Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([F:27])[CH:18]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:28].C([Li])CCC.CCCCCC.Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>O1CCCC1>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[C:19]([F:27])[CH:18]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH:7]([CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:6]1=[O:28]
Reactant: COc1cc2c(cc1-c1ccc(C(F)(F)F)c(F)c1)CCC(=O)N2Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc2c(cc1-c1ccc(C(F)(F)F)c(F)c1)CC(CC(=O)OC(C)(C)C)C(=O)N2Cc1ccc(F)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (14 mg, 0.03 mmol) in anhydrous tetrahydrofuran (1 mL) at −78° C. in a dry flask equipped with an inlet of dry nitrogen was added fresh 1.6 M n-butyl lithium in n-hexane (40 μL, 0.06 mmol) with stirring. The reaction mixture was stirred at −78° C. for 30 minutes, then at 0° C. for 1 hour. The reaction mixture was re-cooled to −78° C., a solution of tert-butyl bromoacetate (98 mg, 0.50 mmol) in anhydrous tetrahydrofuran added (0.5 mL), and the reaction mixture stirred overnight, allowing it to warm up to room temperature. The reaction was followed by LCMS, and stirring was continued as needed until the starting material was consumed. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (5 mL) with stirring, concentrated under reduced pressure, diluted with ethyl acetate (10 mL) and diluted with aqueous ammonium chloride (5 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL), and the combined organic phase was successively washed with 2N spdium carbonate (10 mL), 30% ammonium chloride (10 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a crude mixture which was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford tert-butyl 2-(1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (12 mg, 0.02 mmol, 67%). LCMS m/z 524.0 (M-tBu), 602.0 (M+Na), anal HPLC >98% in purity. 1H NMR (400 MHz; acetone-d6) δ7.77 (t, J=8.0 Hz, 1H); 7.60 (m, 2H); 7.38 (m, 2H); 7.11 (m, 1H); 7.00 (m, 1H); 6.81 (s, 1H); 5.35 (s, 2H); 3.80 (s, 3H); 2.70-3.30 (m, 3H); 2.40-2.60 (m, 2H); 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH3:22])[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21]>>[CH3:1][O:2][C:3]1[C:7]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]#[C:15][CH2:14][N:13]([CH3:12])[CH3:22])=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)CC#CCCCCN
Product: COC1=NS(=O)(=O)N=C1NCCCCC#CCN(C)C

Procedure:
In a similar manner to Example 1, 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide (1.07 g) and 7-(dimetylamino)hept-5-ynylamine (0.92 g) were reacted to give a solution of 3-methoxy-4-[7-dimethylaminohept-5-ynylamino]-1,2,5-thiadiazole-1,1-dioxide. Reaction with ammonia gas and purification as in Example 1 gave the title compound (1.08 g), m.p. 172°-4° C. (recrystallisation from acetonitrile).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][C:23]([CH3:25])=O.C(Br)C=C>O>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH:23]=[CH2:22]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: O
Product: C=CCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To start with, a three-necked flask was charged with commercially available 4-hydroxybenzophenone (39.6 g) and potassium carbonate (28 g), followed by argon substitution. Subsequently, dehydrated acetone (120 ml) was added, followed by well stirring, and then allyl bromide (18.6 ml) was added. Stirring was performed at 60° C. for 8 hours. After that, the mixture was cooled to a room temperature, and pure water was added, followed by stirring. Extraction with diethylether (100 ml) was performed twice. Extraction-and-washing with a 10% NaOH solution (100 ml) was performed twice, followed by drying over sodium sulfate. The solvent was removed by using an evaporator to obtain a pale yellow residue. The residue was recrystallized from methanol, followed by suction filtration, and then drying in vacuum was performed to obtain 4-allyloxybenzophenone (hereinafter referred to as ABP) which was a pure product (weight: 43.7 g, yield: 91.9%).
Reaction SMILES: C(O[C:9](=O)[N:10](C)[C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:22][O:21][C:19](=[O:20])[C:14]1[CH:15]=[C:16]([O:17][CH3:18])[C:11]([NH:10][CH3:9])=[C:12]([O:23][CH3:24])[CH:13]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc(OC)c(N(C)C(=O)OCc2ccccc2)c(OC)c1
Agent: [Pd]
Solvent: CO
Product: CNc1c(OC)cc(C(=O)OC)cc1OC

Procedure:
A suspension of 33.5 g. of 2,6-dimethoxy-4-(methoxy-carbonyl)-N-methylcarbanilic acid benzyl ester in 1 liter of methanol was hydrogenated in the presence of 1.5 g. of palladium on carbon (5%) until the hydrogen uptake stopped. The suspension was heated to boiling and filtered. The filtrate was evaporated under vacuum and the residue recrystallized from cyclohexane, whereby there was obtained 3,5-dimethoxy-4-(methylamino)-benzoic acid methyl ester having a melting point of 49°-51° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].O.Cl[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:9][CH:8]=1>CN(C=O)C>[C:1]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:9][CH:8]=1)#[N:2]
Reactant: [C-]#N
Reactant: CC(=O)Nc1nc(CCc2ccc(CCl)cc2)cs1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(CCc2ccc(CC#N)cc2)cs1
Temperature: 25 °C
Reaction time: 19 h
Yield: 67 %

Procedure:
NaCN (115 mg), KI (130 mg) and water (1.8 ml) were combined, and then a solution of N-(4-{2-[4-(chloromethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (230 mg) in DMF (7 ml) was added dropwise to the mixture at 0° C. The reaction mixture was stirred at r.t. for 19 hours, poured into water, and extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residual solid was washed with ethyl ether to give N-(4-{2-[4-(cyanomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (149.1-mg) as a colorless solid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH:13](=[O:17])[CH2:14][CH2:15][CH3:16]>>[OH:17][CH:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])[CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)c1ccc(I)c(C)c1
Reactant: CCCC=O
Product: CCCC(O)c1ccc(C(=O)OC)cc1C

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate (16), using methyl 4-iodo-3-methylbenzoate and butyraldehyde. 1H NMR (400 MHz, CDCl3, δ): 7.87 (d, J=8.4 Hz, 1H), 7.81 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 4.98 (q, J=4.4 Hz, 1H), 3.90 (s, 3H), 2.37 (s, 3H), 1.63-1.72 (m, 2H), 1.50-1.54 (m, 1H), 1.39-1.43 (m, 1H), 0.98 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH:14](C1NC=C(C(OCC)=O)N=1)[C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C1C=CC=C2C=1CC(Br)C2=O)=O)C1C=CC=CC=1.[CH2:52]([O:54][C:55]([C:57]1[NH:58][CH:59]=[CH:60][N:61]=1)=[O:56])[CH3:53]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH:14]([C:59]1[N:58]=[C:57]([C:55]([O:54][CH2:52][CH3:53])=[O:56])[NH:61][CH:60]=1)[C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]c(C2Cc3c(C(=O)NCc4ccccc4)cccc3C2=O)n1
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C(NCc1ccccc1)c1cccc2c1CC(Br)C2=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(C2Cc3c(C(=O)NCc4ccccc4)cccc3C2=O)c[nH]1

Procedure:
4-Benzylcarbamoyl-2-(ethoxycarbonylimidazolyl)-1-indanone can be prepared in the following way: a mixture of 0.5 g of 4-benzylcarbamoyl-2-bromo-1-indanone, 0.37 g of 2-ethoxycarbonylimidazole and 10 ml of toluene is heated at reflux for 12 hours. The reaction mixture is concentrated on a rotary evaporator. Dichloromethane is added to the evaporation residue, filtration is carried out and the filtrate is washed with distilled water, dried over sodium sulphate and evaporated on a rotary evaporator. The brown oil obtained (0.26 g) is purified by chromatography on a silica column (diameter: 1.5 cm, height: 30 cm), elution being carried out with a dichloromethane/methanol (95/5 by volume) mixture. The foamy product obtained is triturated with 5 ml of ethyl acetate, filtered and the solid is washed with ethyl acetate (2×5 ml) and dried at 50° C. under vacuum (1 mm Hg; 0.13 kPa). 0.07 g of 4-benzylcarbamoyl-2-(2-ethoxycarbonylimidazolyl)-1-indanone is obtained in the form of an orange solid melting at 218° C.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].[CH:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[C:16](OCC)=[O:17].Cl>O1CCOCC1.O>[O:17]=[C:16]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[CH:6]=1)[CH2:2][C:1]#[N:3]
Reactant: CCOC(=O)c1ccc2c(c1)CCCC2
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCC(=O)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Acetonitrile (21.48 mL, 411 mmol) was added to a stirred suspension of 60% NaH (7.05 g, 176 mmol) in dioxane (200 mL) and the resulting mixture was stirred at rt for 20 min. Solution of ethyl 5,6,7,8-tetrahydronaphthalene-2-carboxylate (12 g, 58.7 mmol) in dioxane (50 mL) was then added and the mixture was heated at reflux for 4 h. After cooling to rt, water followed by 1N HCl (100 mL) was added and the mixture was extracted twice with dichloromethane, dried (Na2SO4), filtered and concentrated to afford 3-oxo-3-(5,6,7,8-tetrahydronaphthalen-2-yl)propanenitrile as dark solid. A mixture of this syrup and hydrazine hydrate (2.77 mL, 88 mmol) in ethanol (200 mL) was refluxed for 16 h. The reaction mixture was then cooled to rt and concentrated in vacuo. The resulting crude was diluted with dichloromethane and washed with water, dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (5-10% CH2Cl2/MeOH) to afford desired 3-(5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazol-5-amine (6.1 g, 28.6 mmol, 48.7% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) δ: 7.26 (d, J=3.5 Hz, 2H), 7.12 (d, J=7.8 Hz, 1H), 5.89 (s, 1H), 4.14 (br. s., 3H), 2.88-2.75 (m, 4H), 1.83 (dt, J=6.1, 3.4 Hz, 4H). LCMS (M+H)=214.2.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:44]1[S:45][CH:46]=[CH:47][CH:48]=1)CCC>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([S:25]([NH:24][C:15]2[N:14]([CH3:38])[N:13]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([C:44]4[S:45][CH:46]=[CH:47][CH:48]=4)=[CH:7][N:6]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:27])=[O:26])=[CH:29][CH:30]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(OCCOc3ncc(-c4cccs4)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 3) (111 mg) in 1,4-dioxane (5 ml) at room temperature was added 2-(tributylstannyl)thiophene (103 mg) and bis(triphenylphosphine)palladium (II) chloride (6.5 mg) the mixture was stirred and heated to reflux for 3 hrs followed by 16 hrs. at room temperature. To the mixture was added bis(triphenylphosphine)palladium (II) chloride (6.5 mg) and the mixture was heated to reflux for a further 4 hrs. The reaction was diluted with ethyl acetate (100 ml), washed with a 10% solution of potassium fluoride in water (100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ethyl acetate:hexane (1:1) to yield the title compound as a white solid (75 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH:12]1[C:17]([CH:18]=O)=[CH:16][C:15]2[O:20][CH2:21][O:22][C:14]=2[CH:13]=1.[OH-].[Na+].C(O)C>O>[O:22]1[C:14]2[CH:13]=[CH:12][C:17]([CH:18]=[CH:1][C:2]([C:4]3[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=3[OH:11])=[O:3])=[CH:16][C:15]=2[O:20][CH2:21]1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
1 g (5.86 mmol) of 5-chloro-2-hydroxyacetophenone, 3 molar equivalents of piperonal, and 3 molar equivalents of sodium hydroxide was mixed in 15 ml of aqueous 80% ethanol solution, and then the mixture was stirred at room temperature for 15 hours. After the reaction was completed, 50 ml of water was added thereto, and the mixture was stirred for about 10 minutes. The obtained pale yellow solid was filtered, washed with water and diethylether, and dried to give 1.42 g (Yield 80%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:14])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][CH2:16][C:17](Br)=[O:18].N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[Br:15][CH2:16][C:17]([NH:1][C:2]1[N:3]=[C:4]([CH3:14])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Cc1nnc(-c2ccccc2)c(N)n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nnc(-c2ccccc2)c(NC(=O)CBr)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-3-methyl-6-phenyl-[1,2,4]triazine (Example 25, step b); 550 mg, 2.96 mmol) in dichloromethane was added bromoacetyl bromide (0.308 ml, 3.55 mmol), pyridine (0.357 ml, 4.44 mmol) and 4-dimethylaminopyridine (10 mg). The reaction mixture was stirred under nitrogen at room temperature for 2 h, then evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 40% ethyl acetate in hexanes) to yield 5-(bromoacetamido)-3-methyl-6-phenyl-[1,2,4]triazine (475 mg), m/z (ES+) 307/309 (M++H). To a solution of this product (470 mg, 1.53 mmol) in 1,2-dichloroethane was added triethylamine (0.235 ml, 1.68 mmol) and sodium iodide (10 mg), and the mixture was heated at reflux for 4 h. On cooling the title compound crystallised out of solution and was collected by filtration to yield 220 mg. δH (400 MHz; d6-DMSO) 2.80 (3H, s), 7.34 (1H, s), 7.56 (3H, m), 8.54 (2H, m), 11.35 (1H, bs); m/z (ES+) 227 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.O.O.[Sn](Cl)Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([CH:3]=1)[NH2:10]
Reactant: O=[N+]([O-])c1cc(Cl)cc(F)c1F
Agent: Cl[Sn]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Cl)cc(F)c1F
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of 5-chloro-1,2-difluoro-3-nitrobenzene (1.62 g, 8.4 mmol) in acetic acid (30 mL) was added tin(II) dichloride dihydrate (11.4 g, 50.4 mmol). The mixture was stirred for 1.25 h at rt, and then the acetic acid was removed in vacuo. The residue was transferred to a 500-mL Erlenmeyer flask in a minimal amount of ethyl acetate. The resulting suspension was then diluted with approximately 200 mL of ether, and then the flask was placed into an ice bath. To the vigorously stirring mixture was added 50% aqueous sodium hydroxide (10 mL), and a pale yellow solid formed. Celite and sodium sulfate were added to adsorb and dry the precipitate. All the solids were removed by filtration, rinsed with ethyl acetate, and discarded. The filtrate was concentrated, and the residue was purified by flash chromatography (80% hexanes: 20% ethyl acetate). The desired 5-chloro-2,3-difluoroaniline was isolated as an orange oil (913 mg, 5.6 mmol, 66% yield). 1H NMR (400 MHz, CDCl3): 6.57-6.52 (m, 2H), 3.91 (br s, 2H); GCMS for C6H4ClF2N: 163 (M+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)[C:13]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:8][CH:7]=1.O>CS(C)=O>[N:1]([CH2:19][CH2:18][CH2:17][N:14]1[CH:15]=[CH:16][C:12]([C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=2)=[C:13]1[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCCn2ccc(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCCn1ccc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
0.38 g (5.90 mmol) of sodium azide were added to a solution of 1.33 g (2.95 mmol) of 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1-[3-(p-toluenesulfonyloxy)propyl]-1H-pyrrole [prepared as described in step 22(iii) above] in 13 ml of dimethylsulfoxide. The resulting mixture was stirred at 70° C. for 1 hour. At the end of this time water was added to the reaction mixture and then this was extracted with dichloromethane. The organic extract was washed with water and then concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethylacetate as the eluant to afford 100 mg (yield 11%) of the title compound as a pale brown powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[N:34](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH2:34])=[O:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C(=O)O)cc3c2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C(N)=O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.9 %

Procedure:
A mixture of 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (1.59 g), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.4 g), 1-hydroxybenzotriazole ammonium salt (1.1 g) and N,N-dimethylformamide (40 mL) was stirred at room temperature for 16 hr. Water was added to the reaction solution, and the precipitated solid was collected by filtration, and washed successively with water, ethanol and diethyl ether to give the title compound (1.6 g, yield 100%) as a pale-yellow solid. The pale-yellow solid was recrystallized from N,N-dimethylformamide-water to give pale-yellow crystals. melting point 251-252° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=1>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:24][C:25]4[CH:26]=[N:27][N:28]([CH2:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:29]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cnn(CCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cnn(CCc5ccccc5)c4)ncnc3[nH]2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (110 mg, 0.33 mmol) and 4-amino-1-phenethyl-1H-pyrazole (74 mg, 0.39 mmol) in 1-butanol (3 mL) was heated at 120° C. overnight, LC-MS showed the desired product and some de-Boc product (ca. 1:1 ratio). After the mixture was cooled to rt, it was diluted with methylene chloride (3 mL), then N,N-diisopropylethylamine (0.11 mL, 0.66 mmol) and di-tert-butyldicarbonate (72 mg, 0.33 mmol) were added, the resulting mixture was stirred at rt for 30 min. The mixture was diluted with EtOAc (30 mL), then washed with brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized with EtOAc to give the title compound as an off-white solid. LC-MS (ES, Pos.): 486 [MH+]. 1H NMR (CDCl3, 400 MHz): δ=1.50 (s, 9H), 2.50 (m, 2H), 3.23 (t, J=7.3 Hz, 2H), 3.66 (m, 2H), 4.17 (m, 2H), 4.38 (t, J=7.3 Hz, 2H), 6.08 (s, 1H), 6.17 (s, 1H), 6.55 (s, 1H), 7.17-7.32 (m, 5H), 7.60 (s, 1H), 7.80 (s, 1H), 8.37 (s, 1H), 10.99 (br s, 1H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[C:13]([C:18](=[N:24][O:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:12]=1.Cl>CN(C)C=O.O>[NH2:10][C:11]1[CH:16]=[C:15]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:14]=[C:13]([C:18](=[N:24][O:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:12]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)C(=NOC)c1nc(N)cc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC)c1nc(N)cc(Sc2ccccc2)n1
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
To a solution of thiophenol (2.55 g) in N,N-dimethylformamide (20 ml) was added 50% sodium hydride (1.1 g) under cooling in an ice bath and the mixture was stirred for 20 minutes at 0° C. to 5° C. To the mixture was added ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (2.0 g) and the mixture was stirred for 6 hours at ambient temperature. The resultant mixture was poured into cold water, adjusted to pH7 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was subjected to column chromatography on silica gel (50 g) using a mixture of chloroform and ethyl acetate (3:1 by valume) as an eluent. The fractions containing the object product were collected and evaporated to give ethyl 2-(4-amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (460 mg), mp 154°-156° C.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.[S:13]1[C:17]2[CH:18]=[C:19]([NH2:22])[CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH2:23]>>[NH2:23][C:14]1[S:13][C:17]2[CH:18]=[C:19]([NH:22][C:3](=[O:5])[CH2:2][NH:1][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:20]=[CH:21][C:16]=2[N:15]=1
Reactant: Nc1ccc2nc(N)sc2c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2nc(N)sc2c1
Yield: 20 %

Procedure:
The title compound was prepared from Boc-Gly-OH and 1,3-benzothiazol-2,6-diamine according to the procedure of EXAMPLE 51. The product was obtained as a yellow solid.