Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1>C(OCC)C.O1CCCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:28]2([OH:31])[CH2:29][CH2:30][CH:25]([N:22]3[CH2:23][CH2:24][N:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)[CH2:20][CH2:21]3)[CH2:26][CH2:27]2)[CH:3]=1
Reactant: O=C1CCC(N2CCN(c3ccccn3)CC2)CC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2cccnc2)CCC(N2CCN(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4.74 g (30 mmol) of 3-bromopyridine in 100 ml of diethyl ether is cooled to --78° C. under a nitrogen atmosphere. n-Butyllithium (18.75 ml, 30 mmol) is added dropwise. The resulting suspension is stirred for 30 minutes. To this solution is added a solution of 5.19 g of 4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanone in 175 ml of tetrahydrofuran dropwise. The cold bath is removed and the mixture is allowed to warm to room temperature and quenched with 50 ml of saturated ammonium chloride solution. The tetrahydrofuran is evaporated under vacuum and the residue is partitioned into water/dichloromethane. The organic phase is separated and dried over magnesium sulfate and evaporated in vacuo to give the title compound as a mixture of cis and trans isomers.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:14]([N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:15]
Reactant: CCNCCOC
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CCOC)c1ccc(C(F)(F)F)cc1C=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzaldehyde (2.7 g) and ethyl-(2-methoxy-ethyl)-amine (2.18 g) are dissolved in toluene (20 ml), and thereto is added potassium carbonate (5.83 g) and the mixture is stirred at 120° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a saturated brine and the mixture is separated, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give 2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzaldehyde (3.75 g). MS (m/z): 276 [M+H]+
Reaction SMILES: I[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:3]=1[CH:25]=[O:26].ClC1C2C([C:37]3[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=3)[C:40]#[N:41])=C(C)N(COCC[Si](C)(C)C)C=2N=CN=1>>[CH:25]([C:3]1[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2[N:6]=[CH:7][N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:10]=2[C:2]=1[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[C:40]#[N:41])=[O:26]
Reactant: Cc1c(-c2cccc(C#N)c2)c2c(Cl)ncnc2n1COCC[Si](C)(C)C
Reactant: C[Si](C)(C)CCOCn1c(C=O)c(I)c2c(N3CCOCC3)ncnc21
Product: C[Si](C)(C)CCOCn1c(C=O)c(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc21

Procedure:
5-Iodo-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (C29) was converted to the product using the method described for synthesis of 3-(4-chloro-6-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C7) in Example 2. The product was obtained as a yellow solid. Yield: 1.5 g, 3.2 mmol, 78%. 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 8.60 (s, 1H), 7.77-7.83 (m, 2H), 7.72-7.76 (m, 1H), 7.67 (br dd, J=8, 8 Hz, 1H), 6.09 (s, 2H), 3.66-3.71 (m, 2H), 3.38-3.44 (m, 4H), 3.23-3.28 (m, 4H), 0.94-1.01 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([NH:21][CH3:22])=[N:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[CH2:23]([N:28]=[C:29]=[O:30])[CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([N:21]([CH3:22])[C:29]([NH:28][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:30])=[N:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCO[C@@H](Cc1ccc(-c2cnc(NC)s2)cc1)C(=O)OC
Reactant: CCCCCN=C=O
Product: CCCCCNC(=O)N(C)c1ncc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)s1
Yield: 26.1 %

Procedure:
In a manner similar to that of Example 7i, starting with 0.17 g (0.53 mmol) of methyl 2(S)-ethoxy-3-[4-(2-methylaminothiazol-5-yl)phenyl]propionate and 0.14 ml (1.1 mmol) of pentyl isocyanate, 0.06 g (26%) of methyl 2(S)-ethoxy-3-{4-[2-(1-methyl-3-pentylureido)thiazol-5-yl]phenyl}propanoate is obtained.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O.O>[CH2:24]([S:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CCc2cc(OCCCCS)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCc2cc(OCCCCSCc3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2.5 gm of 6-(4-mercapto-butoxy)-3,4-dihydro-carbostyril in 25 ml of dimethysulfoxide was mixed whilst stirring with 1.4 gm of potassium carbonate and subsequently with 1.3 ml of benzyl chloride. After stirring for 15 hours at room temperature, the reaction mixture was diluted with 200 ml of water, and the precipitated oily substance was separated and recrystallized from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[N-:22]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:17])(=[NH:22])=[O:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(C)Nc1nc(Nc2ccc(S(C)=O)cc2)ncc1Br
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)Nc1nc(Nc2ccc(S(C)(=N)=O)cc2)ncc1Br
Temperature: 45 °C
Reaction time: 16 h

Procedure:
185 mg (0.50 mmol) of (RS)-5-bromo-N4-isopropyl-N2-[4-(methyl sulfinyl)phenyl]-pyrimidine-2,4-diamine in 1 ml of DCM is mixed with 40 mg (0.55 mmol) of sodium azide. The batch is slowly mixed with 0.13 ml of concentrated sulfuric acid at 0° C. and then heated to 45° C. After 16 hours, the batch is cooled to room temperature, mixed with 2 ml of 1N NaOH solution and extracted from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 9:1). 38 mg (0.10 mmol, corresponding to 20% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2([CH3:25])[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2([CH3:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CN1CCN(C2(C)CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1CCN(C2(C)CCNCC2)CC1
Reaction time: 12 h

Procedure:
A suspension of 0.44 g (1.10 mmol) ethyl[4-(1-benzyl-4-methyl-piperidin-4-yl)-piperazin-1-yl]-acetate and 100 mg 10% Pd/C in 20 mL EtOH was hydrogenated for 12 h at 50° C. and 3447 hPa hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated to dryness. The product was reacted further without purification.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][CH2:38][C:39](Cl)=[O:40]>C1COCC1>[CH2:1]([N:8]([CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=1)[OH:12])[C:39](=[O:40])[CH2:38][Cl:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(CN(Cc1ccccc1)C(=O)CCl)C(O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (1RS,2SR)-3-(benzylamino)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(4-chloro-3-fluorophenyl)propan-1-ol (29.3 g) and triethylamine (11.2 ml) in THF (335 ml) was added chloroacetyl chloride (5.37 ml) under ice-cooling, and the mixture was stirred at 0° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (35.0 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=O.C(O)(=O)C.C([NH2:18])(C)C>>[NH2:18][C@H:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)N
Reactant: CC(=O)c1cccc(O)c1
Solvent: CC(=O)O
Product: C[C@H](N)c1cccc(O)c1
Temperature: 37 °C

Procedure:
A total of 65 g of the 3-hydroxyacetophenone (compound (1)) substrate was charged to the stirred mixture as a powder. After addition of substrate was complete, the volume of the reaction was topped up to 1 L (if necessary) with the appropriate amount of 0.1 M TEA buffer, pH 7.5. The resulting slurry was stirred at 150 rpm at 37° C. (internal temperature). The temperature was monitored using an external temperature probe. The reaction was conducted under a constant nitrogen sweep of 5 L/min. Additional 5 M isopropylamine acetate (100 mL) was charged to the stirred mixture after 24 h and again after 48 h.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[Br-:7].[CH2:8]([N+:4]1[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Cn1ccnc1
Reactant: CCCCCCBr
Product: CCCCCC[n+]1ccn(C)c1
Product: [Br-]
Temperature: 90 °C
Yield: 97.9 %

Procedure:
A 35 mL glass pressure tube (Ace Glass Cat#8648-07) containing a stir bar was charged with 6.158 g (0.075 moles) of 1-methylimdazole followed by 12.380 g (0.075 moles) of 1-bromohexane. The tube was sealed with a threaded Teflon plug and an O-ring and the tubes were placed in an oil bath on a VWR stirring hot plate. The temperature was raised to 90° C. and maintained at this temperature for 16 hours during which time the solution became viscous and the stir bar had stopped. The tube was removed from the bath and mixed vigorously on a vortexing mixer to completely mix the two layers and the was tube replaced into the oil bath at 90° C. The tube was heated for another hour and then mixed vigorously a second time followed by another hour of heating at 90° C. The cycle was repeated once more until the viscous liquid was homogeneous. The liquid was extracted with equal volumes of ethyl acetate three times followed by rotary evaporation to remove the residual ethyl acetate to give 18.147 g of the 1-hexyl-3-methylimidazolium bromide as a viscous lightly yellow colored oil. Compound is also available from loLiTec (Heilbronn, Germany).
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])=[CH:14][CH:13]=2)=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH:6]=1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][N:39]=[C:38]3[NH:42][CH:43]=[CH:44][C:37]=23)O1.C(=O)(O)[O-].[Na+]>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.CN(C)C=O>[C:22]1([NH:21][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C:3]3[C:2]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]5[NH:42][CH:43]=[CH:44][C:37]=45)=[CH:6][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:4]=3)=[CH:13][CH:14]=2)=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2ccnc3[nH]ccc23)OC1(C)C
Reactant: O=C(Nc1ccccc1)Nc1ccc(-c2nn(CC(F)(F)F)cc2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)Nc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccnc3[nH]ccc23)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
A mixture of N-{4-[4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]phenyl}-N′-phenylurea (0.059 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.059 mmol), tetrakis(triphenylphosphine)palladium(0) (0.003 mmol), saturated sodium bicarbonate (0.177 mL) and anhydrous N,N-dimethylformamide (1 mL) was stirred at 100° C. in a sealed tube for 4 h and cooled to room temperature. Filtration through a pad of Celite, concentration in vacuo and Gilson reverse phase HPLC purification furnished the title compound as a white solid (35%). ESMS [M+H]+: 477.2
Reaction SMILES: [C:1](=[O:70])([O:7][C@H:8]([C@@H:37]([NH:45][C:46](=[O:69])[C@@H:47]([N:52]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([OH:67])([CH3:66])[CH3:65])[N:59]=2)[C:53]1=[O:68])[C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:9][C@H:10]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].C(N(CC)[P:74]([O:83][CH2:84][C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)[O:75][CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)C.N1C=NN=N1.ClC1C=CC=C(C(OO)=[O:106])C=1>O1CCCC1.C(OCC)(=O)C.ClCCl>[C:1](=[O:70])([O:2][C:3]([CH3:4])([CH3:5])[CH3:6])[O:7][C@H:8]([C@@H:37]([NH:45][C:46](=[O:69])[C@@H:47]([N:52]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([O:67][P:74]([O:75][CH2:76][C:77]3[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=3)([O:83][CH2:84][C:85]3[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=3)=[O:106])([CH3:66])[CH3:65])[N:59]=2)[C:53]1=[O:68])[C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:9][C@H:10]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:17]=1
Reactant: CCN(CC)P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)OC(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C(C)(C)O)n2)C1=O)C(C)(C)C)C(C)(C)C
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)OC(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C(C)(C)OP(=O)(OCc3ccccc3)OCc3ccccc3)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: -45 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
A solution of the compound of Example 194A (1.16 mmol), dibenzyl diethylphosphoramidite (1.25 mL, 4.17 mmol), and 1H-tetrazole (0.40 g, 5.71 mmol) in tetrahydrofuran (11.0 mL) was stirred at room temperature for 12 hours. Dichloromethane (11.0 mL) was added and the mixture was cooled to −45° C., followed by addition of m-chloroperbenzoic acid (1.15 g, 6.66 mmol). After stirring for 1 hour at −45° C., the reaction was diluted with ethyl acetate and washed twice with 10% Na2CO3 and then with brine. The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with dichloromethane and ending with 75% ethyl acetate in dichloromethane, to give the title compound (0.684 g, 48% yield over two steps).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][C:20](=[O:24])[NH:21]3)=[CH:17][CH:16]=2)=[O:14])[CH:8]=1)=[O:5].[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:19]1[C:18]2[C:22](=[CH:23][C:15]([C:13]([C:9]3[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=4[CH3:1])[CH:12]=[CH:11][CH:10]=3)=[O:14])=[CH:16][CH:17]=2)[NH:21][C:20]1=[O:24]
Reactant: CCOC=O
Reactant: Cc1ccccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 83 %

Procedure:
2-Methyl-N-[3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-benzamide (5.00 g, 13.499 mmol) and ethyl formate (3.24 mL, 40.3 mmol) were dissolved in anhydrous ethanol (135 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (25.2 mL, 67.47 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a light yellow precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-2-methyl-benzamide (4.464 g, 11.2 mmol, 81%).
Reaction SMILES: ClC1C=CC([N+:8]([O-:10])=[O:9])=CC=1C.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:8]([O-:10])=[O:9])[C:14]=1[CH3:19]
Reactant: Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1ccccc1Cl
Product: Cc1c(Cl)cccc1[N+](=O)[O-]
Yield: 43 %

Procedure:
2-Chloro-5-nitrotoluene, which is required as a starting product, is accessible by nitrating o-chlorotoluene (Rec. Trav. Chim. Pays-Bas 32, (1913) 244 et seq.). It can be isolated from the resulting mixture of isomers by distillation in 43% yield (Loc. cit. 286). This distillation gives pure 2-chloro-6-nitrotoluene as first runnings the other isomers can be separated in a known way. Since all isomers, by virtue of their reactive groups, are intermediates which can be put to many uses and for which there is adequate demand, no undesirable by-products are obtained in this reaction. Thus, even if this preliminary stage is included, this invention represents a very favorable procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[S:19](N)(N)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][S:19]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: NS(N)(=O)=O
Reactant: NCCCN1CCCC1
Reactant: NCc1ccc(Cl)cc1
Product: O=S(=O)(NCCCN1CCCC1)NCc1ccc(Cl)cc1
Yield: 22 %

Procedure:
A solution of 4-CHLOROBENZYLAMINE (0.610 ml, 5.00 mmol), 1-(3-aminopropyl)pyrrolidine (0.632 ml, 5.00 mmol) and sulfamide (480 mg, 4.99 mol) was heated at reflux for 2 h. The reaction was allowed to cool and partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous was discarded and the organic phase washed with water (20 ml) and brine (20 ml). The organic phase was dried over anhydrous sodium sulfate and the filtrate was evaporated at reduced pressure. The residue was purified by flash column chromatography (100:10:1 DCM: methanol) to obtain the title compound as a white solid (365 mg, 22%). 1HNMR 7.35-7.28 (4H, m), 4.18 (2H, s), 3.15 (2H, t, 6), 2.61 (2H, t, 6), 2.51 (4H, br m), 1.82-1.67 (6H, m). Microanalysis found C 49.97 H 6.73 N 12.50 C14H22ClN3O2S-0.26H2O requires C 49.96 H 6.74 N 12.49.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[O:18][CH:19]=[N:20][N:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[CH2:26]>>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1/[CH:25]=[CH:26]/[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[O:18][CH:19]=[N:20][N:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(F)cc1F
Reactant: O=S(=O)(c1ccc(Br)cc1)c1ccccc1-c1nnco1
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)cc1)c1ccccc1-c1nnco1

Procedure:
The title compound was prepared according to the method of preparation of Intermediate 1, Step 2, using 2-{2-[(4-bromophenyl)sulfonyl]phenyl}-1,3,4-oxadiazole (Step 1) in place of 3-[(4-bromophenyl)sulfonyl]propanenitrile and 2,4-difluorostyrene in place of 4-fluorostyrene. δH (500 MHz, d6 DMSO): 9.45 (1H, s), 8.35 (1H, d, J 7.8), 7.97-7.85 (8H, m), 7.47-7.31 (3H, m), 7.17 (1H, t, J 8.6). m/z (ES+) 425 [MH+].
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[OH:18])=[O:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:27]([C:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][CH2:32][CH2:33]Br)#[N:28]>CN(C)C=O.O>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:2][CH:1]=2)=[O:3])=[C:5]([O:18][CH2:33][CH2:32][CH2:31][CH2:30][C:29]([CH3:36])([C:27]#[N:28])[CH3:35])[CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C#N)CCCCBr
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C#N)CCCCOc1cc(OCc2ccccc2)ccc1C(=O)c1ccccc1
Yield: 111 %

Procedure:
A solution of 4-benzyloxy-2-hydroxyacetophenone (2.45 g), potassium carbonate (3.25 g), potassium iodide (0.42 g), and 5-cyano-5-methyl-1-bromohexane (2.6 g) in dimethylformamide (40 mL) was heated at 90° C. for 22 hours under nitrogen. The slurry was cooled, poured into water (150 mL) and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4), filtered, and concentrated under reduced pressure to an orange oil. This was purified by flash chromatography (ethyl acetate:hexane) to afford the product (2.4 g) as a clear oil. NMR(CDCl3): 1.37, s (6H); 1.64, m (4H); 1.89, m (2H); 2.58, s (3H); 4.03, t (3H); 5.09, s (2H); 6.50, s (1H); 6.58, d (1H); 7.37, m (5 H); 7.81, d (1H). Mass Spec (GC-MS) m/z=365 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(Cc2cnc(OC)c(-c3cccc(Cl)c3)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncc(Cn2cc(C(=O)O)cn2)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a solution of ethyl 1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carboxylate (Example 169, 25.00 mg, 0.07 mmol) in THF (2 mL), methanol (2 mL) was added lithium hydroxide (1.00 mL, 1.00 mol/L, 1.00 mmol). The mixture was stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the crude residue dissolved in water. The aqueous reaction mixture was acidified with 1 N HCl (5 mL), and extracted into ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound (20 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ 12.30 (br s, 1H), 8.39 (br s, 1H), 8.19 (br s, 1H), 7.80 (br s, 2H), 7.68-7.26 (m, 4H), 5.34 (br s, 2H), 3.87 (br s, 3H). [M+H]=344.31.