Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[O:44])=[CH:38][CH:37]=1>ClCCl>[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:44])=[CH:40][CH:41]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.25 g, 0.67 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (0.168 g, 1.67 mmol) (Aldrich), followed by the addition of 4-isocyanato-benzoic acid methyl ester (0.142 g, 0.80 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-4-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid methyl ester as a white solid. (Yield 0.3 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH2:8])[CH:7]=1.[F:17][C:18]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:19]=1[C:20]([NH:22][C:23]1[C:24]([C:28](O)=[O:29])=[N:25][NH:26][CH:27]=1)=[O:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH:8][C:28]([C:24]2[C:23]([NH:22][C:20](=[O:21])[C:19]3[C:18]([F:17])=[CH:34][CH:33]=[CH:32][C:31]=3[F:35])=[CH:27][NH:26][N:25]=2)=[O:29])[CH:7]=1
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Reactant: CN1CCC(Oc2ccc(F)cc2N)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCC(Oc2ccc(F)cc2NC(=O)c2n[nH]cc2NC(=O)c2c(F)cccc2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-fluoro-2-(1-methyl-piperidin-4-yloxy)-phenylamine) (0.049 g, 0.22 mmol) was combined with 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (0.053 g, 0.20 mmol), EDC (0.048 g, 0.25 mmol), HOBt (0.034 g, 0.25 mmol) and DMF (1 ml) and the resulting reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was reduced in vacuo and purified by preparative LC/MS to give 4-(2,6-Difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid[5-fluoro-2-(1-methyl-piperidin-4-yloxy)-phenyl]amide as a buff solid. (0.010 g, 11%) (LC/MS: Rt 2.19, [M+H]+ 474.27).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1)#[N:13]>C(O)C>[NH2:13][CH2:12][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1
Reactant: N#Cc1ccccc1-n1cccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1ccccc1-n1cccc1

Procedure:
To a well stirred suspension of (0.05 mol) of lithium aluminum hydride in 100 ml of anhydrous tetrahydrofuran, (0.043 mole) of 1-(2-cyanophenyl)pyrrole were added by small portions. Then the mixture was maintained with stirring at room temperature for 18 hours. Addition of aqueous ethanol to destroy the excess lithium aluminium hydride, followed by filtration afforded a solution, which was then evaporated in vacuo. The residue was extracted with ethyl ether, the organic layer washed with water and dried over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave a crude product, which was purified by passing through an alumina column eluting with chloroform to give 1-(2-aminomethylphenyl)pyrrole.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>C(Cl)Cl>[CH2:21]([S:23]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)(=[O:25])=[O:24])[CH3:22]
Reactant: CCS(=O)(=O)Cl
Reactant: NCCSc1cccc2nccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCCSc1cccc2nccn12
Yield: 78.1 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (1.93 g, 10 mmoles) and triethylamine (1.53 ml, 11 mmoles) in methylene chloride (100 ml) was added ethanesulfonyl chloride (0.95 ml, 10 mmoles) at room temperature with stirring and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed in turn with an aqueous saturated sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:5) to obtain 2.23 g of the desired product (78.2%, colorless crystals).
Reaction SMILES: [C:1]([S:9]/[CH:10]=[CH:11]\[C:12](Cl)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([NH2:18])[C:16]#[CH:17].C(N(CC)CC)C.Cl>ClCCl>[CH2:15]([NH:18][C:12](=[O:13])/[CH:11]=[CH:10]\[S:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16]#[CH:17]
Reactant: O=C(Cl)/C=C\SC(=O)c1ccccc1
Reactant: C#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)/C=C\SC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
To a stirred, cooled (0° C.) solution of 0.70 g (0.0039 mol) of cis-3-(benzoylthio)propenoyl chloride in 40 ml of dichloromethane under nitrogen was added dropwise 0.21 ml (0.0039 mol) of propargylamine as a solution in 10 ml of dichloromethane. After 15 min, 0.43 ml (0.0039 mol) of triethylamine was added dropwise. The reaction was allowed to stir at 0° C. for 2 h, poured into 10% aqueous hydrochloric acid, and extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, and dried over magnesium sulfate. Filtration and removal of solvents gave 0.49 g (65% yield) of N-(2-propynyl)-cis-3-(benzoylthio)acrylamide as a white powder, m.p. 131°-134° C., as described in Table 1.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:26][CH2:27][Cl:28].C([O-])([O-])=O.[K+].[K+]>CCCCCC.C1COCC1>[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][C:16]([CH2:26][CH2:27][Cl:28])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1CCCN(Cc2ccccc2)CC1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCl)CCCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To DIPA (3.22 mL) was added dropwise a 2.64 M solution of n-butyl lithium in hexane (7.97 mL) at −78° C., followed by stirring for 30 minutes. To the reaction mixture was added ethyl 1-benzylazepane-4-carboxylate (5.0 g), followed by stirring for 30 minutes. Next, a solution of 1-bromo-2-chloroethane (3.02 g) in THF was added dropwise thereto, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture was added an aqueous K2CO3 solution, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia). Desired fractions were collected, and concentrated under reduced pressure. After concentration under reduced pressure, to the residue, a part of which was solidified, was added EtOAc, followed by purification by silica gel column chromatography (EtOAc) to obtain ethyl 1-benzyl-4-(2-chloroethyl)azepane-4-carboxylate (4.11 g) as a colorless oily substance.
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[CH:16]([C:22]([OH:24])=[O:23])[CH2:15][CH2:14]2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25]O>>[CH3:25][O:23][C:22]([CH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:3](=[O:10])[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[C:19]([O:20][CH3:21])[CH:18]=2)[CH2:14][CH2:15]1)=[O:24]
Reactant: COc1cc2c(cc1C(=O)c1ccccc1)CCC2C(=O)O
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1CCc2cc(C(=O)c3ccccc3)c(OC)cc21

Procedure:
Analogously to the description in Example 2, 4.7 g of 5-benzoyl-6-methoxy-indane-1-carboxylic acid methyl ester and 20 ml of N sodium hydroxide solution in 50 ml of methanol give 5-benzoyl-6-methoxy-indane-1-carboxylic acid of melting point 126°-128° C. (from ether-petroleum ether).
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].C([O:10][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:20][CH2:19]2)=[N:16][N:17]=1)=O)C>>[CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:22][CH2:23]2)=[N:16][N:17]=1)=[O:10]
Reactant: CC(C)CCCN
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Product: CC(C)CCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-methylpentylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.045 g, yield 79%). 1H NMR (300 MHz, CDCl3) δ 7.73-7.7 (m, 1H), 7.64-7.5 (m, 2H), 7.34-7.32 (m, 1H), 7.06 (br., t, 1H), 4.09-3.8 (m, 1H), 3.93-3.81 (m, 1H), 3.75-3.6 (m, 2H), 3.56-3.48 (m, 2H), 3.43-3.29 (m, 4H), 1.63-1.48 (m, 3H), 1.46-1.16 (m, 2H), 0.85 (d, J=6.6 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.5, 158.2, 156.0, 133.9, 132.3, 129.6, 126.9, 126.8, 126.7, 125.3, 121.7, 49.5, 48.9, 45.9, 40.7, 39.9, 35.9, 27.7, 27.3, 22.4. MS (ES+) m/z 470 (M+1).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[N:2]([NH:1][C:22](=[O:23])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[N:11]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(Cl)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(Cl)c2ccccc2c1=O

Procedure:
The product from Example 19A and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.70 (s, 2H) 7.23-7.56 (m, 4H) 7.97-8.17 (m, 3H) 8.36 (d, J=7.63 Hz, 1H) 11.77 (s, 1H); MS (ESI) m/z 349 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Br)c1ccc(C(=O)CCCCl)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (5.00 g, 22.2 mmol) and N-bromosuccinimide (4.1 g, 23.0 mmol) in carbon tetrachloride (25 mL) and add AIBN radical initiator (300 mg). Stir and maintain under a nitrogen atmosphere at 80-90° C. or optionally irradiate with a sunlamp until a vigorous exotherm occurs at which point momentarily remove until reflux subsides and then reapply the heat. Reflux for 30 minutes and add another potion of N-bromosuccinimide (100 mg) while maintaining reflux and reflux an additional 15 minutes. Cool to room temperature and precipitate the succinimide from the solution by allowing to stand overnight. Filter and wash the succinimide (2.25 g) with carbon tetrachloride (20 mL). Combine the filtrates and evaporate the solvent in vacuo to give the title compound as a yellow oil (6.80 g, 100%).
Reaction SMILES: [N+]([O-])(O)=O.[I:5]I.[CH:7]1([C:10]2[O:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH2:9][CH2:8]1>O>[CH:7]1([C:10]2[O:14][N:13]=[C:12]([CH3:15])[C:11]=2[I:5])[CH2:9][CH2:8]1
Reactant: Cc1cc(C2CC2)on1
Reactant: II
Solvent: O=[N+]([O-])O
Solvent: O
Product: Cc1noc(C2CC2)c1I
Yield: 109.6 %

Procedure:
Concentrated nitric acid (10 ml) was added dropwise to a stirred heated mixture of iodine (23.8 g) and 5-cyclopropyl-3-methylisoxazole (24.6 g coming approximately 20% 3-cyclopropyl-5-methylisoxazole) whilst maintaining the temperature in the range 90°-95° C. The mixture was stirred and heated at 95°-100° C. for 1 hour. It was cooled, poured into cold water and extracted with ether. The combined extracts were washed with aqueous sodium bicarbonate solution (saturated), aqueous sodium metabisulphate solution (saturated), water, dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated to dryness and the residue was triturated with petroleum spirit and filtered. The solid was recrystallized from petroleum spirit to give 5-cyclopropyl-4-iodo-3-methylisoxazole (25.6 g) as a white solid, m.p. 71° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:7].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccc([N+](=O)[O-])cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(4-nitrophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 438.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[CH3:15])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:35]([O:37]CC)=[CH2:36])CCC.[F-].[Cs+].C(OCC)(=O)C>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[S:9][C:10]([C:35](=[O:37])[CH3:36])=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1cc(Br)sc1NC(=O)OC(C)(C)C
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Reaction time: 0.17 h

Procedure:
(5-Bromo-3-{[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-sulfamoyl}-thiophene-2-yl)carbamic acid tert-butyl ester (the compound of Preparation Example 97) (5.5 g), tributyl(1-ethoxyvinyl)tin (6.7 g), cesium fluoride (5.3 g) and tetrakis(triphenylphosphine)palladium (0.73 g) were stirred in 1,4-dioxane (50 mL) at 100° C. for 2 hours. After ethyl acetate was added and insoluble matter was removed by filtration, 2N hydrochloric acid was added, and the solution was stirred for 10 minutes. After washing the organic layer with water, an aqueous solution of sodium bicarbonate and saturated sodium chloride water, and was dried with anhydrous magnesium sulfate. The residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (3.2 g9 was obtained as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH:21]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:21]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: N#Cc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)cc1
Yield: 16.6 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 4-Formylbenzonitrile (36.8 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 17.15 mg (17%) of the title compound. (300 MHz, DMSO-d6) 13.55 (s, 1H), 8.29 (d, J=8 Hz, 1H), 8.05-7.99 (m, 3H), 7.78 (s, 1H), 7.36 (m, 1H), 7.25 (s, 1H), 6.43 (m, 1H), 6.38 (m, 1H), 5.18 (t, J=17 Hz, 8.5 Hz, 1H), 2.90 (s, 1H), 2.81 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=405 (M+H), HPLC: 2.42 min. (G Method)
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[Si:25]([O:15][CH2:14][C@H:11]1[CH2:12][CH2:13][N:9]([C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:8])[CH2:10]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](c1ccccc1)N1CC[C@H](CO)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](c1ccccc1)N1CC[C@H](CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of {(3S)-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}methanol (6.62 g, 32 mmol) and imidazole (4.77 g, 70 mmol) in N,N-dimethylformamide (90 ml) was added tert-butyldimethylchlorosilane (5.28 g, 35 mmol) at 0° C. and the resulting mixture was warmed to room temperature. The reaction mixture was stirred overnight and poured into water. Extraction with ethyl acetate was performed. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=90/10 to 75/25) to afford (3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-[(1R)-1-phenylethyl]pyrrolidine (8.81 g, 27.6 mmol, 86%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[C:3]=1[N+:19]([O-:21])=[O:20].[F:22][C:23]([F:39])([F:38])[O:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[C:3]([N+:19]([O-:21])=[O:20])=[C:2]([N:33]3[CH2:34][CH2:35][CH:30]([O:29][C:28]4[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:38])[F:39])=[CH:37][CH:36]=4)[CH2:31][CH2:32]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)c2[N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
A mixture of compound (6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (400 mg, 1.22 mmol), 4-(4-trifluoromethoxy-phenoxy)-piperidine (399 mg, 1.34 mmol) and potassium carbonate (336 mg, 2.44 mmol) in DMF (8 ml) was heated in an oil bath at 60° C. for 2 hours. The crude mixture was cooled to 0° C. and quenched with water. The solid was filtered off, rinsed with water and dried in vacuum oven to give product B119 as a yellow solid (604 mg, 90%). 1HNMR (CDCl3, 400 MHz) d 2.01-2.08 (m, 4H), 3.06 (s, 3H), 3.64-3.66 (m, 2H), 3.73-3.75 (m, 2H), 4.62-4.66 (m, 1H), 6.93 (d, 2H), 7.17 (d, 2H), 7.93 (dd, 4H), 8.21 (s, 1H), 10.2 (s, 1H). Exact mass calculated for C23H22F3N5O6S 553.1, found 554.3 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([C:12]2[C:13]([CH3:22])=[N:14][C:15]([O:20]C)=[C:16]([CH2:18][CH3:19])[CH:17]=2)[CH:9]=[CH:8][CH:7]=1)=[O:5])C.C[Si](Cl)(C)C>C(#N)C>[CH2:18]([C:16]1[C:15](=[O:20])[NH:14][C:13]([CH3:22])=[C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[N:11]=2)[CH:17]=1)[CH3:19]
Reactant: CCOC(=O)c1cccc(-c2cc(CC)c(OC)nc2C)n1
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Product: CCc1cc(-c2cccc(C(=O)O)n2)c(C)[nH]c1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
5′-Ethyl-6′-methoxy-2′-methyl-[2,3′]bipyridinyl-6-carboxylic acid ethyl ester (750 mg, 2.5 mmol) is suspended in acetonitrile and, after addition of KI (1.04 g, 6.25 mmol) and trimethylsilyl chloride, heated to 80° C. under argon for 3 h. This is followed by cooling to room temperature, concentration, addition of 50 ml of water and filtration with suction. The resulting ester (710 mg) is dissolved in MeOH/THF (4/1, 10 ml) and stirred with 1N LiOH solution (7.5 ml) at RT. After 1.5 h, 2N KHSO4 solution is used to acidify, and the precipitate is filtered off with suction. The mother liquor is concentrated and dried in vacuo overnight. The precipitate and the residue are combined and purified by chromatography on silica gel with ethyl acetate/methanol (1/1); yield: 630 mg (98%). MS: m/e=259 (M+H). 1H-NMR (D6-DMSO, δ ppm) 11.65 (s, 1H); 7.91 (t, 1H, J=7.7 Hz); 7.84 (d, 1H, J=7.7 Hz); 7.60 (d, 1H, J=7.7 Hz); 7.51 (s, 1H); 2.42 (q, 2H, J=7.4 Hz); 2.33 (s, 3H); 1.11 (t, 3H, J=7.4 Hz).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][NH:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])[CH3:29]>>[C:28]([C:31]1[CH:36]=[CH:35][C:34]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:27])=[O:26])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[CH:33][CH:32]=1)(=[O:30])[CH3:29]
Reactant: CCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CCCC(Oc1ccc(-c2ccc(C(C)=O)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
This compound is made in a substantially similar manner as Example 117 using isomer 1 of 3-{4-[1-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid methyl ester and 4-acetylphenylboronic acid as starting materials in step D. MS (ES): 458.3 [M−H]−.
Reaction SMILES: S(=O)(=O)(O)O.C(OC([NH:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([CH3:21])=[C:14]([CH3:22])[C:13]=1[N+:23]([O-:25])=[O:24])=O)C>>[CH3:22][C:14]1[C:13]([N+:23]([O-:25])=[O:24])=[C:12]([C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]=1[CH3:21])[NH2:11]
Reactant: CCOC(=O)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1C

Procedure:
Into 30 ml. of concentrated sulfuric acid is added 2.85 grams of N-(ethoxycarbonyl)-3,4-dimethyl-2,6-dinitroaniline. The mixture is heated to a temperature in the range of from 110° C. to 120° C. for 15 minutes and then poured over ice. The precipitated solid is collected and crystallized from absolute ethanol yielding the desired product having a melting point of from 141.5° C. to 142.5° C.