Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[CH3:9][S:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH3:22])[C:14]=1[CH2:23][O:24][CH3:25])(=[O:12])=[O:11].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[C:14]([CH2:23][O:24][CH3:25])[C:15]=2[CH3:22])[CH:5]=[N:4]1)[CH3:2]
Reactant: COCc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(COC)c2C)c1O
Yield: 65.3 %

Procedure:
1.12 g (0.01 mol) of 1-ethyl-5-hydroxypyrazole is dissolved in 30 ml of t-amyl alcohol, and then 2.59 g (0.01 mol) of 4-methanesulfonyl-3-methoxymethyl-2-methylbenzoic acid, 2.06 g (0.01 mol) of N,N'-dicyclohexylcarbodiimide and 0.69 g (0.005 mol) of anhydrous potassium carbonate were sequentially added thereto. The mixture was reacted at a temperature of from 80° to 90° C. for 8 hours under stirring. After completion of the reaction, t-amyl alcohol was distilled off under reduced pressure, and 30 ml of water was added to the residue to dissolve the soluble components. The mixture was subjected to filtration to separate out the insolubles. The aqueous solution thus obtained was washed with chloroform, and concentrated hydrochloric acid was added to adjust pH<1. The precipitated oil component was extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column chromatography (eluent: ethyl acetate/ethanol=9/1) to obtain 2.3 g of the desired product. (Yield: 66%, melting point: 116°-118° C.)
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[OH-].[Na+]>C(O)(=O)C>[NH:11]1[C:12]2[C:8](=[CH:7][C:6]([OH:5])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 0.34 g sodium cyanoborohydride were added batchwise to 0.60 g (4.5 mmol) 5-hydroxyindole in 5.0 mL glacial acetic acid and the mixture was stirred for 60 min at RT. Then the reaction mixture was poured onto a 4N aqueous sodium hydroxide solution and extracted with EtOAc. The combined organic phases were washed several times with saturated sodium hydrogen carbonate solution, dried on sodium sulphate and evaporated down.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][OH:15])[C:6](=[O:16])[N:5]([CH2:17][CH3:18])[C:4]=2[N:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Cl:1][C:2]1[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][OH:15])[C:6](=[O:16])[N:5]([CH2:17][CH3:18])[C:4]=2[N:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCn1c(=O)n(CCCO)c(=O)c2[nH]c(Cl)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Cl)n2Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a solution of 8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (2.2 g, 8.09 mmol) in DMF (10 mL) was added 1-(bromomethyl)-4-chlorobenzene (2.47 g, 12.11 mmol), followed by potassium carbonate (2.23 g, 16.18 mmol) and TBAI (15 mg, 0.042 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over sodium sulfate, and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum/ethyl acetate (5:1 to 1:2) to give 8-chloro-7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (2.3 g, 71.8% yield) as white solid. LCMS retention time 1.485 min; LCMS MH+ 397.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[O:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:51][C:52]([F:67])([F:66])[C:53]1[CH:54]=[C:55]([CH:63]=[CH:64][CH:65]=1)[O:56][CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>CN(C=O)C.O>[O:27]=[C:25]([N:60]1[CH2:59][CH2:58][CH:57]([O:56][C:55]2[CH:63]=[CH:64][CH:65]=[C:53]([C:52]([F:51])([F:66])[F:67])[CH:54]=2)[CH2:62][CH2:61]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:20][N:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Reactant: FC(F)(F)c1cccc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2)on1
Reaction time: 8 h
Yield: 51.1 %

Procedure:
DIPEA (96 mg, 0.745 mmol) was added to a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (67 mg, 0.27 mmol) in DMF (3 mL) followed by HOBt (36 mg, 0.273 mmol) and EDCI.HCl (62 mg, 0.32 mmol). After 2 minutes 4-(3-trifluoromethyl-phenoxy)-piperidine hydrochloride (70 mg, 0.248 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by column chromatography (using 60-120 silica gel and 50% EtOAc in hexane as eluent) to afford 60 mg (34% Yield) of 5-phenyl-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 474, 70.17%. 1H NMR (300 MHz, DMSO-d6): δ8.7-8.6 (t, 1H), 8.0-7.9 (m, 2H), 7.6-7.5 (m, 4H), 7.4 (s, 1H), 7.3-7.26 (t, 3H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.5 (m, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.8-1.4 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:22][CH:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:25]1[C:26]2[CH:33]=[CH:32][N:31]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:27]=2[N:28]=[CH:29][N:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:22][CH:21]([NH:23][C:25]3[C:26]4[CH:33]=[CH:32][N:31]([S:34]([C:37]5[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=5)(=[O:35])=[O:36])[C:27]=4[N:28]=[CH:29][N:30]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: NC1CN(C(=O)CNc2cc(Cl)cc(Cl)c2)Cc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CN(C(=O)CNc5cc(Cl)cc(Cl)c5)Cc5ccccc54)ncnc32)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)-1-(4-amino-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (0.2 g, 0.6 mmol) in DMF was added 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (0.17 g, 0.57 mmol) and DIEA (0.11 g, 0.85 mmol). The reaction mixture was stirred at 90° C. overnight, the mixture was diluted with EtOAc (100 mL) and washed with water (20 mL×3). The EtOAc layer was concentrated in vacuo to give a mixture which was purified by column chromatography (silica gel, gradient EtOAc in Hexanes) to give (0.160 g, 57%) of the titled intermediate. 1H NMR (CDCl3, 400 MHz): δ 8.41 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.54 (d, 1H, J=3.6 Hz), 7.33-7.19 (m, 6H), 6.83-6.67 (m, 3H), 6.35 (s, 2H), 5.35-5.25 (m, 1H), 5.18 (d, J=16.4 Hz, 1H), 4.76 (d, J=16.4 Hz, 1H), 4.51 (dd, J=1.8, 16 Hz, 1H), 4.33 (t, J=1.8 Hz, 1H), 3.82 (dd, J=1.8, 10 Hz, 1H), 3.72 (d, J=5.2 Hz, 1H), 2.38 (s, 3H). LCMS: M/z: (M+1):621
Reaction SMILES: [OH-].[K+].Cl[C:4]1[S:12][C:11]2[S:10](=[O:14])(=[O:13])[N:9]=[C:8]([NH:15][CH:16]([CH3:18])[CH3:17])[NH:7][C:6]=2[CH:5]=1>CO.[Pd]>[CH:16]([NH:15][C:8]1[NH:7][C:6]2[CH:5]=[CH:4][S:12][C:11]=2[S:10](=[O:13])(=[O:14])[N:9]=1)([CH3:18])[CH3:17]
Reactant: CC(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)NC1=NS(=O)(=O)c2sccc2N1

Procedure:
Powdered potassium hydroxide (128 mg, 2.28 mmol) was added to a solution of 6-chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (319 mg, 1.14 mmol) in 25 ml of methanol and the mixture was hydrogenated at room temperature and atmospheric pressure for 3 days with 150 mg of 10% palladium on carbon. The catalyst was removed by filtration and washed with ethanol and water. The combined filtrate was acidified with 4 M hydrochloric acid and evaporated to dryness. The residue was recrystallised from water/ethanol and finally from ethyl acetate with decolorising charcoal affording the title compound contaminated with starting material, which could be removed by silica gel column chromatography; 1H-NMR (DMSO-d6): δ1.16 (d, 6H, 2×CH3), 3.88 (m, 1H, CH), 6.95 (d, 1H, H-5), 7.03 (br d, 1H, NH), 7.88 (d, 1H, H-6), 10.70 (br s, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]#[N:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][N:23]=1>CS(C)=O.ClCCl.O>[Cl:21][C:22]1[CH:27]=[C:26]([N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([C:12]#[N:13])=[CH:9]2)[CH:25]=[CH:24][N:23]=1
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Reactant: Clc1cc(I)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: N#Cc1cn(-c2ccnc(Cl)c2)cc1-c1ccccc1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a solution of 4-phenyl-1H-pyrrole-3-carbonitrile (0.168 g), cupper (I) iodide (0.019 g), N,N-dimethyl grycine (0.021 g) and cesium carbonate (0.325 g) in dimethylsulfoxide (10 mL) was added 2-chloro-4-iodopyridine (0.287 g) at room temperature, and this mixture was at 180° C. in a sealed tube under microwave irradiation for 5 minutes. After cooling to ambient temperature, this reaction mixture was diluted with dichloromethane and water, and the insoluble material was removed by filtered though a Celite pad. This organic layer was separated and this organic solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=80/20) to give the title compound (0.16 g).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.B>C(COC)OC.O1CCCC1>[CH2:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(I)cc1
Agent: B
Solvent: COCCOC
Solvent: C1CCOC1
Product: Ic1ccc(NCc2ccccc2)cc1

Procedure:
2.19 Grams of p-iodoaniline and 1.06 g of benzaldehyde were dissolved in 50 ml of glyme and the resulting solution heated to 60° for two hours. The temperature was maintained for an additional hour after the addition of 30 ml of a 1 M solution of borane in tetrahydrofuran. The excess boron hydride was then destroyed by the addition of about 10 ml of methanol. To this mixture was added 100 ml of a 0.3 M solution of sodium hydroxide and the resulting solution extracted with 100 ml of ether to yield N-benzyl-p-iodoaniline, Rf =0.70.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([CH:20]([C:22]3[N:23](COCC[Si](C)(C)C)[C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[C:26]([C:31]#[N:32])[CH:25]=4)[OH:21])[C:13]([O:18][CH3:19])=[CH:14][C:15]=2[CH3:17])[CH:10]=[CH:9]1)=O)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N)CN>C1COCC1>[OH:21][CH:20]([C:12]1[C:13]([O:18][CH3:19])=[CH:14][C:15]([CH3:17])=[C:16]2[C:11]=1[CH:10]=[CH:9][NH:8]2)[C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([C:31]#[N:32])[CH:25]=2
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1cc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: COc1cc(C)c2[nH]ccc2c1C(O)c1cc2ccc(C#N)cc2[nH]1
Temperature: 65 °C

Procedure:
tert-Butyl-4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (70 mg, 0.125 mmol) was dissolved in THF (1.3 mL) and TBAF (1.3 mL, 1.246 mmol) was added. Ethylenediamine (0.084 mL, 1.25 mmol) was then added. The reaction was heated at 65° C. for 4 days. The reaction cooled to room temperature and quenched with saturated aq. ammonium chloride (10 mL) and then diluted with DCM. The layers were separated and the organic layer was washed with water, dried over MgSO4 filtered and concentrated. The resulting residue was absorbed onto silica and purified via flash chromatography (0-75% EtOAc:heptanes) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.39 (s, 1H) 10.80 (s, 1H) 7.66-7.85 (m, 1H) 7.50 (d, J=8.08 Hz, 1H) 7.21 (dd, J=8.15, 1.45 Hz, 1H) 7.14 (t, J=2.78 Hz, 1H) 6.76 (s, 1H) 6.56 (d, J=4.42 Hz, 1H) 6.42 (dd, J=3.03, 2.02 Hz, 1H) 6.07-6.14 (m, 1H) 5.88 (d, J=4.55 Hz, 1H) 3.82 (s, 3H) 2.45 (d, J=0.63 Hz, 3H). MS (ESI−) m/z 330.05 (M−H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[CH2:56][NH:55][CH2:54][C@H:53]([CH3:57])[NH:52]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][C@H:53]([CH3:57])[NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (0.033 g, 0.05 mmol), (2R,6S)-2,6-dimethylpiperazine (0.00685 g, 0.06 mmol), and acetic acid (0.0036 g, 0.06 mmol) were combined in CH2Cl2 (2 mL). Sodium triacetoxyborohydride (0.0148 g, 0.07 mmol) was added and the mixture stirred overnight at room temperature. Solvents were concentrated, and the residue taken up in EtOAc, washed with 1N NaOH, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The product was purified using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed 3× with 2.5 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound as a white solid. LC-MS m/z 757.2 (M+H)+, 1.37 min (ret time); mp 109-112° C. Analytical HPLC shows 99.8% purity, (ret time 10.205 min).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C)=[O:29])=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.COCCOC.C1COCC1.[OH-].[Na+]>O>[Br:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Br)cnc(OC)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(Br)c2c1c(-c1ccc(CC(=O)O)cc1)nn2-c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a mixture to methyl (4-(7-bromo-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetate (270 mg) in a mixed solvent of DME (1.0 mL), THF (1.0 mL) and water (0.5 mL) was added 8N aqueous sodium hydroxide solution (0.346 mL), and the mixture was stirred at 60° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The aqueous layer was neutralized with 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (235 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:51]1[C:55]2([CH2:60][CH2:59][O:58][CH2:57][CH:56]2[NH2:61])[O:54][CH2:53][CH2:52]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([NH:61][CH:56]1[CH2:57][O:58][CH2:59][CH2:60][C:55]21[O:54][CH2:53][CH2:52][O:51]2)=[O:7]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Reactant: NC1COCCC12OCCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1COCCC12OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A, 400 mg, 1.5 mmol) was dissolved in 10 mL dimethylformamide. N,N-Diisopropyl ethyl amine (505 mg, 3.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (571 mg, 1.5 mmol) were added. After 10 minutes of stirring at room temperature 1,4,8-trioxaspiro[4,5]decan-6-amine (CAS 1068523-26-1) (359 mg, 2.2 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate/triethylamine 1:0:0→10:10:1) yielded 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,4,8-trioxa-spiro[4.5]dec-6-yl)-benzamide as a white solid (462 mg, 75%), MS: m/e=408.2 [(M+H)+].
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:4]1([S:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[NH:14][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccccc1Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1Sc1ccccc1)Oc1ccccc1
Temperature: 5 °C

Procedure:
2-Amino diphenylsulfide (0.4 mole) was dissolved in toluene (500 ml) and cooled to 5° C. Phenyl chloroformate (0.24 mole) in toluene (50 ml) was added slowly to the stirred solution over 1 hour. When addition was complete a simultaneous addition of phenyl chloroformate (0.24 mole) in toluene (50 ml) and an aqueous solution of sodium hydroxide (0.3 mole) and sodium carbonate (0.35 mole) (200 ml) was started.
Reaction SMILES: N12CCCC=C1CCCCN2.[CH3:12][O:13][C:14](=[O:26])[C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=1.[NH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>C(#N)C>[CH3:12][O:13][C:14]([C:15]1[C:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH3:25])=[CH:21][CH:22]=2)=[N:27][N:28]2[C:33]=1[CH:32]=[CH:31][CH:30]=[N:29]2)=[O:26]
Reactant: N[n+]1ccccn1
Reactant: CCOc1ccc(C#CC(=O)OC)cc1
Agent: C1=C2CCCCNN2CCC1
Solvent: CC#N
Product: CCOc1ccc(-c2nn3ncccc3c2C(=O)OC)cc1
Reaction time: 5 h

Procedure:
Diazabicyclo[5.4.0]undec-7-ene (1.47 ml, 2 eq) was added dropwise to a solution of methyl 3-(4-ethoxy-phenyl)-prop-2-ynoic acid (1.0 g) and 1-amino pyridazinium iodide2 (2.19 g) in acetonitrile (10 ml) under nitrogen and stirred for 5 h. Concentration and aqueous workup gave the title compound (1.2 g) as a sticky brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([F:18])[CH:12]=[C:11](F)[C:10]=2[F:20])=[C:4]([F:21])[CH:3]=1.[CH3:22][O-:23].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([F:18])[CH:12]=[C:11]([O:23][CH3:22])[C:10]=2[F:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(Br)cc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of (4-bromo-2-fluoro-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine (Intermediate 13, 1.5 g, 4.1 mmol) in THF (10 mL) was dropwise added NaOMe solution [prepared by dissolving Na metal (100 mg, 4.1 mmol) in methanol (10 mL)] at −78° C. After complete addition, the reaction mixture was warmed to room temperature and stirred for 1 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure and residue obtained was purified by flash column chromatography to yield (4-bromo-2-fluoro-phenyl)-(2,5-difluoro-3-methoxy-6-nitro-phenyl)-amine as a yellow solid (912 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:20]2[CH:19]=[CH:18][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc2ccccc2c1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc3ccccc3c2)CN1C(=O)OC(C)(C)C
Yield: 84.1 %

Procedure:
To a stirred mixture of methyl (2S, 4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.22 g, 17.2 mmol), 2-naphthol (2.73 g, 18.9 mmol) and PPh3 (4.96 g, 18.9 mmol) in THF (80 ml) was added DIAD (3.72 ml, 18.9 mmol) at room temperature under an atmosphere of nitrogen. After stirring over night, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [600 g, CHCl3/EtOAc (10/1)], to give methyl (2S, 4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g), which was used to the next reaction without further purification.