Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:27]#[N:28].[NH4+].[Cl-]>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[N:36]1[CH2:35][CH2:34][CH:33]([O:32][C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:23])[CH2:38][CH2:37]1
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: N#Cc1ccc(OC2CCNCC2)c(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 2,3-dichloropyrido[3,4-b]pyrazine (1.00 g, 5.00 mmol) in DCM (10.0 mL) at 0° C. was added DIPEA (2.62 mL, 15.00 mmol) and 3-fluoro-4-(piperidin-4-yloxy)benzonitrile hydrochloride (1.283 g, 5.00 mmol). The reaction mixture was stirred for 30 min, warming gradually to room temperature. The reaction mixture was treated with saturated aqueous NH4Cl. The organic layer containing yellow solid was collected and concentrated under reduced pressure. The solid was filtered, washing with water, and was lyophilized overnight to give the title compound as a yellow solid (1.325 g, 69%). ESI-MS m/z [M+H]+ 384.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:10])[C:7]=1[O:8][CH3:9].Br[C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=2[C:23]2[CH:24]=[CH:25][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Cl)cc(B(O)O)cc1Cl
Reactant: NS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Product: COc1c(Cl)cc(-c2cc(F)c(F)cc2-c2ccc(S(N)(=O)=O)cc2)cc1Cl

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 3,5-dichloro-4-methoxyphenylboronic acid (Step 2) was reacted with 4-(2-bromo-4,5-difluorophenyl]benzenesulfonamide (Step 3) to give 4-[2-(3,5-dichloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide as a colorless solid: mp 145.5-146.0° C.; NMR (CDCl3) δ 3.89 (s, 3H), 4.78 (s, 2H), 6.98 (s, 2H), 7.18-7.29 (m, 4H), 7.85 (d, J=8 Hz, 2H); MS (FAB) m/z 450 (M+Li)+; HRMS calc'd for (M+H)+ 444.0039, found 444.0052. Anal. Calc'd for C19H13NCl2F2O3S: C, 51.37; H, 2.95; N, 3.15. Found: C, 51.59; H, 3.03; N, 3.15.
Reaction SMILES: [N:1]([CH:4]1[CH:13]([OH:14])[C:12]2[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[N+:2]=[N-:3].Cl.[NH2:18][OH:19].C(=O)(O)[O-].[Na+]>CC(O)C.CCOC(C)=O>[N:1]([CH:4]1[CH:13]([OH:14])[C:12]2[C:7](=[CH:8][C:9]([C:15](=[N:18][OH:19])[NH2:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: N#Cc1ccc2c(c1)OCC(N=[N+]=[N-])C2O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: [N-]=[N+]=NC1COc2cc(C(N)=NO)ccc2C1O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Racemic (3R*,4S*)-3-azido-4-hydroxychroman-7-carbonitrile Int-2-C (5.08 g, 23.5 mmol) and hydroxylamine hydrochloride (3.27 g, 47.0 mmol) were mixed in 2-propanol (94.0 mL). To this suspension was added sodium bicarbonate (7.90 g, 94.0 mmol) and the resulting mixture was heated at reflux for 2 h. After the reaction mixture was cooled to room temperature, it was diluted with EtOAc (250 mL) and washed with water and brine. The combined aqueous layers were extracted again with EtOAc. The combined organic layers were dried (MgSO4) and concentrated to afford racemic (3R*,4S*,E/Z)-3-azido-N′,4-dihydroxychroman-7-carboximidamide Int-2-D (5.71 g, 22.9 mmol, 97.5% yield): LCMS=250.08 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[N:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][C:11]=1[CH3:19].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH3:9][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][N:10]=[C:11]([CH3:19])[CH:12]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2cc(C)nc(N)n2)ccn1
Reaction time: 8 h

Procedure:
A mixture of 2.00 g (13.9 mmol) 2-amino-4-chloro-6-methylpyrimidine, 2.48 g (18.1 mmol) 2-picoline-4-boronic acid, 0.43 g (2.8 mmol) tetrakis(triphenylphosphine)palladium(0) and 3.85 g (27.9 mmol) potassium carbonate in 40 mL 1,2-dimethoxyethane and 4 mL water is heated to reflux temperature and stirred overnight. The reaction mixture is concentrated under reduced pressure, water is added and the precipitated product is filtered off and dried in vacuo at 40° C. Yield: 1.94 g (69%).
Reaction SMILES: O.NN.[CH3:4][C@H:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:6][N:7]1C(=O)C2C(=CC=CC=2)C1=O.[ClH:23]>C(O)C>[ClH:23].[CH3:4][C@H:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:6][NH2:7]
Reactant: C[C@@H](CN1C(=O)c2ccccc2C1=O)CC(F)(F)F
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: C[C@@H](CN)CC(F)(F)F
Yield: 88 %

Procedure:
Hydrazine monohydrate (3.1 mL) was added to a stirred solution of (R)-2-(2-methyl-4,4,4-trifluorobutyl)-1H-isoindole-1,3(2H)-dione (17.1 g) in anhydrous ethanol (85 mL) and heated to reflux. After three hours' reflux, the solution was cooled; ethanol (40 mL) was added; and the solution was acidifed to pH 1 by addition of concentrated hydrochloric acid and was filtered. The filtrate was evaporated, and the residue was purified by sublimation (bath temperature 170° C., at 6.6 Pa) to yield (R)-2-methyl-4,4,4-trifluorobutylamine hydrochloride as a white solid (9.89 g, 88%); mp 187°-191° C.; partial NMR (300 MHz, DMSO-D6 -D2O shake): 1.05 (d, 3H, CH3), 2.06-2.36 (m, 2H, CF3CH2) 2.36-2.54 (m, 1H, CHCH3) 2.73 (dd, 1H, CH2N), 2.87 (dd, 1H, CH2N) 8.20 (br s, 2H, NH2).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:12][CH2:13][O:14]C(=O)C)=[C:6](Br)[CH:5]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[F:10][C:8]1[CH:9]=[C:4]([C:3]([OH:2])=[O:19])[CH:5]=[C:6]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:32])([F:31])[F:20])[CH:27]=2)[C:7]=1[O:11][CH2:12][CH2:13][OH:14]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(F)c(OCCOC(C)=O)c(Br)c1
Product: O=C(O)c1cc(F)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The compound of step 1 was coupled to 3-trifluoromethyl-phenylboronic acid in analogy to step 3 of example 92, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield 5-fluoro-6-(2-hydroxy-ethoxy)-3′-trifluoromethyl-biphenyl-3-carboxylic acid. This intermediate was coupled to the compound of step 1 of example 355 in analogy to step 1 of example 3, and the obtained ester intermediate hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]1[O:12][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[O:7][CH2:10]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)cc1

Procedure:
A mixture of 100 g 4-bromobenzaldehyde, 40 ml ethylene glycol, 800 ml of toluene and a catalytic amount of p-toluenesulfonic acid was refluxed for 2 hours, removing water with a Dean-Stark trap. The mixture was then cooled and poured into cold dilute potassium carbonate solution, extracted three times with ether and dried (MgSO4). Solvent was removed under reduced pressure, giving 118 g of 4-bromobenzaldehyde ethylene ketal (23) as a solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:22]([C:20]1[S:21][C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)=[CH:18][CH:19]=1)(=[O:23])=[O:24]
Reactant: Cc1noc(N)c1Br
Reactant: COc1cccc(-c2ccc(S(=O)(=O)Cl)s2)c1
Product: COc1cccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)c1
Yield: 48 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-(3-methoxyphenyl)thiophene-2-sulfonyl chloride in 48% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[N:4]1[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1c(Cl)cccc1Cl
Solvent: O
Solvent: CC(=O)O
Product: Clc1cccc(Cl)c1-n1cccc1
Yield: 83.3 %

Procedure:
A mixture of 5 g of 2,6-dichloroaniline, 4.5 g of 2,5-dimethoxytetrahydrofuran and 30 ml of acetic acid was heated to reflux for 10 hours. The reaction mixture was allowed to cool, poured into water, and extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 5.45 g of 1-(2,6-dichlorophenyl)-1H-pyrrole of the formula:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38])#[N:30]>>[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][N:23]([S:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:29]#[N:30])(=[O:39])=[O:38])[CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4C#N)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and 2-cyanobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)[OH:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:18][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(F)c(Cl)c1
Reaction time: 1 h
Yield: 98.7 %

Procedure:
Triethylamine (0.480 mL, 3.44 mmol) was added to (R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanol (0.70 g, 2.30 mmol) in DCM (10 mL) cooled in ice, and then methanesulfonyl chloride (0.213 mL, 2.76 mmol) was added. After 1 hour, the reaction mixture was diluted with DCM, washed with aqueous NaHCO3, dried over MgSO4, filtered, and evaporated to yield (R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl methanesulfonate (0.87 g, 2.27 mmol, 98.9% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.47-7.44 (m, 1H), 7.29-7.24 (m, 1H), 7.16 (t, 1H), 5.51-5.47 (m, 1H), 3.94-3.89 (m, 1H), 3.81-3.76 (m, 1H), 2.97 (s, 3H), 0.88 (s, 9H), 0.04 (d, 6H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2
Reactant: COc1ccc2cccc(F)c2c1
Agent: BrB(Br)Br
Product: Oc1ccc2cccc(F)c2c1

Procedure:
The title compound was prepared by reacting 1-fluoro-7-methoxynaphthalene (7.99 g, 45.34 mmol) with boron tribromide (68 mL of 1 N solution, 68 mmol) according to method D to yield 3.99 g (54%) of a red solid. An analytical sample was prepared by preparative reverse phase HPLC to yield a white solid: mp 89-92° C.;
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:16])[CH3:15])(=[O:11])=[O:12])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)c1ccc(C(C)=O)cc1
Yield: 76.4 %

Procedure:
A solution of 4-acetylbenzenesulfonamide (0.726 g, 3.64 mmol), acetic anhydride (0.7 ml, 7.42 mmol) and DMAP (22.26 mg, 0.182 mmol) in pyridine (0.7 ml) was stirred at room temperature 16 hrs. The volatiles were removed under reduced pressure, the residue was taken up in toluene (5 mL) and concentrated again (3×). The residue was dissolved in EtOAc (20 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The solid residue was triturated in Et2O and filtered to give N-[(4-acetylphenyl)sulfonyl]acetamide (670 mg, 2.78 mmol, 76% yield) as a pale yellow solid. MS ESI: [M+Na]+ m/z 264.0. 1H NMR (500 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.13 (d, J=9.9, 2H), 8.01 (d, J=9.9, 2H), 2.62 (s, 3H), 1.91 (s, 3H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:31][NH:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[NH2:30][C:28]([C:16]1[CH:17]=[C:18]([C:21]2[CH:25]=[C:24]([CH2:26][N:32]([CH3:31])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[S:23][CH:22]=2)[CH:19]=[C:20]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH:9]1[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]1)=[O:29]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: CCOC(=O)CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCOC(=O)CN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (45 mg, 100 μmol) in dimethyl sulfoxide (1.0 mL) was added ethyl N-methylglycinate (320 μmol) and 2 to 3 drops of glacial acetic acid. The resulting mixture is agitated overnight. After 18 h, sodium triacetoxyborohydride (200 mg, 1000 μmol) is added. This mixture is agitated for 1.5 h followed by purification by Gilson Preparatory HPLC to give 16.5 mg of the title compound (30.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:41])[CH:29]([NH2:40])[C:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)=[O:31]>>[CH3:26][O:27][C:28](=[O:41])[CH:29]([NH:40][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][S:12]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[CH:22]=[CH:23][CH:24]=1)(=[O:14])=[O:13])[C:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)=[O:31]
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)C(N)C(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: COC(=O)C(NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12)C(=O)c1ccc(Cl)c(Cl)c1

Procedure:
4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid was coupled to (±)-2-amino-3-(3,4-dichloro-phenyl)-3-oxo-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=10.65 min. MS (ESI+): mass calcd. for C25H17Cl3N4O6S, 605.99; m/z found, 607/609 [M+H]+. 1H NMR (500 MHz, CDCl3): 11.23 (s, 1H), 8.88 (d, J=1.8, 1H), 8.85 (d, J=1.8, 1H), 8.58 (dd, J=7.4, 1.4, 1H), 8.32 (dd, J=8.5, 1.4, 1H), 8.24 (d, 2.1, 1H), 8.03 (dd, J=8.4, 2.1, 1H), 7.89-7.86 (m, 1H), 7.79 (d, J=2.0, 1H), 7.69 (d, J=8.4, 1H), 7.45 (d, J=8.5, 1H), 7.30 (d, J=6.9, 1H), 6.97 (dd, J=8.4, 2.0, 1H), 6.19 (d, J=6.9, 1H), 3.78 (s, 3H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1.[CH3:19][C:20]([CH3:23])([O-:22])[CH3:21].[Na+]>C(O)(C)C.C(O)(C)(C)C>[C:20]([O:22][C:12]([NH:11][CH2:10][CH2:9][S:8][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1)=[O:13])([CH3:23])([CH3:21])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCSCc1csc(Br)n1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NCCSCc1csc(SCCNC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-[(2-tert-butoxycarbonylaminoethyl)thiomethyl]-1,3-thiazole (421 mg, 1.2 mmol) and 2-(tert-butoxycarbonylamino)ethylthiol (234 mg, 1.3 mmol) in isopropyl alcohol (5 mL) was added 1.0 M sodium t-butoxide in t-butanol (1.2 mL) and stirred at 80° C. for 1 h. After cooling, the mixture was concentrated and partitioned between ethyl acetate and water. The ethyl acetate extract was concentrated. The residue was chromatographed on silica gel (1% methanol/dichloromethane), affording 364 mg of the title compound. 1H NMR (CDCl3) δ 1.63 (18H), 2.78 (t, 2H), 3.42 (m, 4H), 3.61 (t, 2H), 3.90 (s, 2H), 5.18 (br s, 1H), 7.13 (1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]#[CH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2ON1C2C=CC=CC=2N=N1)(=[O:3])[CH3:2].[F:35][C:36]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:37]=1[NH2:38]>>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]#[CH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:38][C:37]1[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:36]=1[F:35])(=[O:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1F
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: C#C[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C

Procedure:
(2R,3R,4R,5R)4-(acetyloxy)-2-[6-(1H-1,2,3-benzotriazol-1-yloxy)-9H-purin-9-yl]-5-ethynyltetrahydrofuran-3-yl acetate was treated with 2-fluoro-4-chloroaniline (0.63 ml), and the mixture was heated at 60° C. for 22.5 h. The mixture was purified by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate:cyclohexane 10:90-60:40, to give the title compound (55 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([CH3:13])=[N:8]2)C=CC=CC=1.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:13]1([C:9]2[C:10]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:11]([NH2:12])[N:7]([CH3:1])[N:8]=2)[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCCCC1
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Product: Cn1nc(-c2ccccc2)c(C2CCCCC2)c1N

Procedure:
It is obtained by following essentially the procedure of example 1, reacting 1-phenyl-3-methyl-5-pyrazolamine with cyclohexanone (1:2, molar ratio) at a temperature of about 45° C. for about 8 hours. M.p. 212°-214° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14].[N+:17]([CH3:20])([O-:19])=[O:18]>O>[OH:14][C:7]1([CH2:20][N+:17]([O-:19])=[O:18])[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:15])[F:16])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1Nc2ccc(OC(F)(F)F)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
5-trifluoromethoxy isatin ((0.115 g) and nitromethane (0.1 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 20 minutes. The obtained product was extracted with ethyl acetate and the solvent was removed to give pure product.
Reaction SMILES: C[O-].[Na+:3].[CH2:4]([SH:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>CO>[CH2:4]([S-:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Na+:3]
Reactant: CCCCCCCCCCCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCC[S-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In another flask, sodium methoxide (8.1 g, 150 mmol) was dissolved in 10 ml methanol, and dodecanethiol (32.8 ml, 136.6 mmol) was added. The resulting solution was stirred at room temperature for 15 minutes. The solvent was then evaporated under reduced pressure at 90° C. Traces of methanol were evaporated by adding toluene and evaporating it at reduced pressure at 100° C. for two hours.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[N:27][C:28]#[N:29])[C:6]=2[CH:30]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1COCC1>[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[N:27][C:28]#[N:29])[C:6]=2[CH:30]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(OC)[C@@]1(C)Oc2ccc(N)cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(OC)[C@@]1(C)Oc2ccc(NC(=O)c3ccccc3)cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
100 mg (0.24 mmol) of the compound obtained in example 5 was dissolved in 1 ml of THF, then 28 μl (0.24 mmol) of benzoyl chloride and 51 μl (0.37 mmol) of triethylamine were added thereto. The reaction was stirred at room temperature for 2 hours, 10 ml of saturated NaHCO3 solution was added, and aqueous layer was extracted with 20 ml of ethyl acetate. Organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2), to give 68 mg (yield: 54%) of the target compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:18])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:6]=1[CH:7]=[O:8].N1C=CN=C1.[H][H]>[Pd]>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:5]2[C:6]([CH:7]=[O:8])=[CH:2][N:3]=[C:4]2[CH3:18])=[CH:11][CH:12]=1)#[N:17]
Reactant: Cc1nc(Br)c(C=O)n1Cc1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: c1c[nH]cn1
Product: Cc1ncc(C=O)n1Cc1ccc(C#N)cc1
Reaction time: 2 h

Procedure:
A solution of 4-bromo-1-(4-cyanobenzyl)-2-methylimidazole-5-carboxaldehyde (1.33 g, 4.37 mmol) (Step B) and imidazole (0.600 g, 8.74 mmol) in 1:1 ethyl acetate-alcohol (150 mL) was stirred with 10% palladium on carbon (0.020 g) under 1 atm hydrogen. After 2 h, the reaction was filtered through celite and concentrated to give the title compound as a white solid.