Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)C(O)=O)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2].C([N:37](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH2:1]([N:3]([CH2:33][CH3:34])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:32]=[CH:31][CH:30]=[C:26]([NH2:37])[CH:25]=3)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCC(C)CN1CCC(c2cccc(C(=O)O)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCCC(C)CN1CCC(c2cccc(N)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Temperature: 120 °C
Reaction time: 22 h
Yield: 63.5 %

Procedure:
To a stirring solution of 3-[4-(5-Diethylcarbamoyl-pyrimidin-2-yl)-1-(2-methyl-pentyl)-piperidin-4-yl]-benzoic acid (210 mg, 0.45 mmol) in 8 mL Toluene and 2 mL tert-butyl alcohol at room temperature was added triethylamine (0.066 mL, 0.48 mmol) and diphenylphosphoryl azide (0.07 mL, 0.45 mmol). The resulting mixture was heated at 120° C. for 20 hours, cooled to room temperature, washed with water, dried and concentrated. The resulting residue was taken up in EtOH/5N HCl (1:1) and stirred at room temperature for 22 hours. The resulting mixture was basified (pH=9) with NaOH and extracted with EtOAc (3×20 mL). The combined organic layers were dried and concentrated. Purification of the crude material was accomplished by flash chromatography with a solvent gradient of 5% and 10% MeOH/CH2Cl2 to yield 125 mg of the desired product. 1HNMR (400 MHz, CDCl3) δ 8.71 (s, 2H), 7.02 (t, 1H), 6.76 (d, 1H), 6.71 (s, 1H), 6.45 (d, 1H), 3.57-3.52 (comp, 4H), 3.28-3.26 (comp, 2H), 2.93-2.89 (comp, 2H), 2.71 (br s, 2H), 2.33 (br s, 2H), 2.15-1.96 (comp, 4H), 1.61 (br s, 1H), 1.38-1.17 (comp, 10H), 1.03-0.96 (comp, 1H), 0.86-0.83 (comp, 6H); MS (M+1) 438.6.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:49]=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[CH:44]=[CH:45][C:46](O)=O>CN(C)C=O>[CH2:9]([N:6]1[C:7]2[N:8]=[C:46](/[CH:45]=[CH:44]/[C:43]3[CH:49]=[C:50]([O:54][CH3:55])[C:51]([O:52][CH3:53])=[C:41]([O:40][CH3:39])[CH:42]=3)[NH:1][C:2]=2[C:3](=[O:13])[NH:4][C:5]1=[O:12])[CH2:10][CH3:11]
Reactant: CCCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(/C=C/c3cc(OC)c(OC)c(OC)c3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
5,6-Diamino-1-propyluracil (2.00 g, 11 mmol) was suspended in 40 ml of N,N-dimethylformamide. To the suspension were added 3.37 g (16 mmol) of N,N'-dicyclohexylcarbodiimide and 2.00 g (13 mmol) of 1-hydroxybenzotriazole. Then, 2.59 g (11 mmol) of 3,4,5-trimethoxycinnamic acid was slowly added thereto in several portions, and the mixture was stirred overnight at room temperature. After insoluble substances were removed by filtration, the filtrate was concentrated under reduced pressure and 40 ml of a 2N aqueous solution of sodium hydroxide was added to the residue. The mixture was heated under reflux for 30 minutes, followed by neutralization. Deposited crystals were collected by filtration and recrystallized from isopropanol/water to give 2.51 g (overall yield: 60%) of Compound 22 as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][CH:32]=1)[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH3:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][CH:32]=1)[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH:22]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC(=O)C(CCC(=O)O)(Cc1cccc(Cl)c1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1cccc(Cl)c1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of 4-(m-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.8 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (200 ml.) and extracted with ether to remove the excess p-chlorobenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (10 ml.), and the white solid which precipitates is collected and air-dried to yield 5.05 g., m.p. 65°-130°C. Several recrystallizations from n-butyl chloride and petroleum ether (30°-60°C.) give a material with m.p. 137°-139°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4].II.FC(F)(F)C(O[I:17](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([I:17])=[CH:8][CH:9]=1)=[O:4]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1cccs1
Agent: II
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(I)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.4 %

Procedure:
To a solution of thiophene-2-carboxylic acid methyl ester (5.0 g, 28.7 mmol) in 35 mL of anhydrous carbon tetrachloride was added iodine (3.65 g, 14.37 mmol) and [Bis(trifluoroacetoxy)iodo] benzene (6.67 g, 15.52 mmol). This mixture was stirred overnight at room temperature. Dichloromethane was then added and the mixture was extracted with a solution of sodium thiosulfate 10%. The organic layer was evaporated and the residue was purified flash chromatography (hexane 40%:chloroform 60%) to give a solid which was triturated with pentane in order to remove remaining starting material affording compound P-1 as a white solid (4.8 g, 63% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[S:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:20].[C:30]([NH:33][C@@H:34]([CH3:46])[CH2:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)(=[O:32])[CH3:31]>>[C:30]([NH:33][C@@H:34]([CH3:46])[CH2:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([C:41]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][C:3]=2[S:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])=[O:42])=[CH:44][CH:45]=1)(=[O:32])[CH3:31]
Reactant: CCCCC(CC)COC(=O)CCSc1cc(OCc2ccccc2)ccc1N
Reactant: CC(=O)N[C@@H](C)COc1ccc(C(=O)O)cc1
Product: CCCCC(CC)COC(=O)CCSc1cc(OCc2ccccc2)ccc1NC(=O)c1ccc(OC[C@H](C)NC(C)=O)cc1
Yield: 66.8 %

Procedure:
Using 2-ethylhexyl 3-{[2-amino-5-(benzyloxy)phenyl]sulfanyl}propanoate (1.00 g) and 4-{[(2S)-2-(acetylamino)propyl]oxy}benzoic acid (628 mg), and in the same manner as in Example 2, step C, the title compound (1.02 g) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]([CH:15]=O)=O>O>[CH3:15][C:13]1[CH:12]=[N:11][C:6]2[C:7](=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CC(=O)C=O
Solvent: O
Product: Cc1cnc2cc([N+](=O)[O-])ccc2n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
To a suspension of 4-nitro-1,2-phenylenediamine (10.0 g) in water (150 mL) was added dropwise a 40% aqueous solution of pyruvic aldehyde (11.76 g) at room temperature. The reaction solution was stirred at 80° C. for 4 hours, and cooled to room temperature. Water (200 mL) was added to the mixture, and the mixture was extracted with chloroform (150 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residual solid was recrystallized from ethanol, collected by filtration, and dried to give 2-methyl-6-nitroquinoxaline (7.38 g, 60%) as red solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:10]([OH:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:25](OC)([CH2:28][CH3:29])[CH2:26][CH3:27]>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:16][C:25]1([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(CC)(OC)OC
Reactant: CCOC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1OC(CC)(CC)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 20 °C
Yield: 75.4 %

Procedure:
A solution of 2.5 g of ethyl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, 1.12 g of 3,3-dimethoxypentane and 25 mg of pyridinium p-toluene-sulphonate in 25 cm3 of toluene is stirred for 3 hours at a temperature in the region of 20° C. The reaction mixture is heated to boiling and the distillate is collected in a graduated vessel. After 20 cm3 of distillate have been collected, a solution of 1.12 g of 3,3-dimethoxypentane and 25 mg of pyridinium p-toluenesulphonate in 10 cm3 of toluene is added to the reaction medium and the mixture is heated to reflux of the toluene for 5 hours. The reaction medium is cooled to a temperature in the region of 20° C. and 10 cm3 of saturated aqueous sodium hydrogen carbonate solution are then added. The aqueous phase is separated after settling has taken place and then extracted with 2 times 10 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 2.3 g of ethyl (4S,5R)-3-tert-butoxycarbonyl-2,2-diethyl-4-phenyl-5-oxazolidinecarboxylate are thereby obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]4[CH2:26][CH2:27][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]4)=[CH:21][CH:22]=3)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: O=C(NC1CC1)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)NC4CC4)cc3)cc2)CC1
Yield: 14.9 %

Procedure:
The title compound (13 mg, 12%) was prepared from {4-[(cyclopropylamino)carbonyl]phenyl}boronic acid (41 mg, 0.2 mmol), 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, 2H, J=8.4 Hz), 7.59 (d, 2H, J=8.6 Hz), 7.53 (d, 2H, J=8.8 Hz), 6.96 (d, 2H, J=8.8 Hz), 6.24 (s, 1H), 4.97-4.84 (m, 1H), 4.21 (bs, 2H), 3.84 (d, 2H, J=6.4 Hz), 2.96-2.86 (m, 1H), 2.83-2.73 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.36-1.26 (m, 2H), 1.24 (d, 6H, J=6.4 Hz), 0.93-0.84 (m, 2H), 0.66-0.60 (m, 2H); LRMS (ESI), m/z 437 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[C@H:12]([CH3:24])[CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[O:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH2:32][CH2:33][O:29][C:30]3=[O:34])=[CH:3][C:4]=2[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][C@H:12]1[CH3:24]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)C[C@H]2C)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3S(C)(=O)=O)C[C@H]2C)c(C)c1
Yield: 39.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[(R)-4-(2,4-dimethylphenyl)-3-methylpiperazin-1-yl]methanone (814 mg) and oxazolidin-2-one (168 mg), the title compound (327 mg) was obtained.
Reaction SMILES: [OH-].[Li+].O.[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:14]=2[C:15]([O:17]CC2C=CC(F)=CC=2)=[O:16])=[CH:7][CH:6]=1>O1CCCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:14]=2[C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1
Reactant: O=C(OCc1ccc(F)cc1)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1

Procedure:
Lithium hydroxide (0.70 g, 29.1 mmol) and water (20 ml) were added to a solution of (4-fluorophenyl)methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-(trifluoromethyl)benzoate (may be prepared as described in Description 118; 4.1 g, 9.71 mmol) in tetrahydrofuran (100 ml) and the mixture was heated to reflux for 2 hours. The mixture was evaporated under reduced pressure on a buchi. Water (100) ml was added and the mixture was acidified to pH=1 using 2M aqueous hydrochloric acid. The precipitate was filtered and washed with water (2×50 ml). The solid was dried in air, under vacuum to yield the title compound as a white solid. 2.39 g
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:15][CH2:14][C@@H:13]3[CH2:16][C@H:10]2[C:11](=O)[O:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH3:32][O:33][C:34]([CH2:36]P(OC)(OC)=O)=[O:35].Cl>C1COCC1.O>[CH3:32][O:33][C:34](=[O:35])/[CH:36]=[CH:11]/[C@@H:10]1[CH2:16][C@H:13]([OH:12])[CH2:14][CH2:15][N:9]1[C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: C[C@H](c1ccccc1)N1CC[C@@H]2C[C@H]1C(=O)O2
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/C=C/[C@@H]1C[C@H](O)CCN1[C@H](C)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 172.6 %

Procedure:
Dissolve 2.0 g (8.647 mmol) of (1S,5R)-2-[(1R)-1-phenylethyl]-6-oxa-2-azabicyclo[3.2.1]octan-7-one [prepared from N-[(1R)-1-phenylethyl]but-3-en-1-amine according to Bioorg. Med. Chem. Lett. 6 (8), 964 (1996)] in 8 ml of abs. THF, cool to −78° C. and add 9.5 ml (9.5 mmol) of a 1M solution of L-Selectride in THF. After the end of the addition, continue stirring at −78° C. for 1 h, then warm to −20° C. and add 2.1 ml (13 mmol) of phosphonoacetic acid trimethyl ester. Then warm the reaction mixture to 0° C. and stir for 1 h. Water is then added and 1N hydrochloric acid is used to set a pH of approx. 7-8. Extract the mixture with dichloromethane three times, and combine the organic phases, dry over magnesium sulphate and concentrate under reduced pressure. 4.32 g of crude product are obtained, which are used without further purification in the next stage.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1Cl)([O-:3])=[O:2].[CH:18]([NH2:22])([CH2:20][CH3:21])[CH3:19].C1(C)C=CC=CC=1>C(O)C>[CH:18]([NH:22][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH2:20][CH3:21])[CH3:19]
Reactant: CCC(C)N
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
One gram of 2,6-dinitro-4-t-butylchlorobenzene was allowed to react with one gram of sec-butylamine by adding the amine dropwise to a refluxing mixture of 50 ml. dry toluene, and the 2,6-dinitro-4-t-butylchlorobenzene. After complete addition, the mixture was refluxed eight hours, cooled to room temperature, the amine hydrochloride filtered off, and toluene and unreacted amine were removed under reduced pressure. The thick material that resulted was dissolved in hot ethanol and the product was crystallized upon cooling to yield N-sec-butyl-2,6-dinitro-4-t-butylaniline melting at 60°-62° C.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[Cl:16][C:17]1[C:22]([C:23]([N:25]2[CH2:29][CH:28]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH:27](O)[CH2:26]2)=[O:24])=[CH:21][C:20]([C:38]#[N:39])=[CH:19][C:18]=1[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[Si:7]([O:6][CH:27]1[CH:28]([N:30]2[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]2)[CH2:29][N:25]([C:23]([C:22]2[C:17]([Cl:16])=[C:18]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])[CH:19]=[C:20]([C:38]#[N:39])[CH:21]=2)=[O:24])[CH2:26]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CN1CCN(C2CN(C(=O)c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2O)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCN(C2CN(C(=O)c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
tert-Butyldimethylsilyl trifluoromethanesulfonate (0.240 mL, 1.026 mmol) was added to a solution of (+/−)-tert-butyl (2-chloro-5-cyano-3-(3-hydroxy-4-(4-methylpiperazin-1-yl)pyrrolidine-1-carbonyl)phenyl)carbamate (119 mg, 0.256 mmol) and imidazole (69.8 mg, 1.026 mmol) in DMF (3 mL) and the reaction solution was stirred at room temperature over the weekend. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 1-6% methanol/dichloromethane). (+/−)-tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-4-(4-methylpiperazin-1-yl)pyrrol idine-1-carbonyl)-2-chloro-5-cyanophenyl)carbamate (120 mg) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(Cl)ccc2c1CCNCC2
Temperature: 25 °C
Reaction time: 42 h
Yield: 94 %

Procedure:
Slurry 7-chloro-6-(ethoxycarbonyl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (176 g, 503 mmol) and potassium carbonate (348 g, 2516 mmol) in ethanol (1.4 L) and water (1.4 L). Stir the mixture at room temperature for 42 h. Partition the mixture between water (2.6 L) and EtOAc (2.6 L). Collect the organic layer and back extract the aqueous layer with EtOAc (1.8 L). Wash the combined organic extracts successively with water (1.8 L) and brine (1.8 L). Collect the organic layer, dry over Na2SO4 and concentrate in vacuo to obtain the desired intermediate as a green oil (120 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[C:5]2[C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[H][H]>CO.[Pd].ClCCl>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=2)=[CH:18][CH:19]=1)(=[O:24])=[O:25]
Reactant: [H][H]
Reactant: Cc1ccc2cc(CC(=O)O)cc(C(=O)c3ccc(S(C)(=O)=O)cc3)c2c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2cc(CC(=O)O)cc(Cc3ccc(S(C)(=O)=O)cc3)c2c1
Yield: 21.4 %

Procedure:
A solution of [6-methyl-4-(4-methanesulfonyl-benzoyl)-naphthalen-2-yl]-acetic acid (example 2-28) (70 mg, 0.183 mmol) in methanol (8 mL) was hydrogenated using a H-cube hydrogenation reactor with a flow rate of 1 mL/min and a 10% palladium on carbon catalyst cartridge at 30° C. under 10 bar hydrogen pressure. After the reaction was complete (monitored by TLC, 4% methanol in dichloromethane), the solvent was evaporated in vacuo. Reverse-phase preparative HPLC (using a Waters® Delta-Prep™ 3000 with a Varian Pursuit® C-18 column [10 μm, 20×150 mm]) gave [4-(4-methanesulfonyl-benzyl)-6-methyl-naphthalen-2-yl]-acetic acid (14.4 mg, 21%) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm: 7.83 (d, J=8.4 Hz, 2 H), 7.74 (d, J=8.7 Hz, 1 H), 7.66 (s, 1H), 7.60 (s, 1 H), 7.38 (d, J=8.4 Hz, 2 H), 7.32 (d, J=8.7 Hz, 1 H), 7.22 (s, 1 H), 4.48 (s, 2 H), 3.78 (s, 2 H), 3.02 (s, 3 H), 2.46 (s, 3 H); HRMS cald. for O21H20O4S (ESI+) [(M+Na)+] 391.0974, obsd. 391.0976.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[N:49]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:36]>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH2:55][N:49]([C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:50][CH2:51]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CC[C@@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Product: CCOCCn1c(N2CCCN(CC[C@@]3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using (R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:37])([CH2:34][CH2:35][CH3:36])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:33])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=3[F:31])=[CH:20][C:19]([CH3:32])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:37])([CH2:34][CH2:35][CH3:36])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:33])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=3[F:31])=[CH:20][C:19]([CH3:32])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3cccc(F)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3cccc(F)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 35 mg (0.066 mmol) of rac-{1-[({7-[(2,3-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 118A) in 2 ml of dichloromethane was admixed with 0.079 ml (1.03 mmol) of trifluoroacetic acid. The resulting solution was stirred at room temperature overnight. The solvent was drawn off under reduced pressure and the residue was purified by preparative HPLC chromatography (Method 21), which gave 6 mg (27% of theory) of the target compound.