Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:26]1[CH:30]=[CH:29][CH2:28][CH2:27]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:23])[F:24])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:19][CH:27]3[CH2:28][CH2:29][CH2:30][O:26]3)=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(C(=O)NC2CCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a solution of 0.25 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)benzoic acid amide that was synthesized under Synthetic Example 9 in 3 mL of dichloromethane, 68 mg of 2,3-dihydrofuran and a catalytic amount of p-toluenesulfonic acid monohydrate were added and the mixture was stirred for 18 hours at room temperature. The solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue was purified using silica gel column chromatography that was eluted with ethyl acetate-hexane (2:3) followed by crystallization from a mixed solvent of hexane and a small amount of ethyl acetate to obtain 0.12 g of aimed product as yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[C:12]([NH2:26])[N:11]=2)[CH:7]=[CH:6][C:5]=1[F:27].CO>C1COCC1.O>[NH2:26][C:12]1[N:11]=[C:10]([C:8]2[CH:7]=[CH:6][C:5]([F:27])=[C:4]([CH:9]=2)[C:3]([OH:28])=[O:2])[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[C:14]([CH3:25])[N:13]=1
Reactant: COC(=O)c1cc(-c2nc(N)nc(C)c2C#Cc2ccc(N)nc2)ccc1F
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2ccc(F)c(C(=O)O)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 1.95 g (5.1 mmol) 5-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-fluoro-benzoic acid methyl ester using 500 mg (11.9 mmol) LiOH in 40 mL THF and 10 mL water. The product precipitates and is isolated by filtration. The product is washed with MeOH yielding 1.76 g (4.48 mmol) of the desired product.
Reaction SMILES: [CH2:1]([N:8]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][CH:10]([OH:23])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[C:14]=1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C.[Ni]>[CH2:1]([N:8]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][CH:10]([OH:23])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[C:14]=1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N(Cc1ccccc1)CC(O)COc1cccc([N+](=O)[O-])c1O
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)N(Cc1ccccc1)CC(O)COc1cccc(N)c1O

Procedure:
A solution of 16.1 g of crude 1-(N-benzyl-tert.-butylamino)-3-(2-hydroxy-3-nitro-phenoxy)-2-propanol in 150 ml of ethanol is reduced, analogously to Example (4d), with 15 ml of hydrazine hydrate and Raney nickel to give 1-(N-benzyl-tert.-butylamino)-3-(3-amino-2-hydroxy-phenoxy)-2-propanol. The base forms a dark oil which is used further without further purification. The base crystallises from ether as greenish crystals with a melting point of 105°-110°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH2:9])=[NH:8].C[O-:11].[Na+].Cl[C:14]1C=C(C2C=CC=C(C)N=2)N=[C:16]2[NH:27][CH:28]=[CH:29][C:15]=12>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:9]=[C:14]([OH:11])[C:15]2[CH:29]=[CH:28][NH:27][C:16]=2[N:8]=1
Reactant: Cc1cccc(-c2cc(Cl)c3cc[nH]c3n2)n1
Reactant: N=C(N)c1ccccn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(-c2ccccn2)nc2[nH]ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridine-2-carboxamidine (1 eq, 24.8 mmol, 5.69 g) is dissolved in EtOH (60 ml). After addition of NaOMe (30% in MeOH, 1.5 eq, 37 mmol, 6.9 ml) the mixture is stirred for 3 h at r.t. and then filtered. The filtrate is added to 2-cyano-4,4-diethoxy-butyric acid ethyl ester (see Journal of Heterocyclic Chemistry (2006), 43 (6), 1523-1531) (1 eq, 24.8 mmol, 3.01 g) and the resulting mixture is heated at 80° C. for 18 h. The solvents are evaporated, then water (50 ml), EtOH (50 ml) and aqueous HCl solution (2M, 50 ml) are added and the mixture is stirred at 0° C. for 2 h. The mixture is adjusted to pH 8 using aqueous NaOH solution (8 M) and the resulting precipitate is filtered and washed with cold water. The crystals are dried in vacuo giving the title compound; [M+H]+=213.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[N:10][CH:11]=1.C(Cl)Cl>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[N:10][CH:11]=1
Reactant: COC(=O)C=Cc1cnc(C)nc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCc1cnc(C)nc1
Yield: 98.7 %

Procedure:
3-(2-Methyl-pyrimidin-5-yl)-acrylic acid methyl ester (450 mg, 2.53 mmol, 1 eq) and Pd/C, 10% (0.05 eq, 135 mg) were stirred in a DCM (4 ml)/ethanol (4 ml) mixture under hydrogen atmosphere at room temperature for 20 minutes. Pd/C was filtered off over a celite pad, the solvent was evaporated and obtained was 3-(2-methyl-pyrimidin-5-yl)-propionic acid methyl ester (450 mg, yield=90%, purity=88%). MS: [M+H]+=181.14 1H NMR (300 MHz; CDCl3) δ/ppm 2.60 (t, d, J=7.66 Hz, 2H), 2.66 (s, 3H), 2.87 (t, J=7.66 Hz, 2H), 3.63 (s, 3H), 8.47 (s, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][CH2:8][C:7]([CH:16]([OH:36])[C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:21]=[CH:20]3)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1)=[O:4]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]([N:5]1[CH2:9][CH2:8][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:16]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([Si:26]([CH:30]([CH3:32])[CH3:31])([CH:33]([CH3:34])[CH3:35])[CH:27]([CH3:28])[CH3:29])[CH:21]=[CH:20]3)=[O:36])[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCC(c2ccccc2)(C(O)c2ccc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COC(=O)N1CCC(C(=O)c2ccc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)(c2ccccc2)C1
Temperature: 100 °C
Yield: 109.5 %

Procedure:
Manganese dioxide (85%, 256 mg, 2.95 mmol) was added to a solution of 3-[hydroxy-(1-triisopropylsilanyl-1H-indol-5-yl)-methyl]-3-phenyl-pyrrolidine-1-carboxylic acid methyl ester (300 mg, 0.59 mmol) in toluene (8 mL). The reaction mixture was heated at 100° C. for 2 hours, then cooled to room temperature and filtered through a celite pad. The filtrate was evaporated under reduced pressure to give 326 mg of 3-phenyl-3-(1-triisopropylsilanyl-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid methyl ester as a colorless foamy oil. A portion of this product (298 mg, 0.59 mmol) was dissolved in THF (8 mL) and a solution of tetrabutylammonium fluoride (1.0 M in THF, 0.60 mL, 0.59 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes, then was quenched by addition of water. The resulting mixture was extracted with EtOAc, and the combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (30% to 50% of EtOAc in hexane) to give 167 mg (81% 2 steps yield) of 3-(1H-indole-5-carbonyl)-3-phenyl-pyrrolidine-1-carboxylic acid methyl ester as a white foam.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)(=O)C(C)(C)C.[OH-].[Na+].CCOC(C)=O>C1COCC1.CO>[C:44]([O:43][C@@H:9]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)[CH2:8][OH:7])([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 40 °C

Procedure:
The reaction mixture of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)phenyl)benzo[d]thiazol-6-yl)ethyl pivalate (10 mg, 0.015 mmol), 2N NaOH (150 μL) in THF/MeOH (1:1, 1 mL) was heated at 40° C. After reaction finished, the reaction mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C34H32ClN3O2S: 582.2 (M+H+); Found: 582.2 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]([CH3:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:13]([N+:28]([O-:30])=[O:29])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].C1COCC1.O.[OH-].[Li+].Cl>O.CO>[CH3:27][C@H:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)=[CH:12][C:13]=1[N+:28]([O-:30])=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC[C@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCC[C@H](C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
Ester 41b (390 mg, 0.94 mmol) was dissolved in 3. ml THF and 15 ml methanol. Water was added with vigorous stirring until the solution remained cloudy, followed by the addition of lithium hydroxide monohydrate (56 mg, 1.30 mmol). After refluxing overnight, the solution was acidified with concentrated HCl and extracted with ether. The organic layer was washed with brine and dried over MgSO4. Evaporation of the solvent yielded 323 mg (86%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:22])[N:3]=1.[CH3:23][O-:24].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:24][CH3:23])[C:5]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:22])[N:3]=1
Reactant: Cc1nc(Cl)nc(Cl)c1CN(C)[C@H]1CCCc2ccccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)nc(C)c1CN(C)[C@H]1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a flask containing (1S)-(2,4-dichloro-6-methyl-pyrimidin-5-ylmethyl)methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (6.41 g, 19.06 mmol) is added MeOH (100 mL) and the solution is cooled to 0° C. using an ice bath. NaOMe (0.5 M, 38 mL) is added via addition funnel over 20 min. Once addition is complete, the ice bath is removed and the reaction is allowed to proceed overnight warming to room temperature. HOAc (2.0 mL) is added and the reaction mixture is allowed to stir for 10 min, followed by concentration at reduced pressure. The resulting oil is dissolved in EtOAc (100 mL) and washed sat. NaHCO3 (100 mL), brine (100 mL) and dried over Na2SO4. Flash chromatography on SiO2 using first CHCl3 followed by 20:1 hexanes:Et2O affords the title compound as a colorless oil. [mass expected (331.84); mass found (331.28)]
Reaction SMILES: [P:1](=[O:42])([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([O:34][CH3:35])[O:2][CH:3]([CH2:11][O:12]C(C1C=CC(OC)=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(Cl)(Cl)Cl.CO>[P:1](=[O:42])([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([O:34][CH3:35])[O:2][CH:3]([CH2:11][OH:12])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1)OP(=O)(OC)OCCCCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCOCC(CO)OP(=O)(OC)OCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a solution of 13.5 g of phosphoric acid, 1-[[(4-methoxyphenyl)diphenylmethoxy]-methyl]-2-(pentyloxy)ethyl methyl pentyl ester in 68 ml of chloroform and 136 ml of methyl alcohol heated to boiling is slowly added 6.8 g of Amberlyst®-15 resin. The heat is removed and the mixture stirred at ambient temperature for 2 hours. The volatiles are removed and the residue dissolved in chloroform then washed with dilute sodium bicarbonate, dried and evaporated to an oily residue which is purified on silica gel using 1:1 ethyl acetate:hexanes to give 6 g of the desired compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH2:13]OS(O)(=O)=O>CN(C=O)C>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([NH2:13])[CH:5]=1
Reactant: NOS(=O)(=O)O
Reactant: Cc1c[nH]c2cnccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(N)c2cnccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
60% Sodium hydride (6.69 g, 167 mmol) is added to a stirred solution of 3-methyl-1H-pyrrolo[2,3-c]pyridine (1.47 g, 11.2 mmol) in DMF (33 mL) portion wise at 0° C. for 1 h. Hydroxylamine-O-sulfonic acid (6.3 g, 55.8 mmol) is added in portions at 0° C. and stirred for 2 h at 0° C. The reaction mixture is quenched at 0° C. with water, concentrated in vacuo to remove DMF. The residue is triturated in DCM. The solid is filtered off and the filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10% MeOH in DCM to afford 3-methyl-pyrrolo[2,3-c]pyridin-1-ylamine (1 g, 61%). MS: 148 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 8.27 (d, 1H), 7.46 (d, 1H), 7.09 (s, 1H), 2.30 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[Cl:29][C:30]1[N:31]=[C:32](Cl)[C:33]2[CH:38]=[CH:37][N:36]([CH3:39])[C:34]=2[N:35]=1.O1CCOCC1>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.O>[Cl:29][C:30]1[N:31]=[C:32]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:19]([F:20])([F:21])[F:22])[CH:6]=2)[C:33]2[CH:38]=[CH:37][N:36]([CH3:39])[C:34]=2[N:35]=1
Reactant: Cn1ccc2c(Cl)nc(Cl)nc21
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(-c2nc(Cl)nc3c2ccn3C)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
2-[4-ethoxy-3-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (188 mg), Na2CO3 (217 mg), and tetrakis(triphenylphosphine)palladium (0) (29 mg) were added to a mixture of 2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (100 mg), dioxane (2 mL), and water (0.3 mL) in an argon atmosphere, and the reaction mixture was stirred at 100° C. for 6 hours. After the reaction mixture was cooled to room temperature, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 7:3), whereby 2-chloro-4-[4-ethoxy-3-(trifluoromethyl)phenyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (130 mg) was obtained as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:20]=2[CH3:21])=[O:15])[CH2:10][CH:11]=C)[CH:6]=[CH:7][CH:8]=1.[O:31]=[O+][O-]>C(Cl)Cl>[O:31]=[CH:11][CH2:10][C@H:9]([NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:20]=1[CH3:21])=[O:15])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:30])([F:29])[F:1])[CH:4]=1
Reactant: C=CC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cccc(C(F)(F)F)c1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: Cc1c(C(=O)N[C@@H](CC=O)c2cccc(C(F)(F)F)c2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-but-3-enyl]-amide (400 mg, 0.92 mmol) in CH2Cl2 (25 mL) at −78° C. is treated with ozone gas by bubbling for 30 min until a blue color is sustained. After stiffing for an additional hour at −78° C., dimethylsulfide (4.2 mL) is added. The reaction mixture is warmed to room temperature and concentrated in vacuo to afford 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-3-oxo-1-(3-trifluoromethyl-phenyl)-propyl]-amide (390 mg, 98%) which is used without further purification.
Reaction SMILES: [CH3:1]I.[C:3]([NH:7][C:8]([NH:10][C:11]1[C:12]([CH:28]([CH3:30])[CH3:29])=[N:13][C:14]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[S:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([NH:7][C:8](=[N:10][C:11]1[C:12]([CH:28]([CH3:30])[CH3:29])=[N:13][C:14]([O:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])[S:9][CH3:1])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1NC(=S)NC(C)(C)C
Reactant: CI
Solvent: CCO
Product: CSC(=Nc1c(C(C)C)cc(Oc2ccc(Cl)cc2)nc1C(C)C)NC(C)(C)C

Procedure:
2.0 g of methyl iodide are added at room temperature to 2.50 g of 1-tert.-butyl-3-[2,4-diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl]-thiourea in 30 ml of ethanol and the mixture is heated at +75° C. for 5 hours. The mixture is then concentrated by evaporation and the residue is taken up in methylene chloride and washed twice with dilute sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is evaporated. The crude product is purified by column chromatography on silica gel (eluant: ethyl acetate/hexane 1:3). 1-tert.-Butyl-3-[2,4-diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl]-S-methyl-isothiourea is obtained in the form of a colourless crystalline powder, m.p. 95°-100° C.
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([CH3:35])[C:26]3[C:31]([C:32]=2O)=[CH:30][C:29]([CH3:34])=[CH:28][CH:27]=3)=O)CCCCC1>C1(C)C=CC=CC=1>[CH2:35]([N:25]1[C:26]2[C:31](=[CH:30][C:29]([CH3:34])=[CH:28][CH:27]=2)[C:32]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[CH2:2][CH2:3]2)=[C:23]([C:21]#[N:20])[C:24]1=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2C
Reactant: O=C(c1cccs1)N1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2Cc1ccccc1
Temperature: 110 °C
Yield: 154.5 %

Procedure:
piperazine-1-yl-thiophen-2-yl-methanone (490 mg, 2.5 mmol) was added to a solution of Compound 20 (309 mg, 1 mmol) in toluene (20 mL) and heated overnight at 110° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered. The crude product was purified by flash chromatography eluting with 0-2% methanol in dichloromethane gradient to yield 362 mg (77%) of white solids. M.P. 183° C. 1H NMR (DMSO-d6): δ 2.36 (s, 3H), 3.69 (m, 4H), 3.94 (m, 4H), 5.47 (s, 2H), 7.16-7.20 (m, 4H), 7.23-7.33 (m, 3H), 7.44 (d, J=8.8 Hz, 1H), 7.50 (d, J=3.8 Hz, 1H), 7.70 (s, 1H), 7.81 (d, J=4.8 Hz, 1H). EIMS m/z 491 (M+23). Anal. (C27H24N4O2S) C, H, N.
Reaction SMILES: [CH3:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH:8]([C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH3:22][C:17]1[CH:18]=[C:19]([CH3:21])[N:20]=[C:15]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:7])[N:16]=1
Reactant: CS(=O)(=O)N=C=O
Reactant: Cc1cc(C)nc(Nc2ccccc2)n1
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methylsulphonyl isocyanate (3.15 g) was added dropwise to a solution of 2-anilino-4,6-dimethylpyrimidine (3.98 g) in toluene (40 ml). The mixture was then stirred for 2 hours at room temperature. The solid was separated and dried in vacuo, to give 1-(4,6-dimethylpyrimidine-2-yl)-3-methylsulphonyl-1-phenylurea, m.p. 186°-192°. (Compound 5).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[H-].[Na+].[S:20]([O:30][CH2:31][CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN(C=O)C>[C:26]1([CH3:27])[CH:25]=[CH:24][C:23]([S:20]([O:30][CH2:31][CH2:32][O:1][CH:2]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]2)(=[O:22])=[O:21])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COC(=O)C1CC(O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(OCCOS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 27.1 %

Procedure:
A solution of 2.45 g (10.0 mmol) of 1-tert-butyl 2-methyl 4-[hydroxy]pyrrolidine-1,2-dicarboxylate (24) in DMF (10 ml) was added to a suspension of 0.65 g (15 mmol) of sodium hydride in DMF (20 ml). After 15 min, a solution of 5.56 g (15.0 mmol) of 1,2-ethanediol bistosylate in DMF (10 ml) was added. The batch was subsequently reacted in 3 portions at 100° C. in a microwave for 45 minutes. The batch was concentrated and treated with water and ethyl acetate. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate). 1.2 g (27%) of 1-tert-butyl 2-methyl 4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1,2-dicarboxylate were obtained.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](=[O:14])([O-])[O-:12].[Na+].[Na+].[C:17](Cl)(=[O:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.Cl>O.CC(C)=O>[C:17]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11]([OH:12])=[O:14])(=[O:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1C(=O)O)c1ccc(C(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anthranilic acid (14.0 parts) and 11.7 parts of sodium carbonate were dissolved in 250 parts of water, and a solution obtained by dissolving 10.1 parts of terephthalic acid dichloride in 60 parts of acetone was added dropwise to the above solution with stirring at 20 to 30° C. Reaction was carried out at room temperature for 2 hours after the dropwise addition and further under acetone reflux for one hour. Then, concentrated hydrochloric acid was added to make the reaction system acidic, and the precipitate was filtered and dried to obtain 19.1 parts of terephthaloyl-bisanthranilic acid.