Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH:16][CH:17]1[CH:22]([OH:23])[CH:21]([OH:24])[CH:20]([CH2:25][OH:26])[O:19][C:18]1=[O:27]>CO.C(=O)([O-])[O-].[Na+].[Na+]>[OH:19][CH:20]([CH:21]([OH:24])[CH:22]([OH:23])[CH:17]([OH:16])[CH2:18][OH:27])[C:25]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:26]
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: O=C1OC(CO)C(O)C(O)C1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCCCCCCCCCCNC(=O)C(O)C(O)C(O)C(O)CO
Temperature: 25 °C
Reaction time: 30 h

Procedure:
3.5 g of 12-aminododecanoic acid are dissolved in 500 ml of methanol and, with 2.7 g of finely powdered sodium carbonate and 4.8 g of 3,4,5-trihydroxy-6-hydroxymethyltetrahydropyran-2-one, stirred at room temperature for 30 hours. The mixture is filtered off, the filtrate is concentrated and the residue is dissolved in 70 ml of water. With ice-cooling, 1N hydrochloric acid is added gradually until the pH is 1-2 (about 50-55 ml). The free acid precipitates out and is filtered off with suction, washed with a little cold water, and dried under high vacuum at 35° C. This gives 9 of molecular weight 393.48 (C18H35NO8); MS (ESI+): 394 (M+H+); (ESI−):392 (M−H)−.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([NH:13][C:11]2[S:12][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:9][N:10]=2)=[O:15])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)Nc2nnc(Cc3ccccc3)s2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C(=O)Nc2nnc(Cc3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.1 %

Procedure:
0.2 g of tert-butyl [4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]carbamate (0.49 mmol, 1 eq.) is placed in 5 mL of dichloromethane. 1 mL of trifluoroacetic acid (13.54 mmol, 27.6 eq.) is added and the reaction medium is stirred for 3 days at room temperature. The solvents are evaporated off and the residue is taken up in diethyl ether and pentane to give 0.14 g of 4-amino-N-(5-benzyl[1.3.4]thiadiazol-2-yl)-benzamide acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].Br[C:36]1[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=1[C:38]([O:40][CH3:41])=[O:39]>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>[CH3:41][O:40][C:38]([C:37]1[C:36]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:23][CH:22]=2)=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:39]
Reactant: COC(=O)c1ccccc1Br
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)c1ccccc1-c1ccc(-c2onc(C)c2NC(=O)OC(C)c2ccccc2Cl)cc1

Procedure:
{3-Methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, methyl 2-bromobenzoate, and bis(triphenylphosphine)palladium(II) dichloride were reacted as described in Example 17, Step 2 to provide 4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([NH:25][C@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][O:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:35][CH2:36][C:37]#[N:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:36]([CH2:37][NH:38][C:31](=[O:33])[C@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:25][C:24]1[C:20]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]3)=[CH:19][CH:18]=2)=[N:21][O:22][CH:23]=1)#[N:35]
Reactant: N#CCN
Reactant: CC(C)C[C@H](Nc1conc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](Nc1conc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N
Reaction time: 1 h
Yield: 31.2 %

Procedure:
To a 0° C. solution of N-(3-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}isoxazol-4-yl)leucine (46 mg, 0.10 mmol), aminoacetonitrile hydrochloride (21 mg, 0.23 mmol) and HATU. (140 mg, 0.36 mmol) in DMF (3 mL) was added triethylamine (0.06 mL, 0.43 mmol). The solution was stirred 1 h, then partitioned between ether and pH 3.5 phosphate buffer. The organic phase was washed with brine and concentrated. Purification by flash chromatography (40% to 60% ethyl acetate/hexanes) gave 15.5 mg of N1-(cyanomethyl)-N2-[3-(4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl)isoxazol-4-yl]leucinamide.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:33])([F:32])[S:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([S:23][C:22]([F:33])([F:21])[F:32])=[CH:25][CH:26]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(SC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-((trifluoromethyl)thio)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 425.95 g/mol.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])O.Cl.CC(C)=O>O>[CH3:8][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][C:6]=1[OH:7])[CH2:9][NH:11][C:12](=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)NCO
Reactant: Cc1ccccc1O
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: C=CC(=O)NCc1ccc(O)c(C)c1
Yield: 66.5 %

Procedure:
A flask was charged with 108 g of o-cresol, 101 g of N-methylolacrylamide, 5 g of 37% aqueous hydrochloric acid solution and 100 ml of acetone, and the mixture was subjected to the condensation reaction at 60° C. for 60 minutes with stirring. The obtained reaction mixture was poured into excess water to separate an organic layer. The organic layer was dissolved in 200 ml of methylene chloride, which was washed with three 100 ml portions of water to give 127 g of N-(3-methyl-4-hydroxybenzyl)acrylamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])O)=[CH:5][CH:4]=1)[CH3:2].C([BH3-])#N.[Na+].C[Si](Cl)(C)C>C(#N)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(O)c2ccccc2OC)cc1
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: CCc1ccc(Cc2ccccc2OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
1.34 g of (4-ethylphenyl)(2-methoxyphenyl)methanol are dissolved in acetonitrile and cooled to 0° C. 1.50 g of sodium cyanoborohydride are added to the mixture and then 3.00 ml of trimethylsilyl chloride are added. The mixture is stirred at room temperature overnight. The reaction solution is filtered through Celite and extracted with saturated NaCl solution. The organic phase is dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel with ethyl acetate/heptane (1/12). 0.83 g of the product is obtained. C16H180 (226.32) MS (DCl) 227.4 (M+H+)
Reaction SMILES: Cl.O.N[CH:4]([CH2:8]C1C=CC=CC=1)[C:5](O)=O.[CH2:15]([O:18][C:19]1[CH:30]=[CH:29][C:22]([CH2:23][C@@H:24]([C:26]([OH:28])=[O:27])[NH2:25])=[CH:21][CH:20]=1)[C:16]#[CH:17]>[OH-].[Na+].CO>[CH2:8]([O:27][C:26](=[O:28])[CH:24]([NH2:25])[CH2:23][C:22]1[CH:29]=[CH:30][C:19]([O:18][CH2:15][C:16]#[CH:17])=[CH:20][CH:21]=1)[C:4]#[CH:5]
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: C#CCOc1ccc(C[C@H](N)C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCOC(=O)C(N)Cc1ccc(OCC#C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The propargyl ester (1.6 g, 5.5 mmol) from the previous step was dissolved in a mixture of aqueous 2 N NaOH (14 mL) and MeOH (10 mL). After stirring for 1.5 h at room temperature, the pH was adjusted to 7 by adding conc. HCl. Water (20 mL) was added and the mixture was kept at 4° C. overnight. The precipitate was filtered, washed with ice-cold H2O, and dried under vacuum yielding, 1.23 g (90%) of 1 in FIG. 11 (2-Amino-3-phenylpropionic acid (1) (also known as p-propargyloxyphenylalanine) as a white solid. 1H NMR (400 MHz, D2O) (as the potassium salt in D2O) δ 7.20 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 4.75 (s, 2H), 3.50 (dd, J=5.6, 7.2 Hz, 1H), 2.95 (dd, J=5.6, 13.6 Hz, 1H), 2.82 (dd, J=7.2, 13.6 Hz, 1H); 13C NMR (100 MHz, D2O) δ 181.3, 164.9, 155.6, 131.4, 130.7, 115.3, 57.3, 56.1, 39.3; HRMS (CI) m/z 220.0969 [C12H13NO3 (M+1) requires 220.0968].
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[N:3]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[S:22])=[N:3]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccn(CCCCO)n1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1ccn(CCCCO)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
A mixture of 3-amino-1-(4-hydroxybutyl)pyrazole (0.966 g.) and benzoylisothiocyanate (1.0 g.) in acetone (30 ml.) was stirred at room temperature for 18 hours. The solvent was evaporated and the residue purified by column chromatography on silica gel using EtOAc as eluant to give 1-(4-hydroxybutyl)-3-(3-benzoylthioureido)pyrazole (30% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7]([CH:11]([NH:19]S(C(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:8][CH:9]=[CH:10][C:2]1=2.Cl.O1CCOCC1>CO>[NH2:19][CH:11]([C:7]1[C:3]2[O:4][CH2:5][CH2:6][O:1][C:2]=2[CH:10]=[CH:9][CH:8]=1)[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1cccc2c1OCCO2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCCC(N)c1cccc2c1OCCO2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) slightly yellow solution of methyl 5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate (160 mg; 0.43 mmol) in MeOH (2 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.22 ml; 0.88 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 5-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pentanoate as a yellow solid. LC-MS (conditions A): tR=0.47 min.; [M+H]+: 266.11 g/mol.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([C:21]#[C:22][CH2:23][O:24][CH3:25])[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][CH2:23][O:24][CH3:25])=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: COCC#Cc1ccc(N)c(F)c1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1

Procedure:
2,3,4-Trifluorobenzoic acid and the product of Example 25, Step A, 2-fluoro-4-(3-methoxy-1-propynyl)aniline, were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, followed by purification by chromatography on silica gel (10% EtOAc/hexanes as eluant), 3,4-difluoro-2-[[2-fluoro-4-(3-methoxy-1-propynyl)phenyl]amino]-benzoic acid was isolated (62%) as a pale yellow solid; m.p. (EtOAc/hexanes) 221-223° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.60 (br s, 1 H), 9.27 (br s, 1 H), 7.85-7.79 (m, 1H,), 7.36 (dd, J=12.0, 1.8 Hz, 1 H), 7.20 (dd, J=8.3, 1.5 Hz, 1 H), 7.18-7.11 (m, 1 H), 6.96 (td, 8.8, 5.5 Hz, 1 H), 4.31 (s, 2 H), 3.32 (s, 3H ). Anal. Calcd for C17H12F3NO3: C, 60.9; H, 3.6; N, 4.2. Found: C, 61.4; H, 3.6; N, 4.2. Step C: Preparation of 3,4-difluoro-2-[[2-fluoro-4-(3-methoxypropyl)phenyl]-amino]benzoic acid
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:12]=2[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: CCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: C1COCCN1
Product: CCCCC(=O)c1c(CN2CCOCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 5, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-valerylquinoline was reacted with morpholine to give 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-morpholinomethyl-3-valerylquinoline. This compound was recrystallized from ethyl acetate-hexane to give colorless prisms. mp. 137°-138° C.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][N:23]=[C:22]2[O:20][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ncnc(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)c2cc1OC
Temperature: 130 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
Dimethyl sulfoxide (1.4 ml) was added to 5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinazoline (94 mg), and cesium carbonate (137 mg), and the mixture was stirred at 130° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, the mixture was filtered, and the residue was washed with chloroform/methanol. The solvent was removed from the filtrate by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (51 mg, yield 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:28]([O:30][C:31](=[O:43])[C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[C:34]([F:42])[CH:33]=1)[CH3:29]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:38]([C:35]1[CH:36]=[CH:37][C:32]([C:31]([O:30][CH2:28][CH3:29])=[O:43])=[CH:33][C:34]=1[F:42])(=[O:39])=[O:40]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)c(F)c1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2nccs2)c(F)c1
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
(2,4-Dimethoxy-benzyl)-thiazol-2-yl-amine (576 mg, 2.30 mmol) was dissolved in THF (7 mL, 80 mmol) and cooled in an ice bath. 1.0 M of lithium hexamethyldisilazide in THF (2.5 mL) was added dropwise to the reaction. After 30 minutes, a solution of 4-chlorosulfonyl-3-fluoro-benzoic acid ethyl ester (559 mg, 2.10 mmol) in THF (5 mL, 60 mmol) was added dropwise to the reaction. The reaction was stirred overnight then quenched with 20 mL saturated aqueous ammonium chloride. The aqueous phase was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on the Isco (80 g SiO2 cartridge, 60 mL/min, hexanes to ethyl acetate) to afford the product as an orange oil (496 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.C(O[Cl:15])(C)(C)C.O>C(Cl)(Cl)Cl>[Cl:15][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1]
Reactant: CC(C)(C)OCl
Reactant: Cc1cc(Cl)c(F)cn1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ncc(F)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 0.87 g (6 mmol) of 4-chloro-5-fluoro-2-picoline, the product of Example 66, in 20 mL of chloroform cooled to -45° C., is added 0.75 mL of t-butylhypochlorite. The reaction mixture is stirred at -45° C. for 2 hours and at 0° C. for 2 hours. The reaction mixture is then poured into water and the resultant aqueous mixture is extracted with methylene chloride. The organic solution is dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and distilled to afford the title compound.
Reaction SMILES: N[C:2](N)=[S:3].[OH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15]COS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].Cl>C(O)C.O>[SH:3][CH2:2][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][OH:5]
Reactant: NC(N)=S
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCOCCOCCOCCS
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of thiourea (0.94 g, 12.35 mmol) and toluene-4-sulfonic acid 2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy)-ethyl ester (4.09 g, 11.75 mmol) in absolute alcohol (32 ml) was heated to reflux under argon atmosphere for 24 h. The mixture was cooled and a solution of NaOH (1.23 g, 30.75 mmol) in 15 ml of ethanol/water (9:1, v/v) was added. Refluxing was continued for another 2.5 h under argon. The reaction mixture was then cooled to ambient temperature and acidified to pH 2 using concentrated hydrochloric acid and then concentrated under reduced pressure. The residue was purified by flash chromatography using ethyl acetate/absolute ethanol (10:1) to afford the product as a colourless oil. Yield 1.55 g (66%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11][C:12]1[C:17]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>C(#N)C.O>[Cl:11][C:12]1[C:17]([S:18]([NH:21][C:22]([NH:1][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)=[O:23])(=[O:19])=[O:20])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2Cl)n1

Procedure:
To a stirred suspension of 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 20 ml of dry acetonitrile at room temperature was added 2.2 g of 2-chloropyridine-3-sulfonylisocyanate. The mixture was stirred for several hours and filtered. Evaporation of the filtrate yielded a solid residue which was stirred in approximately 30 ml of water while adjusting the pH of this mixture to 11 by the addition of 10% of NaOH. This solution was filtered, the filtrate pH adjusted to pH 7 by adding 10% hydrochloric acid and the resulting neutral solution was again filtered. The desired product was then precipitated from this filtrate by adjusting the pH to 2, collected in a sintered funnel and dried in a vacuum oven at room temperature. It melted at 165°-168°.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:10][C:11]1[C:16]([N+:1]([O-:4])=[O:2])=[C:15]([OH:17])[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)ccn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nccc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of fuming nitric acid (14.51 mL, 345 mmol), and sulfuric acid (14.45 ml, 271 mmol) was added 2-methylpyridin-4-ol (6.5 g, 59.6 mmol) portion wise at 25° C. and then stirred in oil bat set at 130° C. for 2 hours. The reaction was cooled to room temperature, poured over ice and the pH was adjusted to ˜7 using sodium carbonate. The mixture was cooled and a yellow precipitate formed which was then filtered and dried under vacuum for 2 hours in a rotovap set at 60° C. The solids were then slurried in methanol (100 mL) and sonicated 2×. The suspension was filtered and the solids discarded and the filtrate was concentrated under vacuum to give 2-methyl-3-nitropyridin-4-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (3H, br. s.) 6.18-6.42 (1H, m) 7.71 (1H, d, J=7.58 Hz) 12.09 (1H, br. s.); MS [M+H] found 155.0.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[C:29]3[CH:33]=[CH:32][S:31][CH:30]=3)=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CO>C(O)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[C:29]3[CH:33]=[CH:32][S:31][CH:30]=3)=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]([OH:24])=[O:23])[CH3:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2ccc(/C(=C/CN(C)CC(=O)OC(C)(C)C)c3ccsc3)cc2)cc1
Solvent: CO
Solvent: O=CO
Product: CC(C)c1ccc(-c2ccc(/C(=C/CN(C)CC(=O)O)c3ccsc3)cc2)cc1
Temperature: 40 °C

Procedure:
(Z)-N-(1-(4-(4-Isopropylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine, t-butyl ester F(i) (18.62 g, 40.3 mmol) was dissolved in 96% formic acid (200 mL). The solution was warmed at 40° C. overnight, then concentrated. The residue was co-evaporated twice with CH2Cl2. Column chromatography (2-15% MeOH/CH2Cl2) provided a pale yellow solid. Trituration with methanol (MeOH) provided pure (Z)-N-(1-(4-(4-isopropylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine G(i) (11.38 g, 70%) as a white solid. 1H NMR (300 MHz, methanol-d4) 1.23 (d, 6H), 2.47 (s, 3H), 2.92 (hept, 1H), 3.26 (s, 2H), 3.50 (d, 2H), 6.22 (t, 1H), 6.94 (d, 1H), 7.32 (d, 4H), 7.46 (d, 1H), 7.57-7.65 (m, 5H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)Cc1cccc(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc([N+](=O)[O-])cc(F)c1F
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
(2,3-Difluoro-phenyl)-acetic acid (11, 5 g, 0.0290 mol) is dissolved in concentrated sulfuric acid (20 ml) and the resulting solution cooled to −10° C. with vigorous stirring. A solution of nitric acid (1.88 ml, 69.3%, 0.0290 mol) and sulfuric acid (2 ml) is added dropwise at a rate such that the temperature remains below −5° C. The thickened slurry is stirred for 15 minutes and then poured on ice. The resulting white precipitate is filtered and dried under vacuum (6.3 g, 99%) and consists of a 50/50 mixture of 5 and 6-NO2 regioisomers suitable for use directly in the next step.