Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[CH:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O.C(N(CC)CC)C>C(O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[CH:29][N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: CN(C)C=CC(=O)c1ccccc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2nccc(-c3ccccc3)n2)ccc1-n1cnc(C)c1

Procedure:
A solution of N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (249 mg, 0.67 mmol), 3-(dimethylamino)-1-phenyl-2-propen-1-one (141 mg, 0.80 mmol, CAS 1131-80-2) and triethyl amine (187 uL. 1.34 mmol) in ethanol (4 mL) was heated to 160° C. for 1 hour in a microwave oven. The solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica using methylenechloride and dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound a a yellow solid (67 mg, 28%). MS ISP (m/e): 358.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.90 (s, 1H), 8.60 (s, 1H), 8.20 (br s, 2H), 7.99 (s, 1H), 7.68 (s, 1H), 7.43-7.56 (m, 5H), 7.26 (t, 1H), 7.06 (s, 1H), 3.84 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C1(C)C=CC=CC=1>C(OCC)C>[CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11]([NH:44][C:41]3[CH:42]=[CH:43][C:38]([N:35]4[CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]4)=[CH:39][N:40]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 100 °C
Yield: 27.8 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.936 g, 2.68 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 10.8 mmol) were added to toluene (5 ml) and heated to 100° C. 1 hour. Diethyl ether (10 ml) was added causing a solid to precipitate. This solid was collected by filtration, washed with diethyl ether, and dried in vacuo yielding 2-[5-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a yellow solid (0.42 g, 28%). MS (APCI); M++1: Calc'd 564.29. Found 564.3
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (6.81 g, 20 mmol), pyrrolidine (8.27 mL, 100 mmol) in DMSO (70 mL) at RT according to the general procedure C. Obtained as a yellow solid (7.35 g, 98%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=1.C(=O)([O-])O.[Na+]>CS(C)=O>[Cl:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1cccnc1N1CCNCC1
Temperature: 110 °C
Reaction time: 60 h

Procedure:
Piperazine (15 g, 174 mmol) was dissolved in dimethyl sulphoxide (309 g) and to this was added 2,3-dichloropyridine (23.4 g, 158 mmol). The reaction mixture was stirred for 60 h at 110° C. Portions of saturated aqueous sodium hydrogencarbonate solution (overall 250 ml) were added to the reaction mixture and the precipitate produced was drawn off. The filtrate was extracted several times with ethyl acetate (150 ml each time) and the cleaned organic phase was dried and the solvent was removed under vacuum. The residue was distilled at 2×10−1 mbar. The product was obtained at an overhead temperature of 95° C. and a bottom temperature of 155° C. Yield: 9.6 g (28% of the theoretical amount).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cc1cccc(C#CC=C2CCN(C(=O)Nc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the Compound of Example 3 (0.11 g, 0.52 mmol) in CH2Cl2 (10 mL) was added phenylisocyanate (0.06 mL, 0.54 mmol) and the reaction mixture was stirred overnight at r.t.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Brc1cccc2[nH]ncc12
Reactant: CCOC(=O)C(C)(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCn1ncc2c(Br)cccc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
To a solution of 4-bromo-1H-indazole (commercially available from Insight Chemical Solutions Ltd., 826 mg, 4.19 mmol) in DMF (10 ml) at room temperature were added Cs2CO3 (1.37 g, 4.19 mmol) and ethyl 4-bromo-2,2-dimethylbutanoate (D99) (1.40 g, 6.29 mmol) and the resulting mixture was stirred at 80° C. for 24 h then cooled to room temperature and diluted with AcOEt. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [15-25% EtOAc/cyclohexane] gave the title compound (600 mg, 40%) as orange oil. MS (ES) C15H1981BrN2O2 requires 340, found 341 [M+H]+
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:28][CH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]1=[O:36].O>C(Cl)(Cl)Cl>[C:14]([NH:28][CH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]1=[O:36])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1CCCCNC1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1NCCCCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Triethylamine (1.75 ml, 12.6 mmol) and triphenylmethyl chloride (3.50 g, 12.6 mmol) were added to a solution of 3-amino-2-azepanone (1.46 g, 11.4 mmol) in chloroform (44 ml) at room temperature and stirred overnight at room temperature. The reaction mixture was poured into water and then extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain 3-(tritylamino)-2-azepanone (2.93 g, 69%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[C:15]4[CH2:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([NH2:28])[CH:25]=5)[C:16]=4[NH:17][C:18]=3[C:19]=2[F:20])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CC(O)=O.O.[O:34]([C:36]#[N:37])[Na]>O.CCOC(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[C:15]4[CH2:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([NH:28][C:36]([NH2:37])=[O:34])[CH:25]=5)[C:16]=4[NH:17][C:18]=3[C:19]=2[F:20])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2ccc(N)cc2C4)cc1
Reactant: N#CO[Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2ccc(NC(N)=O)cc2C4)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.6 %

Procedure:
To a suspension of 7-(4-Butyl-phenyl)-6-fluoro-5,10-dihydro-indeno[1,2-b]indol-2-ylamine (25 mg, 0.068 mmol, 1 eq.) in a 1:1 v/v mixture of AcOH/H2O (1 mL) is added a solution of NaOCN (4.4 mg, 0.068 mmol, 1 eq.) in H2O (1 mL). The resulting mixture is stirred at 25° C. for 2 h, at which point an additional NaOCN (4.4 mg, 0.068 mmol, 1 eq.) is added to the reaction. The resulting mixture is stirred at 25° C. for an additional 12 h. The reaction is diluted with EtOAc and sequentially washed with H2O, saturated aqueous NaHCO3, and saturated aqueous NaCl. The resulting organic solution is dried over Na2SO4. After concentration, the crude product is purified by preparative RP LC-MS to give [7-(4-Butyl-phenyl)-6-fluoro-5,10-dihydro-indeno[1,2-b]indol-2-yl]-urea (10 mg, 36% yield): 1H NMR (Acetone-d6) δ 11.09 (s, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 7.59 (d, 2H), 7.58 (s, 1H), 7.48 (d, 1H), 7.42 (d, 1H), 7.33 (d, 2H), 7.18 (dd, 1H), 5.53 (bs), 3.72 (s, 2H), 2.72 (t, 2H), 1.72-1.64 (m, 2H), 1.49-1.36 (m, 2H), 0.96 (t, 3H); LC/MS calculated for [M+H]+ C26H24FN3O: 414.2, found: 414.2.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][Cl:35]>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][Cl:35])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCl)c2n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetic acid salt (for example, as prepared for Intermediate 6) (4.7 g, 13.38 mmol) and potassium carbonate (4.62 g, 33.4 mmol) in dry DMF (50 mL) were stirred and heated at 50° C., under nitrogen, for 75 min. The mixture was allowed to cool to room temperature and then cooled to 0° C. and 1-bromo-3-chloropropane (commercially available, for example, from Aldrich) (2.106 g, 13.38 mmol) was added. The mixture was stirred at 0 to 10° C. for approximately 5 hours then allowed to warm to room temperature and stirred for approximately a further 40 hours when LCMS indicated approximately 70% of the desired product. The mixture was allowed to settle and the supernatant was pipetted off and the solvent evaporated on a rotary evaporator using a high vacuum pump at about 23° C. Chloroform and water was added to the combined residues which were stirred and the phases separated using a hydrophobic frit. The aqueous layer was re-extracted with further portions of chloroform and the combined chloroform extracts were evaporated under high vacuum at 23° C. to give a yellow solid (2.798 g). This crude material was combined with similar material obtained from two similar preparations (0.56 g and 0.995 g) and purified by flash column chromatography on silica using 2:1 ethyl acetate/chloroform as eluant to give the title compound as an off-white solid (3.011 g).
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:28][O:29][CH2:30][CH3:31])[C:12]([NH:14][C@H:15]2[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]([S:23]([O-:26])(=[O:25])=[O:24])[C:16]2=[O:27])=[O:13])[N:10]=1)=O.[Na+:32].C(=S)(SC)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:28][O:29][CH2:30][CH3:31])[C:12]([NH:14][C@H:15]2[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]([S:23]([O-:26])(=[O:24])=[O:25])[C:16]2=[O:27])=[O:13])[N:10]=1.[Na+:32]
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(=O)OC)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CCON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(=O)OC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 110 mg of sodium cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-ethoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) in 8 ml of water is added under ice-cooling 30 mg of sodium monomethyl dithiocarbamate. The mixture is stirred at room temperature for one hour, then another 10 mg of sodium monomethyl dithiocarbamate is added thereto. After the mixture is stirred for further one hour, the resulting reaction mixture is subjected to filtration, and the filtrate is washed with ether. The aqueous layer is purified by column chromatography on Amberlite XAD-II and then lyophilized to give sodium cis-3-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer).
Reaction SMILES: C[O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N+:19]([O-])=O)=[C:15]([CH:18]=1)[CH:16]=O>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[CH:16][N:7]([C:6]3[CH:8]=[CH:9][C:3]([OH:2])=[CH:4][CH:5]=3)[N:19]=2)[CH:18]=1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccc(N)cc1
Product: Oc1ccc(-n2cc3cc(Cl)ccc3n2)cc1

Procedure:
4-(5-chloro-2H-indazol-2-yl)phenol was prepared using a method analogous to that described for Intermediate (Q10), starting from 4-methoxyaniline and 5-chloro-2-nitrobenzaldehyde. Yellow solid. 1HNMR (400 MHz Methanol-d4) δ 8.60 (d, J=1.6 Hz, 1H), 7.71-7.75 (m, 3H), 7.65 (d, J=9.2 Hz, 1H), 7.27 (dd, J=9.2, 2.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[NH2:7].[N:17]#[C:18][NH2:19].Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:7][C:18]([NH2:19])=[NH:17])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: N#CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1

Procedure:
3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline hydrochloride (3 g, 12.52 mmol), cyanamide (0.684 g, 16.27 mmol) and hydrochloric acid (1.564 mL, 18.77 mmol) in ethanol (20 mL) were heated to reflux o.n. The reaction mixture was concentrated under reduced pressure before the resulting mixture was poured on a solution of potassium carbonate (1.730 g, 12.52 mmol) in water (60 mL) and left in refrigerator o.n. The formed carbonate-salt was filtered off, and dried in vacuum oven o.n. The solid was washed with several portions of DCM, dried and used as such in next step.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH2:11][CH2:12][CH3:13])[N:3]=1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[NH2:24][C@H:25]1[C@@H:29]2[O:30][C:31]([CH3:34])([CH3:33])[O:32][C@@H:28]2[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]1.C(=O)(O)[O-].[Na+]>CCCCCC.O.C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([NH:24][C@H:25]2[C@@H:29]3[O:30][C:31]([CH3:33])([CH3:34])[O:32][C@@H:28]3[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]2)=[N:3][C:4]([S:10][CH2:11][CH2:12][CH3:13])=[N:5][C:6]=1[Cl:9]
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 100 °C
Reaction time: 7 h
Yield: 95 %

Procedure:
A flask was charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (25 g), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (42.5 g), water (75 mL) and sodium bicarbonate (53 g). The mixture was heated to about 100° C. and maintained at the same temperature for about 14 hours and completion of the reaction was monitored by TLC. After completion of reaction, the mixture was cooled to 60° C. followed by addition of ethyl acetate (25 mL), water (175 mL) and n-hexane (375 mL). The mixture was stirred for about 7 hours. The solid obtained was isolated by filtration and washed with water (50 mL). The wet compound and water (500 mL) were charged into round bottom flask and stirred for overnight. The solid was isolated by filtration and washed with water (50 mL) and was subjected to drying under vacuum at 60° C. for 9 hours to afford the title compound in about 95% yield having HPLC purity of about 98.5%.
Reaction SMILES: [CH2:1]([C:4]1[O:5][C:6]([C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3].CS([C:22]1[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=1)(=O)=O.C(=O)([O-])[O-]>CN(C=O)C>[CH2:1]([C:4]1[O:5][C:6]([C:10]2[C:15]([O:16][C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=3)=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCCc1nc(C)c(-c2c(O)cccc2Cl)o1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCc1nc(C)c(-c2c(Cl)cccc2Oc2nc(OC)cc(OC)n2)o1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
2 ml DMF solution containing 0.24 g 2-propyl-4-methyl-5-(2-chloro-6-hydroxyphenyl)oxazole, 0.2 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.26 g pottasium carbonate was stirred for 14 hours at 60° C. After completing the reaction, the solution reacted was poured into ice water and was then extracted with ethyl acetate. The organic layer obtained was washed with water and was then dried by using anhydrous magnesium sulfate. After filtration, the solvent used was removed by distillation under reduce pressure. The residue obtained was purified by using silica gel column chromatography, where hexane-ethyl acetate solution in a mixing ratio of 4:1 is used, affording the objective substance in an amount of 0.26 g.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:22][C:21]=1[Cl:32].[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1>C(Cl)Cl.O>[Cl:32][C:21]1[CH:22]=[C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[CH:25][C:20]=1[NH:19][C:5]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1)=[O:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Reactant: c1ccc2c(c1)CCN2
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)N2CCc3ccccc32)c(Cl)c1
Temperature: 0 °C
Yield: 274.2 %

Procedure:
In methylene chloride (50 ml), triphosgene (926 mg, 3.12 mmol) and then pyridine (5 ml) were added to ethyl 4-amino-3-chlorophenylacetate (2.00 g, 9.36 mmol) under stirring at 0° C. After stirring at the same temperature for 15 minutes, indoline (1.05 ml, 9.36 mmol) was added. The reaction mixture was further stirred for 15 minutes at room temperature. Water (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (300 ml). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, whereby ethyl 3-chloro-4-(1-indolinylcarbonylamino)phenylacetate (3.07 g, 91%) was obtained as a pale pink crystalline powder.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C.[C:42]([O:46][C:47](=[O:50])[CH:48]=[CH2:49])([CH3:45])([CH3:44])[CH3:43]>C(#N)CC.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:42]([O:46][C:47](=[O:50])[CH:48]=[CH:49][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:45])([CH3:44])[CH3:43]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of 2-bromo-5-hydroxybenzaldehyde (200 g, 1.0 mole) in propionitrile (6 L) under N2 was added tri-o-tolyl phosphine (75.4 g, 0.25 mol) and diisopropylethylamine (350 mL, 260 g, 2.0 mol). The solution was degassed and purged with N2 three times. To this solution was added tert-butylacrylate (440 mL, 385 g, 3.0 mol) and palladium acetate trimer (27.8 g, 0.12 mol). The mixture was degassed three times and heated to 80° C. over 30 min. After 30 min, the reaction was cooled to ambient temperature and filtered. The solids were washed with acetonitrile. The filtrate was transferred to a separatory funnel with acetonitrile (4 L total) and was extracted with hexanes (4×5 L). The propionitrile/acetonitrile layer was concentrated by rotary evaporation. The residue was dissolved in toluene (4 L) and washed successively with 1N HCl (1 L), water (1 L), and brine (1 L). The organic layer was dried (Na2SO4), filtered, and concentrated to afford crude product as a wet brown solid (293 g). The crude product was dissolved in CH2Cl2 (600 mL) with stirring. To this solution was added hexanes (1.8 L) over ˜2 h, and the resulting slurry was stirred at ambient temperature for 1 h. The slurry was cooled in an ice water bath and stirred for 1 h. The product was isolated by filtration, washed with hexanes, and dried under vacuum to afford the product as a tan solid (199.5 g, 80.6%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.Cl.[CH3:48][C:49]([CH:52]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53]1)([OH:51])[CH3:50]>C(#N)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:54]2[CH2:55][CH2:56][CH2:57][CH:52]([C:49]([OH:51])([CH3:50])[CH3:48])[CH2:53]2)=[O:16])=[CH:7][CH:8]=1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(O)C1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(O)C1CCCN(C(=O)c2cnoc2-c2ccc(C(F)(F)F)cc2)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 3-(1-methyl-1-hydroxyethyl)piperidine hydrochloride (25 mg, 0.14 mmol), and stirred at 60° C. for 30 min. The residue was purified on reversed phase HPLC to yield the title compound (23 mg). HRMS (ESI, pos. ion) m/z calcd for C19H21F3N2O3: 382.1504, found 382.1502.