Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.O.C([O-])(=O)C.[Na+].Br[CH:10](Br)[C:11]([C:13]([F:16])([F:15])[F:14])=O.C(=O)(O)O.[NH2:22][NH:23][C:24]([NH2:26])=[NH:25].[OH-].[Na+]>O>[NH2:26][C:24]1[N:23]=[N:22][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:25]=1
Reactant: N=C(N)NN
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Product: Nc1nncc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
To a stirred solution of sodium acetate trihydrate (22.62 g, 166.2 mmol) in water (80 ml) was added 1,1-dibromo-3,3,3-trifluoroacetone (21.57 g, 79.9 mmol). The solution was heated at reflux under nitrogen for 30 min, then allowed to cool to room temperature before adding solid aminoguanidine bicarbonate (10.88 g, 79.9 mmol). The resulting pale yellow solution (pH 5) was stirred at room temperature for 3 h, then 4 N aqueous NaOH solution (40 ml, 160 mmol) was added causing a precipitate to appear. The mixture (pH 10) was stirred under nitrogen for a further 39 h. The solid was collected by filtration, washed with water and dried at 60° C. under vacuum to give 6.96 g of a mixture of two isomers in a 28:72 ratio. This was further purified by flash chromatography (silica gel, 30% EtOAc/isohexane), then recrystallised from ethanol to afford 3.53 g (27%) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ8.00 (2H, br s), 9.08 (1H, s).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Reactant: Brc1ccccn1
Product: O=C(c1ccccn1)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12l and 2-bromopyridine
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([C:15](=[O:18])[CH2:16][Cl:17])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].Cl>ClCCl.CO>[ClH:17].[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([C:15](=[O:18])[CH2:16][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(C(=O)CCl)cc2CC1
Reactant: C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCc2ccc(C(=O)CN3CCCCC3)cc2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 10 ml of dichloromethane was dissolved 1.50 g of 1-(3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-chloro-1-ethanone obtained in Reference Example 2. To the solution was added 1.7 ml of piperidine, and the mixture was stirred for one hour at room temperature. The reaction mixture was poured into an aqueous solution of potassium carbonate, which was subjected to extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, from which was distilled off the solvent to leave an oily residue. To the residue was dissolved in 5 ml of methanol, to which was added 1.7 ml of 4N methanolic hydrochloric acid. Then the solvent was distilled off to leave 1.50 g of the title compound as colorless powder.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>>[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH:33][C:18]([C:17]2[CH:16]=[N:15][N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:21])=[CH:8][CH:7]=4)=[N:10][C:11]=23)=[O:20])[CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:26]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2ccc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3ccc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.23) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 461.3 [(M+H)+]; mp 254-255° C.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C@H:10]([CH2:27][CH3:28])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[C:18]=2[CH3:26])=[N:13]1>>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@H:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:8])[CH2:27][CH3:28])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: CC[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2C)n1
Reactant: O=C(O)c1cocn1
Product: CC[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2C)n1)NC(=O)c1cocn1
Yield: 29.9 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)butan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 4-oxazolecarboxylic acid (0.2 g, 1.769 mmol) and (R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.532 g, 1.474 mmol). The product was triturated using diethyl ether. Yield 29.9%. 1H-NMR (400 MHz; CDCl3): δ 1.02 (t, 3H), 1.58 (m, 2H), 2.57 (s, 3H), 4.39 (m, 3H), 6.43 (d, 1H), 7.45 (d, 1H), 7.49 (d, 3H), 7.53 (dd, 1H), 7.58 (d, 1H), 7.85 (d, 1H), 8.22 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[O:14][C:13]([CH3:15])=[C:12]([CH:16]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:11]=1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[O:14][C:13]([CH3:15])=[C:12]([CH:16]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:28])=[CH:29][CH:30]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:11]=1
Reactant: CCOC(=O)CCNC
Reactant: COc1ccc(F)c(-c2cc(C(CC(C)C)Nc3ccc(C(=O)O)cc3)c(C)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
A solution of 4-({1-[5-(2-fluoro-5-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)benzoic acid (205 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (209 mg, 84%).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=2)[C:3]([OH:22])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COCC#Cc1ccc(C(CC2CCCC2)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-propionic acid methyl ester (485 mg, 1.61 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was treated with lithium hydroxide (775 mg, 18.5 mmol). The reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. The residue was re-dissolved in water (40 mL) which was then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2×40 mL). The aqueous layers were back extracted with ethyl acetate (1×40 mL). The combined organic extracts were then washed with a half-saturated aqueous sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-propionic acid (447 mg, 96.7%) as a white solid: mp 82-85° C.; EI-HRMS m/e calcd for C18H22O3 (M+) 286.1568, found 286.1563.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10](O)=[O:11])=[C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([F:21])=[C:6]([F:22])[CH:5]=1)(=O)[CH3:2].O.[NH2:24][NH2:25].Cl>C1COCC1.CCOC(C)=O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:8]1[C:7]([F:21])=[C:6]([F:22])[CH:5]=[C:4]2[C:9]=1[C:10](=[O:11])[NH:25][N:24]=[C:1]2[CH3:2]
Reactant: NN
Reactant: CC(=O)c1cc(F)c(F)c(Nc2ccccc2Cl)c1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c(=O)c2c(Nc3ccccc3Cl)c(F)c(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of 6-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (62 mg, 0.19 mmol, prepared by the procedures described in Example 1) and hydrazine monohydrate (0.031 mL, 0.63 mmol) in THF (3 mL) was added catalytic amount of 1 N aqueous HCl (0.15 mL, 0.15 mmol) at room temperature. After stirring for 16 hours at room temperature, the reaction mixture was diluted with EtOAc, and washed with water (2×) and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the desired product (53 mg, 86%) that was used directly without further purification.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:12]=[CH:11]2>>[CH3:22][CH:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:9]=2)[CH:14]=1)[C:19]([OH:21])=[O:20]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCI
Product: CCCCCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-iodopentane and racemic 6-hydroxy-α-methyl-2-naphthaleneacetic acid. White crystals are obtained having a melting point of 97°-99° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:12]4[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:29][C:30]1[O:31][C:32]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=O)[O:41]C3C=CC=CC=3)=[CH:35][C:33]=2[CH:34]=1>C1COCC1>[CH3:29][C:30]1[O:31][C:32]2[CH:38]=[CH:37][C:36]([NH:39][C:40]([N:1]3[C:9]4[C:8](=[CH:7][C:6]([O:10][C:11]5[C:12]6[CH2:19][NH:18][CH2:17][C:13]=6[N:14]=[CH:15][N:16]=5)=[CH:5][CH:4]=4)[CH:3]=[CH:2]3)=[O:41])=[CH:35][C:33]=2[CH:34]=1
Reactant: Cc1cc2cc(NC(=O)Oc3ccccc3)ccc2o1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4[nH]ccc4c3)c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2cc(NC(=O)n3ccc4cc(Oc5ncnc6c5CNC6)ccc43)ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (152.2 mg, 0.432 mmol) is suspended in THF (5 mL), flushed with nitrogen and cooled to 0° C. NaH (33 mg, 0.825 mmol, 60% in mineral oil) is added and mixture is stirred for 10 minutes. Phenyl 2-methylbenzofuran-5-ylcarbamate (280 mg, 1.048 mmol) is added neat and the reaction is allowed to stir to room temperature overnight. The reaction is cooled in an ice bath and quenched with a saturated solution of ammonium chloride (100 mL). The solution is then diluted with ethyl acetate and the product is extracted (2×100 mL ethyl acetate). The organic layers are combined, dried and concentrated to a brown oil that is dissolved in 10 mL of DCM and cooled in an ice bath upon which 10 mL of TFA is added. The TFA is removed and ethyl acetate is added to the residue and ammonium hydroxide is added to quench the remaining TFA. The solution is concentrated and dissolved in DMSO and is purified via semi-prep HPLC (C18; 20-100% I/H2O with 0.1% TFA) to give 5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (2-methyl-benzofuran-5-yl)-amide. MS (ESI) m/z 426.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.53 (s, 1H) 8.30 (d, J=8.84 Hz, 1H) 8.15-8.20 (m, 1H) 7.88-7.92 (m, 1H) 7.58 (ddd, J=6.13, 3.98, 2.27 Hz, 1H) 7.39-7.46 (m, 2H) 7.12 (dd, J=9.09, 2.02 Hz, 1H) 6.74 (d, J=3.79 Hz, 1H) 6.46 (s, 1H) 4.19 (d, J=9.35 Hz, 4H) 2.45 (s, 3H).
Reaction SMILES: C([C:5]([C:19](=[O:26])[CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)([C:16]([OH:18])=[O:17])[N:6]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH:7]1[CH2:9][CH2:8]1)(C)(C)C.[ClH:27]>CCOC(C)=O>[ClH:27].[N:13]1[CH:12]=[CH:11][C:10]([N:6]([CH:7]2[CH2:9][CH2:8]2)[CH:5]([C:19](=[O:26])[CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[C:16]([OH:18])=[O:17])=[CH:15][CH:14]=1
Reactant: CC(C)(C)C(C(=O)O)(C(=O)C1CCCNC1)N(c1ccncc1)C1CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)C(C(=O)C1CCCNC1)N(c1ccncc1)C1CC1
Reaction time: 3.5 h

Procedure:
Ester 22-3 (250 mg, 0.70 mmol) was suspended in EtOAc (25 mL), cooled to 0° and treated with HCl gas for 15 min. The resulting solution was stirred for 3.5 h then evaporated to give 22-4 as a white solid.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[NH2:8][C:9](=[NH:38])[CH2:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH:26][C:27]([C:29]3[S:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[O:28])[C:17]2=[O:35])=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl-].O[NH3+]>C(O)C>[NH2:38][C:9](=[N:8][OH:4])[CH2:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH:26][C:27]([C:29]3[S:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[O:28])[C:17]2=[O:35])=[CH:13][CH:12]=1
Reactant: N=C(N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Reactant: O=C(O)C(F)(F)F
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1)=NO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
37 mg (0.07 mmol) of N-{2-[4-(2-amino-2-iminoethyl)benzyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-5-chloro-2-thiophenecarboxamide trifluoroacetate are suspended in 3 ml of ethanol, and 0.09 ml (0.65 mmol) of triethylamine and 22.7 mg (0.33 mmol) of hydroxylammonium chloride are added. The reaction mixture is stirred at room temperature for 5 h and then concentrated. The residue is stirred with water and filtered. This gives 21 mg (69% of theory) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:17][NH2:18])[CH:14]=[CH:15][CH:16]=3)[C:3]=12.[F:28][C:29]1[CH:30]=[C:31]([CH:43]=[CH:44][C:45]=1[F:46])[CH2:32][N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](Cl)=[O:40])[C:34]1=[O:42]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=3)[CH2:17][NH:18][C:39]([C:35]3[C:34](=[O:42])[N:33]([CH2:32][C:31]4[CH:43]=[CH:44][C:45]([F:46])=[C:29]([F:28])[CH:30]=4)[CH:38]=[CH:37][CH:36]=3)=[O:40])[C:3]=12
Reactant: O=C(Cl)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3nccc(Cl)c23)c1
Solvent: ClCCl
Product: O=C(NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3nccc(Cl)c23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
43 mg of (3-(4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanamine, 32 mg of crude 1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride were dissolved in DCM, TEA was added, then the resulted mixture was stirred at room temperature for overnight. The solvent was removed on a rotary evaporator and the crude was purified by chromatography to give 32 mg of N-(3-(4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, yield: 50%.
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1.[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>C[Si](C)(C)N[Si](C)(C)C.C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O>[CH2:8]([S:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1)[CH2:9][CH2:10][CH3:11]
Reactant: Cc1nnc(S)s1
Reactant: CCCCBr
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CCCCSc1nnc(C)s1
Reaction time: 3 h
Yield: 89.1 %

Procedure:
Using the procedure of Example 19, 1.32 g (10 mmoles) of 5-mercapto-2-methyl-1,3,4-thiadiazole were silylated with 2.6 ml (15 mmoles) of hexamethyldisilazane in 10 ml of toluene and 2.6 ml of hexamethylphosphoric triamide using 5 mg (0.027 mmole) of saccharin as a catalyst by refluxing for 1.5 hour. After concentration by evaporation, 5 ml of acetonitrile were added thereto and the solution obtained was heated at 50° C. while 2.1 ml (20 mmoles) of butyl bromide were added. The conversion was complete after stirring for 3 hours at this temperature and according to quantitative HPLC analysis, there had been formed 8.91 mmoles (89.1%) of 5-butylthio-2-methyl-1,3,4-thiadiazole, while 5.3% of 3-butyl-5-methyl-Δ4 -1,3,4-thiadiazoline-2-thione was found as a by-product.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21]O)=[CH:15][C:14]=3[I:23])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:15][C:14]=3[I:23])=[O:9])=[CH:24][CH:25]=1
Reactant: C1COCCN1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CO)cc2c1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-8-iodo-3-quinolinecarboxamide (0.36 g), DMAP (0.016 g) and collidine (0.12 mL) in 13 mL DMF at 0° C. is added methanesulfonyl chloride (0.065 mL). The solution is allowed to warm to room temperature and is stirred overnight. Morpholine (0.67 mL) is then added and the solution is stirred at room temperature overnight. The mixture is poured into water. The resulting solid is collected and dried. The crude product is adsorbed onto silica and chromatographed (Biotage flash 40S, eluant 1% MeOH/CH2Cl2, then 2% MeOH/CH2Cl2). Product containing fractions are combined and concentrated to yield 0.322 g (78%) of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide, m.p. 230-233° C.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1.O>C1(C)C=CC=CC=1.CCOCC>[OH:8][C@@H:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2)C1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.9 %

Procedure:
A solution of (R)-tert-butyl 3-benzoylpiperidine-1-carboxylate (10.3 g, 35.64 mmol) in anhydrous toluene (120 mL) was cooled to −78° C. and (R)-2-methyl-CBS-oxazaborolidine (1.0M in toluene, 17.8 mL, 17.8 mmol, 0.5 equiv) was added slowly. After 5 min, catecholborane (11.4 mL, 107 mmol, 3 equiv) was added slowly. The reaction mixture was then transferred into the freezer (−14° C.) and left overnight. LC-MS (16 min) showed a 9:1 ratio of the R to the S isomer. The mixture was cooled to 0° C. and water was added dropwise to quench the reaction. The reaction mixture was diluted with ether, washed with 5% aq NaOH (2×150 mL), water (150 mL), 5% aq HCl (100 mL), and brine (100 mL), and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 120-g silica gel column eluted with a 4-35% EtOAc in hexanes gradient. The purified product was recrystallized from an ether/hexanes mixture to afford (R)-tert-butyl 3-((R)-hydroxy(phenyl)methyl)piperidine-1-carboxylate (4.45 g, 43%) as a white solid with the ratio of R/S isomers 23.5:1. LC-MS (3 min) tR=1.70 min; LC-MS (3 min) tR=10.62 min, m/z 314 (M+Na). 1H NMR (CDCl3) δ 7.28 (m, 5H), 4.46 (d, 1H), 3.87 (d, 1H), 3.89-3.51 (br s, free exchange 1H), 3.00 (m, 2H), 2.68 (t, 1H), 2.52 (t, 1H), 1.94 (m, 1H), 1.76 (m, 1H), 1.65 (m, 1H), 1.42-1.20 (m, 10H).
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].[NH2:6][C:7]1[C:14]([Cl:15])=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([O:16][CH3:17])[CH:8]=1.C(N(CC)CC)C.Cl>C(OCC)(=O)C.O>[Cl:15][C:14]1[CH:13]=[C:10]([CH:11]=[O:12])[C:9]([O:16][CH3:17])=[CH:8][C:7]=1[NH:6][C:1](=[O:5])[CH:2]=[CH2:3]
Reactant: COc1cc(N)c(Cl)cc1C=O
Reactant: C=CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cc(OC)c(C=O)cc1Cl
Temperature: 35 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Acrylic acid (commercially available, for example, from Aldrich) (46 ml, 0.67 mol) was added slowly to a stirred suspension of 4-amino-5-chloro-2-methoxybenzaldehyde (Step B) (50.0 g, 0.27 mol) and triethylamine (204 g, 2.02 mol) in ethyl acetate (0.85 L) at 25° C. Propanephosphonic anhydride (50% in ethyl acetate; 429 g, 0.67 mol) was added over 30 minutes keeping reaction temperature at 30-40° C. The mixture was stirred at 30-40° C. for a further 1 hour and then cooled to 25° C. and diluted with water (0.26 L) and acidified with 32% hydrochloric acid (108 g) to pH 2-3. The organic layer was separated and washed with a mixture of water (0.23 L) and 32% sodium hydroxide (14 g)—aqueous layer ca. pH 7. The organic phase was washed with water (0.23 L) and then concentrated under reduced pressure (ca. 300 mbar) to remove 0.56 kg of distillate. Methylcyclohexane (335 g) was added and then a further 286 g of distillate was removed under reduced pressure. Methylcyclohexane (111 g) was added and then the resulting suspension was cooled to 20° C., filtered and washed with methylcyclohexane. The cake was dried at 40° C. under reduced pressure for 12 hours to give N-[2-chloro-4-formyl-5-(methyloxy)phenyl]-2-propenamide (46 g, 71%)