Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18](=[O:19])[C:13]=2[CH:12]=[C:11]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(=O)([O-])[O-].[K+].[K+].[H][H]>[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18](=[O:19])[C:13]=2[CH:12]=[CH:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(cc(Br)n2COCc2ccccc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C[Si](C)(C)CCOCn1ncc2c(ccn2COCc2ccccc2)c1=O
Yield: 195.7 %

Procedure:
To 5.00 g (10.8 mmol) of 1-benzyloxymethyl-2-bromo-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Reference example 33-(a) were added 50 ml of methanol, 30 ml of toluene, 1.5 g of potassium carbonate and 2.5 g of 51 palladium-active carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at room temperature for 3 hours. After completion of the reaction, insoluble material of the reaction suspension was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 8.15 g of the title compound as a pale yellowish solid. (Yield: 77%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:6][N:5]([CH2:4][C:3]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=2[Cl:1])[C:15](=[O:14])[CH:16]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccc(F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(F)cc2Cl)[nH]1
Reaction time: 8 h

Procedure:
53.8 g of 2-chloro-4-fluorobenzylhydrazine were added dropwise, under nitrogen, to a solution of 49.2 g of β-aminoβ-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 250 ml of ethanol, in the course of which the temperature rose from 22° to 32° C. After standing overnight, the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 192°, 25 g (34%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:31])(=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH2:32])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([C:36]1[C:37]([N:43]=[CH:44][N:45]([CH3:47])C)=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=1)#N>>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:30])(=[O:31])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:32][C:47]2[C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][C:37]=3[N:43]=[CH:44][N:45]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(S(=O)(=O)Nc3ccc(Br)cc3)cc2N)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: Cc1ccc2c(Nc3cc(S(=O)(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1

Procedure:
The product from Example 149D was reacted with the product from Example 10B using the procedure described in Example 149E substituting the product from Example 10B for the product from Example 36E to provide {4-[4-(4-Bromo-phenylsulfamoyl)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-phenyl}-carbamic acid tert-butyl ester which was deprotected according to the procedure described in Example 149F, followed by silica gel chromatography provided the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 6.64 (d, J=8.46 Hz, 2H), 6.89 (d, J=8.09 Hz, 1H), 7.05 (d, J=9.19 Hz, 2H), 7.12 (d, J=8.82 Hz, 2H), 7.44 (d, J=8.82 Hz, 2H), 7.63 (dd, J=7.72, 0.74 Hz, 1H), 7.74 (s, 1H), 7.79 (dd, J=7.72, 1.10 Hz, 1H), 8.70-8.83 (m, 1H), 8.88 (d, J=8.09 Hz, 1H), 10.55 (s, 1H); MS (ESI+) m/z 593/595 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.I[C:16]1[CH:30]=[CH:29][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[CH2:23][CH2:22]2)=[CH:18][CH:17]=1>>[O:28]=[S:24]1(=[O:27])[CH2:25][CH2:26][N:21]([CH2:20][C:19]2[CH:29]=[CH:30][C:16]([NH:1][C:2]3[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:3]=3)=[CH:17][CH:18]=2)[CH2:22][CH2:23]1
Reactant: N#Cc1cn(-c2ccccc2)nc1N
Reactant: O=S1(=O)CCN(Cc2ccc(I)cc2)CC1
Product: N#Cc1cn(-c2ccccc2)nc1Nc1ccc(CN2CCS(=O)(=O)CC2)cc1

Procedure:
3-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}amino)-1-phenyl-1H-pyrazole-4-carbonitrile was prepared according to the general procedure in Example 11 Step 1 using 3-amino-1-phenyl-1H-pyrazole-4-carbonitrile (100 mg, 0.543 mmol) and 4-(4-iodobenzyl)thiomorpholine 1,1-dioxide (191 mg, 0.543 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])[CH:2]=[CH2:3].[H-].[Na+].[Si:19]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]I)=[CH:30][CH:29]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[Si:19]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]=[CH2:3])=[CH:30][CH:29]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: C=CCOCCOCCOCCOCCO
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CI)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCCOCCOCCOCCOCc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of 11-allyloxy-3,6,9-trioxaundecanol (83, 2.33 g, 9.94 mmol) in dry THF (40 mL), sodium hydride (0.95 g, 39.8 mmol) is added in several portions under an argon atmosphere. The mixture is stirred for 30 min. A solution of the iodo derivative 45 (3.0 g, 8.28 mmol) in dry THF (10 mL) is added dropwise, and the mixture stirred for 15 h. The reaction is quenched by adding 2 mL of water, and 70% of the amount of THF is evaporated in vacuo. To dilute the mixture, 70 mL of water are added, and the solution extracted with 5 times 50 mL ethyl acetate. The combined organic extracts are dried over MgSO4 and concentrated in vacuo. The yellow oil obtained is purified by flash column chromatography (gradient petrol ether/ethyl acetate 10:1 to 5:1) to give the title product 84 as a pale yellow oil (1.96 g, 4.2 mmol, 51%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=1>ClCCl.CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Reactant: Cc1cc(N)ccn1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4ccnc(C)c4)c3cc2OC)c1
Yield: 19 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (100 mg, 0.22 mmol) with 4-amino-2-methylpyridine (28 mg, 0.26 mmol) and chromatography (silica gel, dichloromethane/methanol: 4/1) gives the desired product in 19% yield (21 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.P(Br)(Br)[Br:12]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][Br:12]
Reactant: BrP(Br)Br
Reactant: OCCc1ccccc1Br
Product: BrCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 145.2 %

Procedure:
To 550.0 g of o-bromophenethyl alcohol, while stirring, is added, dropwise, 375.0 g of phosphorus tribromide. After stirring for three hours at room temperature, the reaction mixture is heated on a steam bath for three hours and then poured into 6 kg of crushed ice. The mixture is extracted with three 600 and two 200 ml portions of ether. The ether extracts are washed, dried, concentrated, and the residue is distilled to give 531.0 g of o-bromophenethyl bromide, bp. about 86°-88° (0.9mm), nD26 1.5922.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[C:13]1([C:19]2[C:23]([CH:24]=O)=[CH:22][NH:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:24]/[C:23]1[C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:20][NH:21][CH:22]=1
Reactant: O=Cc1c[nH]nc1-c1ccccc1
Reactant: NC(=O)c1cc2c(s1)NC(=O)C2
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: NC(=O)c1cc2c(s1)NC(=O)/C2=C\c1c[nH]nc1-c1ccccc1
Temperature: 75 °C
Yield: 45.5 %

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide (30 mg, 0.17 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (2 ml). 3-Phenyl-1H-pyrazole-4-carboxaldehyde (0.18 mmol, 31 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (2 ml) and the precipitated solid was collected by filtration and washed with water to give 26 mg of (Z)-5,6-dihydro-5-oxo-4-[(3-phenyl-1H-pyrazol-4-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxamide as a yellow/brown solid. MS(ES): m/e 337 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][C:31]([F:34])([F:33])[F:32])[CH:29]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]1=[CH:11]2)#[N:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][C:31]([F:34])([F:32])[F:33])[CH:29]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:12]1=[CH:11]2)#[N:2]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3cc(C#N)cc(OC(F)(F)F)c3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(COc2ccc3c(c2)cc2n3CCCC2CC(=O)O)cc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of ethyl 2-(2-(3-cyano-5-(trifluoromethoxy)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (108 mg, 0.229 mmol) in dioxane (1 mL) was added 1 M LiOH aqueous solution (0.914 mL, 0.914 mmol). The reaction was stirred at room temperature for 8 h, diluted with water, and acidified to pH 4 with 0.5 M aqueous citric acid. The solid precipitate was collected to give the title compound (90 mg). LCMS m/z=445.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.57-1.68 (m, 1H), 2.00-2.14 (m, 1H), 2.16-2.27 (m, 2H), 2.65 (dd, J=16.1, 8.5 Hz, 1H), 3.01 (dd, J=16.1, 5.4 Hz, 1H), 3.46-3.55 (m, 1H), 3.85-3.93 (m, 1H), 4.13-4.20 (m, 1H), 5.13 (s, 2H), 6.23 (s, 1H), 6.89 (dd, J=8.8, 2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.58 (s, 1H), 7.70 (s, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([CH2:10][NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:6][CH:5]=1.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([O:21][C:19]([N:11]([CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:3])[N:9]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CNCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
Sodium hydride (88 mg, 2.20 mmol) was suspended in DMF (2.93 mL) and cooled to 0° C. Ethyl N-[(6-bromopyridin-2-yl)methyl]glycinate (200 mg, 0.73 mmol) was added and the solution was stirred for thirty minutes at 0° C. Benzyl chloroformate (0.11 mL, 0.73 mmol) was added and the solution was heated at 50° C. and allowed to stir until completion. The reaction was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[CH:25][C:26]3[O:30][CH2:29][CH2:28][C:27]=3[CH:31]=2)[CH2:19][CH2:18]1)([OH:3])=O.CS([O-])(=O)=O.ClC1C=CC=C[N+:39]=1C.N>CN1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[CH:25][C:26]3[O:30][CH2:29][CH2:28][C:27]=3[CH:31]=2)[CH2:19][CH2:18]1)(=[O:3])[NH2:39]
Reactant: C[n+]1ccccc1Cl
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)CCO5)CC3)c2c1
Agent: CN1CCCC1
Agent: CS(=O)(=O)[O-]
Agent: N
Product: NC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)CCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.8 g of 1-[4-(5-carboxyindol-3-yl)butyl]-4-(2,3-dihydrobenzofuran-5-yl)piperazine are suspended in 100 ml of N-methylpyrrolidine. 3.2 g of 2-chloro-1-methylpyridinium methanesulfonate are then added and the mixture is stirred at room temperature for 12 hours. Dried NH3 gas is then passed into the resulting solution until it is saturated and the mixture is stirred again for 10 hours. Customary working up gives 1-[4-(5-carbamoylindol-3-yl)butyl]-4-(2,3-dihydrobenzofuran-5-yl)-piperazine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>ClCCl>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[O:21])=[CH:22][CH:23]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(N)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
Oxalyl chloride (6.6 ml, 76 mmol, 1.2 eq) is added into a cold (ice bath) solution of 4-benzyloxy-benzoic acid (14.38 g, 63 mmol, 1 eq) and triethylamine (43.8 ml, 315 mmol, 5 eq) in dichloromethane (400 ml). The dark red mixture is warmed to room temperature and stirred for 2 h and then cooled to 0° C. A solution of 2-amino-2-methyl-propan-1-ol (5.6 g, 63 mmol, 1 eq) in dichloromethane (20 ml) is added and the mixture is stirred overnight at room temperature. The solvent is then removed under vacuum and the residue is dissolved in dichloromethane. This solution is washed once with water and the aqueous layer is extracted with dichloromethane. The organic layers are washed with a solution of 0.1 M sodium hydroxide and dried over magnesium sulfate. The solvent is removed under vacuum, to afford 15 g of 4-(benzyloxy)-N-(2-hydroxy-1,1-dimethylethyl)benzamide ax1 as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2Cl)([O-:3])=[O:2].[CH3:22][NH:23][CH3:24].O>CN1C(=O)CCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2[N:23]([CH3:24])[CH3:22])([O-:3])=[O:2]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc2nc(-c3cccc(F)c3)cc(Cl)c2c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C)c1cc(-c2cccc(F)c2)nc2ccc([N+](=O)[O-])cc12
Temperature: 60 °C

Procedure:
6-Nitro-4-chloro-2-(3-fluoro-phenyl)-quinoline, 20 g (59.4 mmoles), was placed in a 500 mL three-neck round-bottom flask equipped with magnetic stirrer, nitrogen inlet, gas outlet, condenser and heating bath. The material was dissolved in 150 mL of N-methyl pyrrolidinone, stirred and 250 mL of a 40% aq. solution of dimethylamine was added. The mixture was then warmed to 60° C. for 48 hrs. At the end of this time the reaction was cooled, poured into 3 L of water in a 4 L Erlenmeyer flask and the mixture stirred until solids formed. The solids were collected by vacuum filtration and dried in a vacuum oven. The product was recrystallised from-ethanol in a −20° C. freezer to give 19.6 g (95%) yield of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:11]C(=O)C)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.CN(C)C1C=CC=CC=1>CC(C)=O>[OH:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:5]=1[C:6]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:8]
Reactant: CC(=O)Oc1cc(C)ccc1C(=O)O
Reactant: COc1ccc(N)cc1
Solvent: CC(C)=O
Solvent: CN(C)c1ccccc1
Product: COc1ccc(NC(=O)c2ccc(C)cc2O)cc1
Yield: 80 %

Procedure:
4-Methyl-acetylsalicylic acid (5 g.) was converted to its acid chloride by a conventional method and dissolved in acetone (200 ml.). Then p-anisidine (3.2 g.) and dimethylaniline (3.1 g.) were dissolved in acetone (100 ml.) and the above acid chloride solution was added by drops while cooling and mixing; agitation was maintained for 1 to 2 hours. Then the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and treated as in the similar method of Example 5 to give 2-hydroxy-4-methyl-4'-methoxybenzanilide (5.3 g.). Yield: 80%, melting point: 185°-186° C.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[N:22]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25][CH:24]2[CH2:27][NH:28][CH2:29][CH:23]12.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([N:28]2[CH2:27][CH:24]3[CH:23]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[CH2:29]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC2CN(c3c(Br)cnc4[nH]cc(NC(=O)c5cccnc5)c34)CC21
Temperature: 140 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (180 mg, 0.537 mmol, Example 1, Step I), tert-butyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate hydrochloride (334 mg, 1.34 mmol), and DIEA (0.234 mL, 1.34 mmol) in n-BuOH (2 mL) was stirred at 140° C. for 5 hours in a sealed tube. The reaction was then cooled to room temperature and concentrated in vacuo. The residue obtained was purified by reverse phase HPLC (Gilson) to provide tert-butyl 5-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo [3,4-b]pyrrole-1(2H)-carboxylate (50 mg, 18% yield).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1)[S:14]([CH3:17])(=[O:16])=[O:15]>>[NH2:11][C:9]1[N:10]=[C:3]2[C:2]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:13]([CH3:12])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: CN(c1ccccc1B1OC(C)(C)C(C)(C)O1)S(C)(=O)=O
Product: CN(c1ccccc1-c1cccn2nc(N)nc12)S(C)(=O)=O

Procedure:
A round bottom flask was charged with potassium carbonate (0.56 g, 4.0 mmol) and acetone (20 mL). To the suspension was added N-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1.0 g, 3.4 mmol) followed by iodomethane (0.25 mL, 4.0 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated to a viscous oil. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as a white solid (1.01 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (dd, J=7.5, 1.4 Hz, 1H), 7.47 (ddd, J=7.9, 7.9, 1.5 Hz, 1H), 7.38 (dd, J=7.9 Hz, 1H), 7.35-7.30 (m, 1H), 3.32 (s, 3H), 2.93 (s, 3H). MS=334 (M+Na)+. 130b) N-[2-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (625.0 mg, 2.934 mmol) and N-methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1000.0 mg, 3.2133 mmol) in a manner analogous to Example 2c. Product was isolated as white solid (0.479 g, 51%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.52 (d, J=6.5 Hz, 1H), 7.62 (d, J=7.4 Hz, 1H), 7.55-7.42 (m, 3H), 7.35 (d, J=7.2 Hz, 1H), 6.94 (t, J=7.1 Hz, 1H), 5.94 (s, 2H), 3.10 (s, 3H), 2.85 (s, 3H). MP=209-211° C. MS=318 (MH)+. 130c) N-Methyl-N-(2-{2-[3-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[2-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (76.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.099 g, 85%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (dd, J=6.8, 0.9 Hz, 1H), 7.59-7.36 (m, 7H), 7.28-7.23 (m, 1H), 6.98 (t, J=7.1 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.76 (s, 1H), 3.17 (s, 3H), 3.02-2.95 (m, 2H), 2.74 (s, 3H), 2.53-2.43 (m, 1H), 2.34 (s, 3H), 2.10-2.00 (m, 2H), 1.89-1.78 (m, 4H). MS=491 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13]([NH:51][C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1ccc(N)nc1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(NC(=O)[C@H](CC2CCC(=O)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 300 mg, 0.84 mmol) and triphenylphosphine (288 mg, 1.09 mmol) in methylene chloride (6.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (192 mg, 1.09 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-picoline (182 mg, 1.68 mmol) and 2,6-lutidine (0.42 mL, 3.36 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution 1×20 mL), a saturated aqueous sodium bicarbonate solution 1×20 mL) and water 1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 4/6 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (231 mg, 61%) as a white foam: [α]23589=−26.22° (c=0.45, chloroform); EI-HRMS m/e calcd for C22H25ClN2O4S (M+H)+ 449.1297. found 449.1302.