Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>O>[Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([N+:21]([O-:23])=[O:22])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Cc1cc(NC(=O)C(C)(C)C)ncc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(Cl)cnc(N)c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
N-(5-chloro-4-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (3.0 g, 13.2 mmol) from Preparation 39 Step 2 was treated with concentrated sulfuric acid (19 ml) and allowed to stir for 30 min before cooling in an ice-water bath to between 0-10° C. and adding fuming red nitric acid (0.67 ml) over a 10 min period. The reaction mixture was heated (35° C.) overnight, then diluted with water (40 ml) and extracted with DCM (6×50 ml). The DCM was removed under vacuum and the residue was re-dissolved in conc. HCl (20 ml) and heated to 40° C. for 18 h, then 100° C. for 4 h, and finally 50° C. for 18 h. The mixture was cooled to RT, diluted with water (50 ml), and extracted with DCM (5×40 ml). The aqueous layer was treated with 30% (w/v) NaOH aq. until the pH=12, then extracted with DCM (6×60 ml). These latter extracts were combined, dried over Na2SO4, filtered, and concentrated to yield 5-chloro-4-methyl-3-nitro-pyridin-2-ylamine (1.0 g). 1H NMR (CDCl3) δ 8.15 (s, 1H), 5.93 (br s, 2H), 2.49 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:42]C(N)C.NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH:36]([CH3:42])[CH3:37])[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Reactant: CC(C)N
Solvent: O=C(O)C(F)(F)F
Solvent: NCCO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNC(C)C)c4)cc23)CC1
Yield: 35 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting 2-propanamine (25 mg, 0.43 mmol) for the 2-aminoethanol to afford 9 mg of the title compound (35%).
Reaction SMILES: ClCCCl.[CH3:5][C:6]1[C:7]([OH:15])=[C:8]([CH3:14])[C:9]([CH3:13])=[C:10]([CH:12]=1)[OH:11].O[CH:17]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)=[CH:29][CH:28]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].B(F)(F)F.CCOCC>O.CO>[N:33]1([C:30]2[CH:29]=[CH:28][C:27]([CH:17]([C:12]3[C:10](=[O:11])[C:9]([CH3:13])=[C:8]([CH3:14])[C:7](=[O:15])[C:6]=3[CH3:5])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:32][CH:31]=2)[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: COC(=O)CCCCCC(O)c1ccc(-n2ccnc2)cc1
Agent: FB(F)F
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)CCCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1ccc(-n2ccnc2)cc1
Temperature: 80 °C
Yield: 78.2 %

Procedure:
1,2-Dichloroethane (15 ml) was added to 0.76 g (5.0 mmole) of trimethylhydroquinone and 1.51 g (5.0 mmole) of methyl 7-hydroxy-7-[4-(1-imidazolyl)phenyl]heptanoate, followed by warming at 80° C. and stirring. 1.42 ml (5.0×2.3 mmole) of boron trifluoride ethyl etherate was added dropwise to the mixture, followed by stirring at 80° C. for 2 hours. Then, methanol (15 ml) was added to the reaction solution, followed by further stirring at 80° C. for 2 hours. After cooling by standing at room temperature, the solvent was distilled off, and the residue was dissolved in tetrahydrofuran (20 ml). A solution of 2.7 g (10.0 mmole) of ferric chloride in water (10 ml) was added to the solution, followed by stirring at room temperature for 20 minutes. The tetrahydrofuran was distilled off, and chloroform was added to the residue to conduct extraction. The organic layer was separated out, washed with aqueous sodium hydrogencarbonate solution added, then washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residue was chromatographed on a silica gel column, and elution was effected with ethyl acetate. The fractions containing the object compound were collected, and the solvent was distilled off under reduced pressure to give 1.70 g (78%) of methyl 7-[4-(1-imidazolyl)phenyl]-7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)heptanoate.
Reaction SMILES: [NH2:1][CH:2]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)[C:3]([NH:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:8][CH:7]=1)=[O:4].C1C[O:39][CH2:38][CH2:37]1.C(N(CC)CC)C.C(Cl)(=O)C>O>[C:38]([NH:1][CH:2]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)[C:3]([NH:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:8][CH:7]=1)=[O:4])(=[O:39])[CH3:37]
Reactant: CC1(C)CCC(C)(C)c2cc(C(N)C(=O)Nc3ccc(C(=O)OCc4ccccc4)cc3)ccc21
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)NC(C(=O)Nc1ccc(C(=O)OCc2ccccc2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
1.5 g (3.2 mmol) of benzyl 4-[α-amino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido]benzoate, 75 ml of THF and 490 μl (3.5 mmol) of triethylamine were introduced into a round-bottomed flask. 250 μl (3.5 mmol) of acetyl chloride were added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction medium was poured into water, extracted with ethyl acetate, the organic phase decanted, dried over magnesium sulfate and evaporated. The residue obtained was triturated in hexane, filtered and dried. 1.6 g (94%) of the expected compound of melting point 258°-259° C. was obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[P:7]([O-:24])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:25](Br)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].Cl>CN(C=O)C.C1COCC1>[CH2:36]([P:7]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:24])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCBr
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of potassium t-butoxide (6.16 g, 55 mmol), in dry DMF (50 mL), under an argon atmosphere was added dropwise via syringe a solution of dibenzyl phosphite (13.1 g, 50 mmol) in dry DMF (5 mL), and the reaction mixture was stirred at room temperature for 20 min. Then a solution of lauryl bromide (18.6 g, 75 mmol) in dry THF (15 mL), was added dropwise under argon atmosphere, and the mixture was stirred at room temperature for an additional 1 h. After completion of the reaction, the mixture was neutralized with dilute HCl (40 mL) and extracted with ethyl acetate (200 mL), the organic phase was dried, concentrated, and purified by flash chromatography to afford the pure dibenzyl phosphate 14 as a colorless oil (Rf 0.46, silica, ethyl acetate and hexane, 1:2, 10.5 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:18]([C:20](O)=[O:21])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.O>[C:26]([O:25][C:23](=[O:24])[NH:17][CH:18]([C:20](=[O:21])[NH:16][C:11]1[C:10]([NH:9][C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:19])([CH3:27])([CH3:28])[CH3:29]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ncccc1Nc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ncccc1Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N3-(3,5-Difluorophenyl)-pyridine-2,3-diamine (750 mg, 3.39 mmol), Boc-L-Ala-OH (640 mg, 3.39 mmol) and HATU (2.57 g, 6.78 mmol) were suspended in DCM-DMF (1:1) (10.2 mL). DIEA (874.6 mg, 6.78 mmol) was added to reaction mixture and stirred at rt for 8 h. After completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-10% MeOH in DCM to provide {1-[3-(3,5-difluorophenylamino)-pyridin-2-ylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester: LC-MS (ESI) m/z 393.2 [M+H]+.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][C:7]1[C:8]([N+:17]([O-:19])=[O:18])=[C:9]([C:13](=[NH:16])OC)[CH:10]=[CH:11][CH:12]=1.Cl.C[O:22][C:23](=O)[CH2:24][CH2:25][NH2:26].C[O-].[Na+]>CO>[CH3:6][C:7]1[C:8]([N+:17]([O-:19])=[O:18])=[C:9]([C:13]2[NH:26][CH2:25][CH2:24][C:23](=[O:22])[N:16]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)CCN
Reactant: COC(=N)c1cccc(C)c1[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CO
Product: Cc1cccc(C2=NC(=O)CCN2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
To a solution of the title compound of Step B (1.7 g, 5.9 mmol) in methanol (20 mL) was added β-alanine methyl ester hydrochloride (832 mg, 5.9 mmol) followed by sodium methoxide (2.7 mL, 25 wt % in methanol, 11.8 mmol) and the mixture was heated at reflux for 1.5 hour. The mixture was then cooled, stirred overnight at ambient temperature and again heated at reflux for 3 hours. The mixture was then cooled, concentrated and triturated with dichloromethane. The soluble fraction was then purified by flash column chromatography (silica gel, ethyl ether) to give the title compound of Step C as a white solid (0.12 g).
Reaction SMILES: CS(C)=O.C(N(CC)CC)C.[N:12]1([CH2:24][CH2:25][OH:26])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]3[O:23][CH:22]=[CH:21][C:19]3=2)[CH:14]=[N:13]1.Cl>O>[N:12]1([CH2:24][CH:25]=[O:26])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]3[O:23][CH:22]=[CH:21][C:19]3=2)[CH:14]=[N:13]1
Reactant: OCCn1ncc2ccc3occc3c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: O=CCn1ncc2ccc3occc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
A dimethyl sulfoxide (15 ml) solution containing 4.20 ml of triethylamine and 4.74 g of SO3-pyridine complex was added to a dimethyl sulfoxide (15 ml) solution containing 1.80 g of 2-(1H-furo[2,3-g]indazol-1-yl)ethanol, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water, acidified with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried with anhydrous magnesium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under a reduced pressure, and the residue was purified by a silica gel column chromatography to give 0.89 g of (1H-furo[2,3-g]indazol-1-yl)acetaldehyde.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2([CH2:28][NH:29][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[O:12])[CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(CNC(=O)c3n[nH]c4ccccc34)CCCC2)cc1OC
Reaction time: 16 h
Yield: 9.9 %

Procedure:
1H-Indazole-3-carboxylic acid (32.4 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (7.47 mg, 0.0197 mmol, 9.84%) ESI-MS m/z calc. 379.2, found 380.4 (M+1)+. Retention time of 3.02 minutes.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:79])[C@@H:15]([CH3:78])[CH2:16][C@H:17]([CH3:77])[C@@H:18]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=1)[C@@H:19]([CH3:66])[CH:20]=[CH:21][C@@H:22]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH2:23][C@H:24]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[C@H:25]([CH3:49])[CH:26]=[CH:27][CH2:28][O:29][C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)C1C=CC=CC=1.CO.[Li+].[BH4-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[C:62]([Si:59]([CH3:60])([CH3:61])[O:58][C@@H:22]([CH2:23][C@H:24]([O:50][Si:51]([C:54]([CH3:55])([CH3:56])[CH3:57])([CH3:52])[CH3:53])[C@H:25]([CH3:49])[CH:26]=[CH:27][CH2:28][O:29][C:30]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:21]=[CH:20][C@H:19]([CH3:66])[C@H:18]([O:67][CH2:68][C:69]1[CH:70]=[CH:71][C:72]([O:75][CH3:76])=[CH:73][CH:74]=1)[C@@H:17]([CH3:77])[CH2:16][C@H:15]([CH3:78])[CH2:14][OH:79])([CH3:64])([CH3:65])[CH3:63]
Reactant: COc1ccc(CO[C@@H]([C@@H](C)C=C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)C=CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)O[Si](C)(C)C(C)(C)C)[C@@H](C)C[C@H](C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CO[C@@H]([C@@H](C)C=C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)C=CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)O[Si](C)(C)C(C)(C)C)[C@@H](C)C[C@H](C)CO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a stirred solution of 69 (0.41 g, 0.37 mmol) in THF (1.5 ml) at 0° C. was added MeOH (0.015 ml) and LiBH4 (0.81 ml, 2.0 M soln in THF) dropwise. After stirring 2 h at 0° C., saturated sodium potassium tartrate (10 ml) was added dropwise. The reaction mixture was warmed to room temperature and extracted with CH2Cl2 (10 ml×2). The combined organic layer were washed with brine (10 ml) and dried over anhydrous MgSO4, evaporated and the residue was chromatographed (hexane/EtOAc 4:1) to yield 70 (0.30 g, 87%) as a colorless oil: IR (CHCl3) 3400, 2956, 2928, 2856, 1613, 1514, 1449, 1377, 1249, 1074, 836, 774, 706 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.48 (m, 6H), 7.29 (m, 11H), 6.84 (m, 2H), 5.78 (dd, J=15.7, 6.0 Hz, 1H), 5.58 (dt, J=15.7, 5.2 Hz, 1H), 5.46 (m, 1H), 5.35 (m, 1H), 4.59 (t, J=9.5, Hz, 1H), 4.48 (q, J=10.9 Hz, 2H), 3.92 (m, 1H), 3.79 (s, 3H), 3.57 (d, J=5.5 Hz, 2H), 3.25 (m 2H), 3.03 (t, J=4.5 Hz, 1H), 2.75 (m 1H), 2.41 (m, 1H), 1.75 (m, 1H), 1.55 (m, 2H), 1.32 (m, 2H), 1.17 (m, 2H), 1.07 (d, J=6.7 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 0.94 (s, 9H), 0.91 (m, 12H), 0.72 (d, J=6.6 Hz, 3H), 0.13 (s, 3H), 0.12 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.9, 144.4, 134.4, 133.4, 131.5, 131.4, 129.1, 128.7, 127.7, 126.8, 126.5, 113.6, 87.6, 86.8, 74.1, 73.0, 68.9, 66.5, 65.4, 55.2, 42.7, 42.4, 37.1, 35.0, 33.1, 26.0, 25.9, 18.9, 18.1, 15.8, 14.9, 14.7, −2.8, −4.0, −4.06, −4.10; HRMS (ESI) calcd for C58H86O6Si2K 973.6301 (M+K)+, found 973.6264; [α]20D −31.7 (c 1.3, CHCl3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([NH2:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=1>CC#N>[N:1]1([C:8]2[N:13]=[C:12]([NH2:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CC#N
Product: Nc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Morpholine (4 equivalents) was added to a suspension of 6-chloro-3-nitropyridin-2-amine (1 equivalent) in CH3CN, and the reaction mixture was stirred at 70° C. for 5 hours. The solvent was evaporated under reduced pressure, and the residue was triturated with ether to afford the desired compound as a bright yellow powder. LC/MS m/z 225.0 (MH+), Rt 1.79 minutes.
Reaction SMILES: Cl[C:2]1[CH:10]=CC(S(C)(=O)=O)=C[C:3]=1C(O)=O.[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([OH:27])=[O:26])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].IC(C)C>O>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH:2]([CH3:10])[CH3:3])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Solvent: CC(C)I
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Yield: 42 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 2-Chloro-5-methanesulfonyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and 2-iodopropane in 20 ml water and obtained in 42% yield. MS (m/e): 261.1 (MH−, 100%).
Reaction SMILES: CN(C=O)C1C=CC=CC=1.C([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=C.ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:44]([CH:51]([CH3:53])[CH3:52])C=2)=[CH:38][CH:37]=1>C(#N)C>[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:44]([CH:51]([CH3:53])[CH3:52])[C:17]=2[CH:16]=[CH:15][CH:14]=[O:13])=[CH:38][CH:37]=1
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Reactant: C=COCCCC
Agent: CN(C=O)c1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)n1c(C=CC=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 5 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of N-methylformanilide (30 g), butyl vinyl ether (22.2 g) in 15 ml of acetonitrile under stirring at 5° C., a solution of bis-trichloromethylcarbonate (26.1 g) in 70 ml of acetonitrile is added dropwise in 80 min. The reaction mixture is kept under stirring at 5° C. overnight, then phosphorus oxychloride (31.4 g) is added dropwise in 30 minutes, then the reaction mixture is stirred at 5° C. for 15 minutes. 3-[3-(4-Fluorophenyl)-1-(1-Methylethyl)-1H-Indole (35.8 g) and acetonitrile (25 ml) are added. The mixture is warmed to 80° C. and kept under stirring for about 24 hours. The reaction mixture is worked up as described in Example 3b to give the product (69% yield).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][OH:24])[CH2:6]1)(=O)C.C[O-].[Na+].[C:28]1([C:34](Cl)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO.O1CCCC1.C(OCC)(=O)C>[OH:24][CH2:23][C@@H:7]1[CH2:6][C@H:5]([S:4][C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:9][N:8]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-hydroxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (15 g) in a mixture of methanol (150 ml) and tetrahydrofuran (150 ml) was added a 28% solution of sodium methoxide in methanol (8.95 ml) under ice-cooling and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added triphenylmethyl chloride (12.39 g) on ice-bath, followed by stirring at the same temperature for 1 hour. The precipitates were filtered off and the filtrate was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (200 ml), washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was chromatographed on silica gel (200 g) eluting with a mixture of dichloromethane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-hydroxymethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (22.24 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([O:23][C:24]([CH2:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:31]([C:33](O)=[O:34])[N:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:25])[CH2:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:31]([C:33](=[O:34])[NH:18][C:16]2[CH:15]=[N:14][N:13]([CH2:12][C:10]3[O:11][C:7]([C:2](=[O:6])[CH3:1])=[CH:8][CH:9]=3)[N:17]=2)[N:32]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)CCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(CCC(=O)OC(C)(C)C)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-(2-tert-butoxycarbonyl-ethyl)-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([NH:11][C@@H:12]([CH3:29])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([C:26]#[N:27])=[C:21]([F:28])[CH:20]=3)=[N:15]2)=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[C:26]([C:22]1[C:23]([F:25])=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:9]([C:6]3[CH:5]=[C:4]([CH:1]([OH:3])[CH3:2])[NH:8][N:7]=3)=[O:10])[CH3:29])[N:15]=2)=[CH:20][C:21]=1[F:28])#[N:27]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(F)c3)n2)n[nH]1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(F)c3)n2)n[nH]1
Yield: 3.3 %

Procedure:
(S)-5-acetyl-N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide (200 mg, 0.50 mmol) was dissolved in ethanol (10 ml) and sodiumborohydride (95 mg, 2.51 mmol) was added. The reaction mixture was refluxed for 2 h, cooled and saturated ammonium chloride (20 ml) was added. The mixture was extracted three times with ethyl acetate and the combined organic fractions were washed with water, dried and evaporated. The residue was purified twice with reversed phase flash chromatography to afford (6.7 mg, 3%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.13 (d, 3H), 1.37 (d, 3H), 4.24-4.40 (m, 2H), 4.39-4.53 (m, 1H), 4.72-4.84 (m, 1H), 6.47 (s, 1H), 6.98 (m, 1H), 7.71-7.80 (m, 2H), 7.79-7.88 (d, 1H), 8.15 (d, 1H).