL) and washed with water (3X). The crude residue Was purified on a silica gel column eluting with hexane to obtain 1.4 g (52%) of 2-phenoxycinnamic acid, 1H NMR (CDCl3): δ 3.78 (s, 3H); 6.56 (d, 1H, J=16.1); 6.87 (d, 1H, J=8.5); 7.00 (d, 2H, J=7.5); 7.10-7.15 (m,2H); 7.28-7.33 (m, 3H); 7.36 (d, 1H, J=8.5); 8.02 (d, 2H, J=16.2).
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:12]([CH3:31])=[N:13][C:14]2[C:19]([N:20]=1)=[C:18]([C:21]1[NH:29][C:28]3[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=3[CH:22]=1)[CH:17]=[CH:16][CH:15]=2.[NH2:32][CH:33]1[CH2:36][CH:35]([OH:37])[CH2:34]1>CS(C)=O>[OH:37][CH:35]1[CH2:36][CH:33]([NH:32][C:11]2[C:12]([CH3:31])=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]([C:21]2[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=2)[CH:17]=[CH:16][CH:15]=3)[CH2:34]1
Reactant: NC1CC(O)C1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CC(O)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using DIPEA (141 μl, 0.803 mmol), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4 (5H)-one (Example 126; 40 mg, 0.135 mmol), 3-aminocyclobutanol (35.3 mg, 0.405 mmol, Sigma Aldrich; mixture of cis- and trans-isomers), and DMSO (1.4 mL) stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(3-((3-hydroxycyclobutyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (mixture of cis- and trans-isomers): 1H NMR (DMSO-d6) δ: 12.31-12.44 (m, 1H), 7.86-7.95 (m, 1H), 7.51-7.61 (m, 1H), 7.26-7.40 (m, 2H), 7.04-7.11 (m, 1H), 6.91-7.02 (m, 1H), 5.12-5.26 (m, 1H), 4.37-4.53 (m, 1H), 3.86-4.07 (m, 1H), 3.41-3.48 (m, 1H), 2.88-3.01 (m, 2H), 2.75-2.85 (m, 1H), 2.55-2.59 (m, 4H), 2.26-2.48 (m, 2H), 1.94-2.09 (m, 1H). m/z (ESI, +ve) 364.1 (M+H)+.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C:29]([CH3:36])([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C:29]([CH3:36])([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)C(C)(C)N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(NC(C)(C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 868 mg of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 255-3 (3.10 mmol, crude form) as starting materials, 1.02 g of the title compound (colorless amorphous) was obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[C:13](S(C)(=O)=O)[N:12]=1>ClCCl>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:3]2[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N:4]2)[N:12]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)n(-c2nc(Cl)cc(Cl)n2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A suspension of 3,5-dimethylpyrazole (3.9 g, 40.7 mmol) and sodium hydride (60% in mineral oil, 1.7 g) in dichloromethane (50 mL) was added dropwise to a cooled (−78° C.) solution of 4,6-dichloro-2-methanesulfonyl-pyrimidine (10 g, 38.7 mmol) in dichloromethane (200 mL). The mixture was stirred at −78° C. for one hour. The reaction was carefully quenched at the same temperature by addition of water (150 mL). The mixture was allowed to warm to room-temperature. Brine (150 mL) was added and the phases were separated. The aqueous phase was extracted with dichloromethane (4×200 mL). The combined organic layers were washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/heptane as eluent) to give 4,6-dichloro-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidine (5.5 g, 59%) as a white crystalline compound.
Reaction SMILES: CC1N2N=NN=C2C2N=C(CCC)N(CCCS(C3C=CC(C(Cl)=O)=CC=3)(=O)=O)C=2C=1C.CNCCCC.N1CCOCC1.[CH2:45]([N:49]([CH3:81])[C:50](=[O:80])[C:51]1[CH:56]=[CH:55][C:54]([S:57]([CH2:60][CH2:61][CH2:62][N:63]2[C:71]3[C:70]([CH3:72])=[C:69]([CH3:73])[N:68]4N=N[N:76]=[C:67]4[C:66]=3[N:65]=[C:64]2[CH2:77][CH2:78][CH3:79])(=[O:59])=[O:58])=[CH:53][CH:52]=1)[CH2:46][CH2:47][CH3:48]>ClCCl>[NH2:76][C:67]1[C:66]2[N:65]=[C:64]([CH2:77][CH2:78][CH3:79])[N:63]([CH2:62][CH2:61][CH2:60][S:57]([C:54]3[CH:55]=[CH:56][C:51]([C:50]([N:49]([CH2:45][CH2:46][CH2:47][CH3:48])[CH3:81])=[O:80])=[CH:52][CH:53]=3)(=[O:59])=[O:58])[C:71]=2[C:70]([CH3:72])=[C:69]([CH3:73])[N:68]=1
Reactant: CCCCN(C)C(=O)c1ccc(S(=O)(=O)CCCn2c(CCC)nc3c2c(C)c(C)n2nnnc32)cc1
Agent: CCCCNC
Agent: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCS(=O)(=O)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Product: CCCCN(C)C(=O)c1ccc(S(=O)(=O)CCCn2c(CCC)nc3c(N)nc(C)c(C)c32)cc1
Reaction time: 8 h
Yield: 76.8 %

Procedure:
The general methods described in Example 101 were used with the following modifications. To one-third of the crude solution of 4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]benzoyl chloride in dichloromethane, described in Part B of Example 101, was added N-methyl butylamine (0.583 mL, 4.92 mmol) in lieu of morpholine, and the reaction was stirred overnight. Additional N-methyl butylamine (0.5 mL) was added, and the reaction was stirred for two hours. The crude product was recrystallized from ethyl acetate:hexane, and the crystals were dried for three hours in a vacuum oven at 90° C. N-Butyl-4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]N-methyl benzamide (770 mg, 1.46 mmol) was treated as described in Part C of Example 101. The crude product was recrystallized from ethyl acetate:hexane with a couple drops of methanol to provide crystals, which were isolated by filtration, washed with hexane, and dried for four hours under high vacuum at 50° C. to provide 0.56 g of 4-[3-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)propane-1-sulfonyl]-N-butyl-N-methylbenzamide as a white powder, mp 127.0–129.0° C. 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J=8.4, 2H), 7.58 (d, J=8.4, 2H), 4.92 (br s, 2H), 4.42 (dd, J=7.8, 7.8, 2H), 3.55 (dd, J=7.8, 7.8, 1H), 3.21–3.05 (m, 4.5H), 2.90 (s, 1.5H), 2.77 (dd, J=7.7, 7.7, 2H), 2.43 (s, 3H), 2.39 (s, 3H), 2.23 (quint, J=7.6, 2H), 1.93–1.36 (m, 5H), 1.15 (quart, J=7.5, 1H), 1.07 (t, J=7.4, 3H), 0.99 (t, J=7.0, 1.5H), 0.81 (t, J=7.4, 1.5H);