Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:39])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][N:33]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:40](Cl)(=[O:42])[CH3:41]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:16]2[C@H:12]([N:10]([C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:39])[CH3:11])[CH2:13][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([O:38][C:40](=[O:42])[CH3:41])=[CH:34][N:33]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:15]2)=[CH:22][CH:21]=1
Reactant: CC(=O)Cl
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(O)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Product: CC(=O)Oc1ccc(N2CCC(C(=O)N3C[C@@H](N(C)C(=O)Oc4ccc(F)cc4)[C@H](c4ccc(Cl)cc4)C3)CC2)nc1

Procedure:
A mixture of [(3S,4R)-4-(4-Chloro-phenyl)-1-(5′-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (example 320, crude) was treated with acetyl chloride and the mixture was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions the title compound as light yellow solid. MS m/e: 595.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.C(N(CC)CC)C.[P:41]([O-:58])([O:50]CC1C=CC=CC=1)[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CS(C)=O.C(OCC)(=O)C.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>[CH2:21]([O:20][C:19]1[C:18](=[O:28])[N:17]2[C:12]([C:13]([CH3:30])([CH3:29])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:8]([NH:7][CH2:6][C:5]1[CH:31]=[CH:32][C:2]([F:1])=[CH:3][C:4]=1[P:41](=[O:50])([OH:58])[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1P(=O)(O)OCc1ccccc1)c(OCc1ccccc1)c2=O
Temperature: 80 °C
Yield: 70.5 %

Procedure:
A solution of N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.200 g, 0.35 mmol) in dimethyl sulfoxide (5 ml) was flushed with argon and then treated triethylamine (0.25 ml, 1.8 mmol), tetrakis(triphenylphosphine)palladium(0) (0.10 g) and dibenzyl phosphite (0.25 ml, 1.06 mmol). The reaction mixture was then sealed and heated at 80° C. for 16 h. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N hydrochloric acid, brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by preparative HPLC (column YMC Pack C-18, 5μ, 20×250 mm, elution gradient acetonitrile-water 0.1% trifluoroacetic acid) gave 0.150 g (60% yield) of the title material as a white solid; mp 142° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.58 (6H, s, 2×CH3), 4.0 (4H, m, 2×CH2), 4.73 (2H, broad s, OCH2), 5.05 (2H, d, J=8.6 Hz, NCH2), 5.28 (2H, s, OCH2), 7.20 (1H, m, aromatic), 7.29-7.34 (6H, m, aromatics), 7.45-7.64 (6H, m, aromatics), 8.24 (1H, broad, NH). MS (ESI+) m/z 608 [M+H+].
Reaction SMILES: [Cl:1][O-].[Na+].[OH:4][C:5]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1>Cl>[Cl:1][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:14]([C:15]([OH:17])=[O:16])[C:5]=1[OH:4]
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2c(Cl)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
The chilled sodium hypochlorite solution is added to the chilled solution of 2-hydroxy-3-naphthoic acid, keeping the temperature below 10° C. When the addition of sodium hypochlorite is completed, the reaction mixture is held at about 10° C. for 2 hours and then heated to the boil. To this solution is then added 250 ml of 14.1% hydrochloric acid. The resulting slurry of deep yellow solid material is heated to the boil and then cooled to ambient temperature. The slurry is filtered, washed with 2 liters of water and dried to constant weight. There is obtained 52.6 grams of 1-chloro-2-hydroxy-3-naphthoic acid (purity 97.2% by HPLC) representing a yield of 91.8% of theoretical.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N:10]=[C:11]=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].[NH2:15][C:16]([CH3:20])([CH3:19])[C:17]#[N:18]>>[F:14][C:2]([F:13])([F:1])[C:3]1[CH:4]=[C:5]([N:10]2[C:17](=[NH:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:11]2=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(N)C#N
Product: CC1(C)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=N

Procedure:
14.5 g. of 3-trifluoromethyl-4-chlorophenyl-isocyanate and 5.5 g. of α-aminoisobutyronitrile are kept at 100° for 20 minutes. For purification, the viscous oil obtained is chromatographed on 500 g. of silica gel (particle size about 0.06-0.2 mm) using methylene chloride/methanol. The product obtained is crystallized from methylene chloride/petroleum ether. After drying under greatly reduced pressure at 50° for 15 hours, 1-(3-trifluoromethyl-4-chlorophenyl)-5-imino-4,4-dimethyl-2-imidazolidinone, which melts at 148°-149°, is obtained.
Reaction SMILES: [CH2:1]([S:8][CH:9]([S:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:10][C@@H:11]([C@H:20]([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:21])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1>[CH2:32]([S:31][CH:9]([S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][C@@H:11]([C@H:20]([CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[O:21][S:40]([CH3:39])(=[O:42])=[O:41])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H](COCc1ccccc1)[C@H](CC(SCc1ccccc1)SCc1ccccc1)OCc1ccccc1
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@@H](COCc1ccccc1)[C@H](CC(SCc1ccccc1)SCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 3,5-di-O-benzyl-2-deoxy-L-threo-pentose dibenzyl dithioacetal (61.4 g, 113 mmol) in dry pyridine (700 ml) was added methanesulphonyl chloride (19.4 g, 169 mmol) in dry pyridine (200 ml) dropwise, with stirring, at 0° C. The temperature of the mixture was raised to room temperature and stirring continued for 18 hours. The pyridine was then removed in vacuo and the residue dissolved in dichloromethane. The dichloromethane extracts were then successively washed with 2M hydrochloric acid, 1M sodium carbonate and water, dried (magnesium sulphate) and evaporated to give the title product as a thick viscous syrup. A sample of this was crystallised from hexane-ethyl acetate to give the title product as white crystals, m.p 82°-83° C.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C@@H:22]3[C@@H:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)[CH2:25][N:24]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:23]3)[CH2:17][CH2:16]2)=[C:11]([CH2:13][CH3:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([C:8]1[S:9][C:10]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][C@@H:22]3[C@@H:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)[CH2:25][N:24]([CH2:34][C:35]([OH:37])=[O:36])[CH2:23]3)[CH2:19][CH2:20]2)=[C:11]([CH2:13][CH3:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nc(Cc2ccccc2)sc1C1CCN(C[C@H]2CN(CC(=O)OC)C[C@@H]2c2cccc(F)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc(Cc2ccccc2)sc1C1CCN(C[C@H]2CN(CC(=O)O)C[C@@H]2c2cccc(F)c2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A solution of 23 mg (0.043 mmol) of (3-(S)-((4-(2-benzyl-4-ethyl-thiazol-5-yl)-piperidine-1-yl)methyl)-4-(S)-3-fluorophenylpyrrolidin-1-yl)-acetic acid, methyl ester in 1 mL of MeOH was treated with 0.1 mL of 1N NaOH. After stirring for 1 hr, another 0.1 mL of 1N NaOH was added and the reaction was heated in a 50° C. bath. After 1.5 hr at 50° C., the solution was cooled and neutralized to pH 7 with 1.2 N HCl. The solution was extracted with EtOAc and the EtOAc layer was washed with brine and dried. After concentration of the filtrate, the residue was purified on a Varian SCX ion exchange column using 2N NH3 in MeOH to elute the product. The isolated free base after concentration of the solution was treated with 1N HCl in Et2O and removal of solvent in vacuo furnished 21 mg of the title compound as a triHCl salt. Mass spec. 522.2 (M+1), HPLC A 1.99 min.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[C:11]([CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([OH:15])=[O:14])=[C:10]([OH:19])[N:9]=[C:8]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:7]=1.[CH3:26]O>>[O:5]=[C:6]1[CH:11]([CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([O:15][CH3:26])=[O:14])[C:10](=[O:19])[NH:9][C:8]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:7]1
Reactant: CO
Reactant: CCCC(C(=O)O)c1c(O)nc(N2CCCCC2)nc1O
Solvent: O=S(Cl)Cl
Product: CCCC(C(=O)OC)C1C(=O)N=C(N2CCCCC2)NC1=O

Procedure:
To a solution cold solution of methanol (50 mL) was added thionyl chloride (7.25 mL; 100 mmol) dropwise. The acidic solution was added to a flask containing 2-(4,6-dihydroxy-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoic acid (3.07 g; 10.4 mmol) and the mixture was heated to reflux for 18 h. The reaction mixture was concentrated under reduced pressure and the product was used as such in the next reaction.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Br[C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.O>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[N:27][CH:28]=1
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccccc3)cc2)OC1(C)C
Reactant: Brc1ccc(Br)nc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1ccc(-c2ccc(Br)cn2)cc1
Temperature: 100 °C
Yield: 41.3 %

Procedure:
A 100 ml, pressure vessel was charged with 4,4,5,5-tetramethyl-2-(4-(phenylsulfonyl)phenyl)-1,3,2-dioxaborolane (1.00 g, 2.91 mmol), 2,5-dibromopyridine (0.860 g, 3.63 mmol, Sigma-Aldrich, St. Louis, Mo.), potassium carbonate (1.20 g, 8.72 mmol), tetrakis(triphenylphosphine)palladium (0) (0.168 g, 0.145 mmol, Strem Chemical Inc, Newburyport, Mass.), 16 mL of 1,2-dimethoxyethane, and 4 mL of water. The vessel was sealed and the reaction was heated at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL), separated, dried (MgSO4) and concentrated to give an oil. Purification via column chromatography (40 g of silica gel, 0 to 50% EtOAc in hexanes) produced a yellow solid that was slurried with cold (0° C.) MeOH (20 mL) to give 5-bromo-2-(4-(phenylsulfonyl)phenyl)pyridine (0.450 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CO.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1CCCCC1
Reactant: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCNC1
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCN(CC2CCCCC2)C1

Procedure:
To a solution of 600 mg of 3-(benzyloxycarbonyl)amino-N-{((3S)-3-piperidyl)methyl}propanamide in 3 ml of methanol, a solution of 150 mg of sodium cyanoborohydrate and 160 mg of zinc chloride in 8.1 ml of methanol, and 0.30 ml of cyclohexanecarbaldehyde were added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was diluted with ethyl acetate and successively washed with saturated aqueous sodium bicarbonate solution and saturated saline, followed by drying over anhydrous sodium sulfate. Upon distilling the solvent off under reduced pressure, 775 mg of the title compound was obtained.
Reaction SMILES: Cl.N1C2C=CN=CC=2C=C1[CH:11]=[O:12].CC(OC([N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[CH:22]=[C:21]1[CH:29]=[O:30])=O)(C)C.FC(F)(F)C(O)=O.[C-]#N.[Na+]>[O-2].[O-2].[Mn+4].CO.ClCCl>[CH3:11][O:12][C:29]([C:21]1[NH:20][C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[CH:22]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)n1c(C=O)cc2cnccc21
Reactant: O=Cc1cc2cnccc2[nH]1
Agent: [Mn+4]
Agent: Cl
Agent: [C-]#N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc2cnccc2[nH]1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Scheme 3 discloses a synthesis of 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester 5b-1. In Scheme 3, step h, a mixture of (3-iodo-pyridin-4-yl)carbamic acid 1,1-dimethylethyl ester (7b-1), 3,3-diethoxy-1-propyne, a base such as for example triethylamine or Hunig's base (N,N-diisopropylethylamine), dichlorobis(triphenylphosphine)palladium(II) and copper iodide is heated in a suitable solvent such as for example dry DMF under an inert atmosphere at about 90° C. for about three hours. The reaction mixture is cooled to about 70° C. and treated with a suitable base such as for example 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), followed by stirring for about three hours at about 70° C. and then stirring at room temperature for about twelve hours. The reaction mixture is poured into ethyl acetate, washed with water and brine and the organic phase dried, filtered and concentrated to provide 2-(diethoxymethyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester (8b-1) which is purified by chromatography or other methods as are well known to one skilled in the art. As shown in Scheme 3, step i, hydrolysis of compound 8b-1 is effected under acidic conditions to afford 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde. Treatment of 8b-1 with a mineral acid such as for example hydrochloric acid for a suitable period of time such as about 20 hours at room temperature affords a mixture of 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde (9b-1) and 2-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester after isolation and chromatographic separation of the product mixture by methods well known to one skilled in the art. Acidic hydrolysis of 2-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester by refluxing with a suitable acid such as for example trifluoroacetic acid and a suitable solvent such as for example dichloromethane affords 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde, 9b-1. As shown in Scheme 3, step j, treatment of 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde (9b-1) in a suitable solvent such as methanol with sodium cyanide and manganese dioxide with cooling at about 0° C. and stirring for about five hours provides 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester 5b-1 after filtering, washing with water and isolation by methods as are well known to one skilled in the art.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CN2C(=O)C3=CC=CC=C3C2=O)C(=O)N(CC(C)C)N=1.[C:32]([C:35]1[C:36](=[O:59])[N:37]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[C:53]([F:58])[CH:52]=2)[N:38]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=2)[CH:40]=1)(O)=[O:33]>>[F:58][C:53]1[CH:52]=[C:51]([CH:56]=[CH:55][C:54]=1[F:57])[CH2:50][N:37]1[C:36](=[O:59])[C:35]([CH2:32][OH:33])=[CH:40][C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=2)=[N:38]1
Reactant: COc1ccc(-c2cc(C(=O)O)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Product: COc1ccc(-c2cc(CO)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Yield: 7.7 %

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as slightly-yellow neeldes (yield: 7.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[C:7]#[N:8].Cl>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:11])([F:12])[F:13])=[C:6]([CH2:7][NH2:8])[CH:9]=1
Reactant: N#Cc1cc(Cl)ccc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: NCc1cc(Cl)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
29.2 ml of borane-THF complex (29.2 mmol) are slowly added dropwise under argon to an ice-cooled solution of 5-chloro-2-(trifluoromethyl)benzonitrile (1.50 g, 7.3 mmol) in 45 ml of anhydrous THF. After the end of the addition, the mixture is heated under reflux for 1 hr, then stirred overnight at RT with cooling. 30 ml of 1 N hydrochloric acid are then added dropwise with ice-cooling. The THF is removed on the rotary evaporator. The precipitated solid is filtered off and discarded. The filtrate is diluted with water and extracted twice with dichloromethane. These organic phases are also discarded. The acidic aqueous phase is adjusted to pH 14 with 1 N aqueous sodium hydroxide and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and freed of solvent on the rotary evaporator. The residue is taken up in 20 ml diethyl ether and treated with 3 ml of a 4 N solution of hydrogen chloride in dioxan, during which the product precipitates. The solvent is completely removed on the rotary evaporator, then in high vacuum. 1.89 g (99% of theory) of the title compound are isolated.
Reaction SMILES: [K+].[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:24])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O-])=[O:22])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1>C1COCC1.CN(C=O)C>[OH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([NH:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[O:22])=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: O=C([O-])/C=C/c1ccc(/C=C/C(=O)c2ccc(CO)cc2)cc1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CO)cc2)cc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A mixture of (E)-3-{4-[(E)-3-(4-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid potassium salt (1.39 g, 4.01 mmol), EDC (1.53 g, 8.03 mmol), HOBT (1.08 g, 8.03 mmol), TEA (1.11 ml, 8.03 mmol), NH2OTHP (939 mg, 8.03 mmol) in THF (20 ml) and DMF (20 ml) was stirred at room temperature overnight and then partitioned between water and AcOEt. The organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The resulting solid was triturated with di-isopropylether and filtered to give 1.15 g of (E)-3-{4-[(E)-3-(4-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:13]([F:12])[CH:14]=1
Reactant: Clc1cc(Br)c2cn[nH]c2c1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1cc(-n2ncc3c(Br)cc(Cl)cc32)ccc1OCc1ccccc1
Yield: 53.4 %

Procedure:
4-Bromo-6-chloro-1H-indazole (413 mg, 1.78 mmol), {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (876 mg, 3.56 mmol), copper (II) acetate (483 mg, 2.67 mmol) and pyridine (0.29 mL, 3.56 mmol) in DCM (30 mL) were stirred in the presence of molecular sieves (4A, 790 mg) in air. After 40 hours the mixture was filtered through a pad of celite and concentrated to afford 1.24 g of crude material. This was purified by flash chromatography (Biotage SP4, 40+M silica column) with a gradient of Et2O (0 to 30%) in hexane to afford 410 mg of desired compound (D10) containing a small amount of the N2-aryl regioisomer.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:9]2[CH:14]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:23])[F:24])[CH:12]=[CH:11][N:10]=2)[S:5][CH:6]=1
Reactant: Cc1csc(N)n1
Reactant: FC(F)(F)c1ccccc1Sc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1csc(Nc2cc(Sc3ccccc3C(F)(F)F)ccn2)n1
Yield: 74.7 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (0.236 g, 2.07 mmol), 2-chloro-4-(2-(trifluoromethyl)phenylthio)pyridine (0.600 g, 2.07 mmol), potassium phosphate (0.484 g, 2.28 mmol), Pd2(dba)3 (0.095 g, 0.104 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.060 g, 0.104 mmol) were reacted to provide 4-methyl-N-(4-(2-(trifluoromethyl)phenylthio)pyridin-2-yl)thiazol-2-amine (0.568 g, 75% yield). 1H NMR (d6-DMSO) δ 11.06 (s, 1H), 8.10 (d, 1H), 7.99 (d, 1H), 7.76-7.83 (m, 3H), 6.66 (s, 1H), 6.59 (m, 1H), 6.52 (s, 1H), 2.19 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]#[CH:15])[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:48])/[C:20](/C)=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25](C#CC2C=C(C3CC3)C3OC4(CC4)C(C)=C(C)C=3C=2)=[CH:24][CH:23]=1)[CH3:17].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:48])/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([C:15]#[C:14][C:9]2[CH:8]=[C:7]([CH2:6][N:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:5])[CH:12]=[CH:11][C:10]=2[CH3:13])=[CH:24][CH:23]=1)[CH3:17]
Reactant: CCOC(=O)/C(C)=C/c1ccc(C#Cc2cc3c(c(C4CC4)c2)OC2(CC2)C(C)=C3C)cc1
Reactant: C#Cc1cc(CN(C)C2CC2)ccc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)/C=C/c1ccc(C#Cc2cc(CN(C)C3CC3)ccc2C)cc1

Procedure:
Following General Procedure B and using cyclopropyl-(3-ethynyl-4-methylbenzyl)-methyl-amine (Intermediate 99, 0.095 g, 0.48 mmol), ethyl-4-iodo-cinnamate (Reagent 3, 0.144 g, 0.47 mmol), triethyl amine (13 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.071 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent, the title compound was obtained (0.14 g, 82%).