Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8](=[O:10])[O:9][C:5]=2[CH:4]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].FC(F)(F)C(O)=O>C1COCC1.CC#N.O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:7]1[C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:9][C:8]1=[O:10])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2[nH]c(=O)oc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cn1c(=O)oc2cc(OC)ccc21
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
A solution of 6-methoxy-2-benzoxazolinone (0.78 g, 4.72 mmol) dissolved in 5 mL of anhydrous THF was added to a suspension of sodium hydride (0.208 g of a 60% dispersion in mineral oil, 5.2 mmol) in 10 mL of anhydrous THF at room temperature and stirred for 10 minutes. Then, ethyl bromoacetate (0.629 mL, 5.67 mmol) was added and stirred at room temperature for two hours. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that almost all of the starting material (Rt=4.36 min) was gone and that a new peak (Rt=6.0 min) had formed. The reaction was quenched with 2 mL of 4.0M HCl in dioxane. The solvent was removed by rotary evaporation and the residue was adsorbed onto approximately 10 g of silica gel and purified by column chromatography (40 g silica gel 40 um, gradient elution from 100% dichloromethane to 35% methanol/65% dichloromethane over 40 minutes) to give ethyl[6-(methyloxy)-2-oxo-1,3-benzoxazol-3(2H)-yl]acetate (0.96 g, 3.84 mmol, 81%) as a white crystalline solid. MS (ES) m/e 252 [M+H]+.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([NH:16][C@H:17]([CH:25]=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:9]([O:8][C:6]([NH:16][CH:17]([CH:25]=[CH2:1])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CC(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (10.72 g, 0.03 moles) in 100 mL of dry tetrahydofuran at −78° C. was added dropwise 1.6M n-butyl lithium (17.5 mL, 0.028 moles), and the mixture was stirred for 0.5 hrs at −78° C. Then was added a solution of N-Cbz-phenylalaninal (5.67 g, 0.02 moles) in 50 mL of dry tetrahydrofuran, and the mixture was stirred for 16 hrs at room temperature. After addition of saturated NH4Cl (50 mL) the mixture was extracted with EtOAc, and the extract was washed with water and brine. It was dried over Na2SO4 and evaporated to give an oily residue. The crude product was purified by column chromatograpy on silica gel with elution by 5:95 EtOAc-hexane to give pure 2-benzyloxycarbonylamino-1-phenyl-3-butene.
Reaction SMILES: [OH:1][C:2]1C=CC(O)=C[C:3]=1[OH:9].[C:10](OCC)([O:15]CC)([O:12][CH2:13][CH3:14])[CH3:11]>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH2:13]([O:12][C:10]1([CH3:11])[O:9][CH2:3][CH:2]([OH:1])[O:15]1)[CH3:14]
Reactant: Oc1ccc(O)c(O)c1
Reactant: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC1(C)OCC(O)O1
Yield: 114.1 %

Procedure:
A solution composed of 5.0 g of 1,2,4-trihydroxybenzene, 9.7 g of triethyl orthoacetate and 50 ml of toluene-carbon tetrachloride (1:1) was refluxed for 1.5 hours. The solvent was evaporated, and the residue was purified by column chromatography to give 6.7 g (yield 86%) of the desired product as pale brown crystals having a melting point of 86° to 87° C.
Reaction SMILES: [OH-].[Na+].[C:3]([CH:7]([CH2:10][OH:11])[CH2:8][OH:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1.Cl>C1(C)C=CC=CC=1.COCCOC.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:28]([C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([O:9][CH2:8][CH:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:10][OH:11])=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:26]=1)[CH3:29]
Reactant: CC(C)(C)C(CO)CO
Reactant: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(CO)C(C)(C)C)c23)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
Add 2.7 ml of 11.25 N sodium hydroxide solution to a solution of 1974 mg (14.93 mmol) 2-tert.-butylpropane-1,3-diol in 25 ml toluene, 8 ml 1,2-dimethoxyethane and 8 ml water at 70° C. After adding 101 mg (0.30 mmol) tetra-n-butylammonium hydrogensulphate and 1000 mg (2.99 mmol) 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine, stir the reaction mixture for 17 h at 70° C. After cooling to room temperature, adjust to pH 7 with concentrated hydrochloric acid. Extract with dichloromethane. Wash the organic phase with satd. sodium chloride solution, dry over sodium sulphate, and filter. Concentrate the filtrate by vacuum evaporation. Mix the residue with methanol, filter, and wash with diethyl ether. Purify the filtrate by preparative RP-HPLC (gradient: water/acetonitrile). 275 mg (21% of theor.) of the desired product (racemate) is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4](NN)[N:3]=1.C(O)(=O)C>S([O-])([O-])(=O)=O.[Cu+2].O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1
Reactant: NNc1nc(F)c(F)cc1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cnc(F)c(F)c1
Yield: 86.7 %

Procedure:
8.2 g of the compound obtained in Step 2 was added to a mixture of 320 ml of acetic acid and 120 ml of water, and 400 ml of 10% aqueous copper sulfate was added thereto. The resulting mixture was refluxed for 24 hours while removing water using a Dean-Stark trap, and the residue was dried to obtain 5.8 g (yield: 87.1%) of the title compound.
Reaction SMILES: [C:1]([O:7][CH:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.S(N=[N+]=[N-])([N:27]=[N+:28]=[N-])(=O)=O>C(#N)C>[N+:27](=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH:8]([C:13]([Cl:14])([Cl:15])[Cl:16])[CH:9]=[C:10]([CH3:11])[CH3:12])=[O:6])=[N-:28]
Reactant: CC(=O)CC(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Reactant: [N-]=[N+]=NS(=O)(=O)N=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)C(=[N+]=[N-])C(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 1-trichloromethyl-3-methyl-2-butenyl acetoacetate (0.575 g, 2 mmole) and triethylamine (0.404 g, 4 mmole) in 10 ml of acetonitrile was added 1 g of polymer-bound sulfonyl azide (prepared by the method of Roush, et al., loc. cit.). The mixture was stirred overnight at room temperature and filtered. The filter cake was washed with ether, and the slurry was filtered. Solvent was removed by evaporation from the combined filtrates to give 1-trichloromethyl-3-methyl-2-butenyl 2-diazoacetoacetate (0.60 g, 96% yield).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[C:11]([C:16]#[N:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][NH:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[CH3:29][O:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25][N:4]1[CH:5]=[C:6]([C:10]2[C:11]([C:16]#[N:17])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:7](=[O:9])[NH:8][C:3]1=[O:2]
Reactant: COC(CCBr)OC
Reactant: N#Cc1ncccc1-c1c[nH]c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2cccnc2C#N)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
A mixture of 3-(2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-pyridine-2-carbonitrile hydrochloride (Prep103, 500 mg, 2 mmol), and K2CO3 (413 mg, 3 mmol) in DMF (7 ml) was stirred for one hour at room temperature. 3-Bromo-1,1dimethoxy-propane (402 mg, 2.2 mmol) was added and stirring continued for 48 hours. Water was added and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 210 mg of a yellow oil (33% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][CH:23]([C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH2:24][OH:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:22][CH:23]([C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:24]=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(-n2nc(CC(CO)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-n2nc(CC(C=O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propane-1-ol (prepared by the method of Example 67; 50 mg, 0.11 mmol, 1.0 equiv) and dichloromethane (2.0 mL) was added Dess-Martin reagent (89 mg, 0.21 mmol, 2.0 equiv) in one portion. The reaction mixture was stirred at room temperature for 30 min then poured into satd aq sodium bicarbonate (5.0 mL) containing sodium thiosulfate pentahydrate (5.0 equiv relative to Dess-Martin reagent). The resulting mixture was then diluted with dichloromethane (3.0 mL) and stirred vigorously for 2 h. The resulting organic layer was washed with water (5.0 mL) then brine (5.0 mL), dried (Na2SO4), and concentrated under reduced pressure, affording the desired aldehyde, which was used in the next step without purification. Rt=3.57 (Method B). MS (ESI): mass calculated for C26H22Cl2N2O2, 464.11; m/z found, 465.0 [M+H]+.
Reaction SMILES: C([O:8][C:9](=[O:57])[C@H:10]([CH2:53][CH2:54][S:55][CH3:56])[NH:11][C:12](=[O:52])[C@H:13]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[NH:14][C:15](=[O:41])[CH2:16][NH:17][C:18](=[O:40])[CH2:19][NH:20][C:21](=[O:39])[C@H:22]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C1C=CC=CC=1.[OH-].[Na+]>CO>[C:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([NH:20][CH2:19][C:18]([NH:17][CH2:16][C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:57])=[O:8])[CH2:53][CH2:54][S:55][CH3:56])=[O:52])[CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)=[O:41])=[O:40])=[O:39])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
21.1 Parts N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-tryptophyl-L-methionine benzyl ester is dissolved in 70 parts methanol and the solution cooled to 10° C. Then, 90 parts by volume of 1 N sodium hydroxide solution is added dropwise with stirring while maintaining the temperature below 20° C. After standing at room temperature for 1 hour, the methanol is removed by evaporation under reduced pressure. The solution is washed once with ethyl ether to remove benzyl alcohol and the aqueous layer acidified with 90 parts by volume 1 N hydrochloric acid. The solid which results is filtered and washed with water to afford N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-tryptophyl-L-methionine.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:17]2[C:12](=[N:13][C:14](Br)=[CH:15][N:16]=2)[C:11]([C:19](=[O:33])[NH:20][C:21]([CH3:32])([CH3:31])[CH2:22][O:23][Si](C(C)(C)C)(C)C)=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:34][N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:44]#[N:45])[CH:42]=2)[C:37]([Sn](CCCC)(CCCC)CCCC)=[N:36]1>CN(C=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.[Cu]I>[C:1]([O:7][CH2:8][N:9]1[C:17]2=[N:16][CH:15]=[C:14]([C:37]3[C:38]4[C:43](=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=4)[N:35]([CH3:34])[N:36]=3)[N:13]=[C:12]2[C:11]([C:19](=[O:33])[NH:20][C:21]([CH3:31])([CH3:32])[CH2:22][OH:23])=[CH:10]1)(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C#N)ccc12
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COC(=O)C(C)(C)C)c2ccc(C#N)cc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
In a round-bottomed flask, (2-bromo-7-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-ylcarbamoyl)-5H-pyrrolo[3,2-b]pyrazin-5-yl)methyl pivalate (305 mg, 0.565 mmol) and a crude mixture of 1-methyl-3-(tributylstannyl)-1H-indazole-6-carbonitrile and 1-methyl-3-(tributylstannyl)-1H-indazole-6-carbonitrile were dissolved in DMF (5 mL) under nitrogen. Pd (PPh3)4 (32 mg, 0.028 mmol) and CuI (21 mg, 0.113 mmol) were added and mixture was sonicated for 5 minutes while bubbling nitrogen. The reaction mixture was stirred at 80° C. for 16 hours. The concentrated mixture was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (1:1, v/v) to give (2-(6-cyano-1-methyl-1H-indazol-3-yl)-7-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl pivalate (45 mg, 16%). MS: (M+H)+=504.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10]1>>[C:18]([O:17][C:16](=[O:22])[NH:15][CH:11]1[CH2:12][CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: Clc1ccnc(Cl)n1
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccnc(Cl)n2)C1

Procedure:
tert-butyl(1-(2-chloropyrimidin-4-yl)piperidin-3-yl)carbamate was prepared using the procedure similar to COMPOUND 54 using 2,4-dichloropyrimidine and tert-butyl piperidin-3-ylcarbamate. MS (ES+) C14H21ClN4O2 requires: 312. found: 313 [M+H]+
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O.C(OC(=O)C)(=O)C>>[N+:10]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([OH:9])=[O:8])([O-:12])=[O:11]
Reactant: O=C([O-])c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1ccccc1[N+](=O)[O-]

Procedure:
Substantially equimolar amounts of 2,5-dichlorobenzoxazole and the potassium salt of 2-hydroxy benzoic acid are reacted, in an inert organic solvent, e.g., dimethylsulfoxide, in the presence of acetic acid giving 5-(5-chloro-2-benzoxazolyloxy) benzoic acid. The benzoate is then nitrated by, for example, reaction with a mixture of nitric acid, sulfuric acid and acetic anhydride to give the corresponding 2-nitrobenzoic acid prepared as previously described. The 2-nitrobenzoic acid is then reacted with ethyl 2-chloropropionate, as previously described, giving the desired 1-(ethoxycarbonyl)ethyl 5-(5-chloro-2-benzoxazolyloxy)-2-nitrobenzoate.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C@H:12]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]2)C.C([O-])(O)=O.[Na+].[BH4-].[Na+].CO>CC(C)=O.Cl>[OH:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C@H:12]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCC(OCC)OCC)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CC(C)=O
Solvent: CO
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCO)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
Ethyl [(1S)-5-(2,2-diethoxyethoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 248, 849 mg, 2.52 mmol) was dissolved in a mixture of acetone (60 mL) and HCl (30 mL of a 2N aqueous solution). The reaction mixture was stirred at rt for 18 h, then neutralized (pH 7) by addition of a saturated solution of NaHCO3. The aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. To a solution of the crude aldehyde in CH2Cl2 (30 mL) were then added NaBH4 (69 mg, 1.82 mmol) and MeOH (5 mL) were added. After stirring for 5 h at rt, the reaction mixture was washed with a saturated solution of NaHCO3, the organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by a plug of silica gel (eluent: EtOAc) to provide the product (264 mg, 38%). 1H NMR (400 MHz, CDCl3) δ 1.21 (t, 3H) 1.65-1.71 (m, 1H), 2.29-2.36 (m, 2H), 2.63 (dd, 1H) 2.75-2.83 (m, 2H), 3.43-3.45 (m, 1H), 3.86 (t, 2H), 3.98 (t, 2H), 4.09 (q, 2H), 6.63 (d, 1H), 6.69 (s, 1H) 6.99 (d, 1H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C([N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1)C1C=CC=CC=1>CCO>[N:18]1([CH:21]2[CH2:26][CH2:25][N:24]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH2:22]2)[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: c1ccc(CN2CCN(C3CCNCC3)CC2)cc1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCC(N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.5 mL (50.8 mmol) ethyl acrylate were added to a solution of 11.7 g (44.9 mmol) 1-benzyl-4-piperidin-4-yl-piperazine in 120 mL dry EtOH and the reaction mixture was refluxed for 1 h and then stirred overnight at RT. The solvent was eliminated i.vac. and the residue was dried for 1 h under an oil pump vacuum. The crude product was reacted further without purification.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3](=[O:27])[CH2:4][O:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[NH:8][N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:42](O)(=[O:44])[CH3:43]>C1(C)C=CC=CC=1>[C:42]([N:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]([O:5][CH2:4][C:3](=[O:27])[C:2]([CH3:29])([CH3:28])[CH3:1])=[N:7]1)(=[O:44])[CH3:43]
Reactant: CC(=O)O
Reactant: CC(C)(C)C(=O)COc1n[nH]c(-c2ccc(S(C)(=O)=O)cc2)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)n1nc(OCC(=O)C(C)(C)C)c(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1
Yield: 19 %

Procedure:
A mixture of 3,3-dimethyl-1-[(5-(4-(methylsulphonyl)phenyl)-4-phenyl-1H-pyrazol-3-yl)oxy]butan-2-one (145 mg, 0.35 mmol), prepared according to the method of Example 32B, p-toluene-sulfonic acid hydrate (15 mg), and molecular sieves (4 g) in toluene (35 mL) and acetic acid (5 mL) was refluxed for 24 hours. The mixture was concentrated in vacuo, and the residue was purified by chromatography (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product (yield: 30 mg; 19%). MP 189-191° C.; MS (APCI+) m/z 455 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ1.22 (s, 9H), 2.48 (s, 3H), 3.28 (s, 3H), 5.37 (s, 2H), 7.23 (m, 5H), 7.60 (d, J=9 Hz, 2H), 7.90 (d, J=9 Hz, 2H); Anal. calc. for C24H26N2O5S.0.5 H2O: C, 62.18; H, 5.87; N, 6.04. Found: C, 62.38; H, 5.81; N, 5.83.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10]>ClC1C=CC=CC=1Cl>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[S:9]([OH:12])(=[O:11])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(Br)cc1
Solvent: Clc1ccccc1Cl
Product: Nc1ccc(Br)cc1S(=O)(=O)O
Temperature: 180 °C

Procedure:
A mixture containing 31 g (180 mmol) of 4-bromoaniline and 9.7 ml (220 mmol) of sulphuric acid in 200 ml of 1,2-dichlorobenzene is heated at 180° C. for 6 hours. The reaction medium is allowed to cool to room temperature and is then filtered. The residue is washed with dichloromethane.
Reaction SMILES: [OH-].[Na+].C(OC([NH:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:21]([C:34]([O:36]CC)=[O:35])=[C:20]([Cl:39])[CH:19]=2)[CH:12]=1)=O)(C)(C)C>CO.O1CCCC1.O>[NH2:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:21]([C:34]([OH:36])=[O:35])=[C:20]([Cl:39])[CH:19]=2)[CH:12]=1
Reactant: CCOC(=O)c1c(Cl)cc(Nc2cc(NC(=O)OC(C)(C)C)ncn2)c(=O)n1Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2c(C(=O)O)c(Cl)cc(Nc3cc(N)ncn3)c2=O)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Sodium hydroxide (0.26 g, 6.6 mmol) was added to a suspension of ethyl 5-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylate (0.70 g, 1.32 mmol) in methanol/tetrahydrofuran/water (2:1:1, 30 mL). The mixture was stirred at 80° C. for 16 h. After completion, the solvent was evaporated to dryness under reduced pressure. The crude was diluted with 1 N hydrochloric acid. The precipitate obtained was collected by filtration, dried, washed with pentane and dried further to afford 5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (5) as brown solid. Yield: 0.45 g, 85%; MS (ESI) m/z 402.09 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 7.67 (brs, 2H), 7.19 (d, J=8.16 Hz, 2H), 6.87 (d, J=8.12 Hz, 2H), 6.39 (s, 1H), 5.18 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.C([NH2:22])=O.CC[O-].[Na+].CC(O)=O>CN(C=O)C.CCO.O>[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:5]([C:6]([NH2:22])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NCc1cccs1
Reactant: NC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)c1cnc(Cl)cc1NCc1cccs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
To a solution of ethyl 6-chloro-4-(thiophen-2-ylmethylamino)nicotinate (1.54 g, 5.19 mmol) in DMF (8 mL) and HCONH2 (2 mL, 50.3 mmol), NaOEt (21% by wt., 7.80 mL, 20.9 mmol) in EtOH was added. The mixture was stirred at room temperature for 20 min. HOAc (2 mL) was added to neutralize NaOEt. Water was then added to induce precipitation. The precipitate was collected, dried on vacuum to give 6-chloro-4-(thiophen-2-ylmethylamino)nicotinamide as a solid (1.10 g).