Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[C:4]([C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[N:10]([CH3:11])[S:23]([CH3:22])(=[O:25])=[O:24])#[N:5]
Reactant: CS(=O)(=O)Cl
Reactant: CNc1cccc(F)c1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(c1cccc(F)c1C#N)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a stirred solution of 2-fluoro-6-methylamino-benzonitrile (1.5 g, 10 mmol) in THF (50 mL) at −78° C. was added LiHMDS (1M in THF, 16 mL, 16 mmol) dropwise over 5 min. The resulting pale yellow solution was stirred for an additional 30 min, then methanesulfonyl chloride (1.16 mL, 15 mmol) was added. After 30 min, the reaction mixture was quenched with saturated NH4Cl (1 mL), diluted with ethyl acetate (100 mL), dried (MgSO4), filtered and concentrated to give viscous yellow oil. The crude product was purified on silica gel column (2:3 EtOAc/hexanes) to give the title compound as a white solid (1.5936 g, 70% yield). 1HNMR (500 MHz, CDCl3) δ: 7.65–7.61 (1H, m), 7.86 (1H, d, J=8.24 Hz), 7.22 (1H, t, J=8.24 Hz), 3.38 (3H, s), 3.13 (3H, s). HRMS (ESI) calcd for C17H22FN2O7S (M+H): 417.1132; found: 417.1116.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([F:33])[CH:27]=1)[NH:9][C:10]([N:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[N:17][C:16]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:15][C:14]=2[CH2:13]1)=[O:11])(=O)=O.[CH3:34][NH2:35]>C1COCC1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH:8]([NH:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[N:17][C:16]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:15][C:14]=3[CH2:13]2)=[O:11])[CH2:7][CH2:6][NH:35][CH3:34])=[CH:27][C:28]=1[F:33]
Reactant: CN
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)NC(CCOS(C)(=O)=O)c1ccc(Cl)c(F)c1)CC2
Solvent: C1CCOC1
Product: CNCCC(NC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(Cl)c(F)c1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a solution of 310 (0.059 g, 0.12 mmol) and THF (3 mL) was added methylamine (0.092 g, 1.2 mmol, 40% aqueous solution) and the reaction was stirred at 45° C. for 1 h. The solution was concentrated, poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:30) to afford 3 mg (5.8%) of I-78: MS m/z (APCI-pos) M+1=435.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][O:36][C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 8 mg of sodium hydride and stirred for 30 minutes at 20° C. 60 mg of 5-bromopentanoic acid methyl ester was added, it was allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][NH:28][CH:29]6[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:29]6[CH2:30][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC(NCc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.1 %

Procedure:
To a solution of 430 (300 mg, 0.496 mmol) in DMF (6 mL) was added ethyl bromoacetate (0.06 mL, 0.546 mmol). The reaction mixture was stirred at RT for 3 days, quenched with water and extracted with DCM. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Biotage (SNAP 10 g cartridge; MeOH/DCM: 0/100 to 10/90), to afford the title compound 431 (93 mg, 27% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.76 (s, 1H), 8.54 (brd, J=1.6 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.35 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.88 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.18 (m, 1H), 6.65 (dd, J=5.2, 0.8 Hz, 1H), 6.61 (brd, J=2.8 Hz, 1H), 4.05 (q, 7.2 Hz, 2H), 3.93-3.75 (m, 5H), 3.79 (s, 2H), 3.31 (s, 2H), 2.58-2.52 (m, 1H), 1.37 (s, 9H), 1.17 (t, J=7.2 Hz, 3H), 0.68-0.62 (m, 2H), 0.47-0.41 (m, 2H). MS (m/z): 691.64 (M+H).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH2:6]([O:8][C:9]([C:11]1[C:12]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:13]([CH2:32][CH2:33][CH2:34][OH:35])[N:14]2[C:19]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[N:15]2)=[O:10])[CH3:7]>C(N(C(C)C)CC)(C)C.CC#N>[CH2:6]([O:8][C:9]([C:11]1[C:12]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:13]([CH2:32][CH2:33][CH2:34][O:35][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[N:14]2[C:19]=1[C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[N:15]2)=[O:10])[CH3:7]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1CCCO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)OCCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Temperature: 50 °C

Procedure:
Ethyl isocyanate (50 μL, 0.063 mmol) and diisopropylethyl amine (1 drop) were added to a solution of 41 (30 mg, 0.062 mmol) in CH3CN (10 mL). The reaction mixture was heated at 50° C. for 18 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 35% EtOAc/hexane) to provide the title compound as a white solid. 1H NMR (DMSO-d6) δ 0.89 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H), 1.91 (m, 2H), 2.96 (m, 2H), 3.22 (m, 2H), 3.53 (m, 6H), 3.71 (m, 4H), 3.96 (m, 2H), 4.19 (q, J=7.1 Hz, 2H), 6.78 (s, 1H), 7.00 (m, 1H), 7.41 (m, 2H), 7.46 (m, 3H). Mass Spectrum (ESI+) m/e=553.2 (M+H).
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17](Br)[CH:18]=1)[C:13]([OH:15])=[O:14].Cl>CS(C)=O.O>[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([S:8][CH:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:18]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: SC1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Br)cc(SC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of sodium hydride (60% in mineral oil, 0.82 g, 20.5 mmol) and DMSO (15 mL) in a sealable flask at 0° C. was slowly added cyclopentanethiol (1.23 mL, 11.9 mmol). The mixture was stirred at room temperature for 30 min and then a solution of 3,5-dibromobenzoic acid (2.5 g, 8.9 mmol) in DMSO (10 mL) was added. The reaction was sealed and stirred at 80° C. overnight. After cooling, the reaction mixture was poured into water and adjusted to pH 5-6 with 15% HCl (aq.) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated to afford the crude product which was used for the next step reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([N+:12]([O-])=O)[CH:3]=1>[Fe].CC(O)=O>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([NH2:12])[CH:3]=1
Reactant: Cc1nc2c(Br)cc([N+](=O)[O-])cc2o1
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1nc2c(Br)cc(N)cc2o1

Procedure:
To a solution of 720 mg of 4-bromo-2-methyl-6-nitro-benzooxazole in 45 mL ETOH was added 642 mg of iron powder and 8.5 mL of AcOH. Solution was refluxed for 2.5 h, during which a chalky white color formed. Solvent was removed, solid was dissolved back into DCM and filtered through Celite. The filtrate was washed with satd. NaHCO3 and brine, dried over MgSO4, and solvent evaporated. 690 mg of title compound as a brown solid was recovered.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[C:45](Cl)=[O:46]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:45]([C:36]3[CH:37]=[CH:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:35]=3)=[O:46])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc4ccccc4c3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure K using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 2-naphthoyl chloride as a colorless oil (93%). M+ (ESI): 594.4. HPLC, Rt: 5.96 min (Purity: 93.2%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([OH:27])=[CH:22][CH:21]=2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([O:27][C:2]1[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=1)=[CH:22][CH:21]=2
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2[nH]1
Yield: 19.4 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (272 mg, 0.830 mmol), 2-methyl-1H-indole-5-ol (244 mg, 1.66 mmol), potassium carbonate (344 mg, 2.49 mmol) and N,N-dimethylformamide (3.0 mL) as starting materials and in the same manner as in Example 95, the title compound (56 mg, 19%) was obtained as a white powder.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=O.Cl.[C:26]1([C@:32]2([OH:53])[CH2:40][CH2:39][C:38]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:37]3[C@H:33]2[CH2:34][NH:35][CH2:36]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl>[C:26]1([C@:32]2([OH:53])[CH2:40][CH2:39][C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C@@H:37]3[C@H:33]2[CH2:34][NH:35][CH:36]3[C:22](=[O:24])[CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: O[C@@]1(c2ccccc2)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)C1NC[C@@H]2[C@H]1C(c1ccccc1)(c1ccccc1)CC[C@@]2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
0.28 g of carbonyldiimidazole is added to a solution of 0.28 g of (2-methoxyphenyl)acetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred at room temperature for 1 hour and a suspension of 0.7 g of (3aS,4S,7aS)-4,7,7-triphenylperhydroisoindol-4-ol hydrochloride in 20 cm3 of dry dichloromethane and then 0.48 cm3 of triethylamine are subsequently added in succession. The reaction mixture is stirred at room temperature for 24 hours, diluted with 100 cm3 of dichloromethane, washed with 100 cm3 of water (twice) and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 16 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting fractions of 20 cm3. Fractions 7 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 16 cm3 of acetonitrile. The crystals are filtered off and dried. 0.3 g of (3aS,4S,7aS)-4,7,7-triphenyl-2-(2-methoxyphenyl)acetylperhydroisoindol-4-ol is obtained in the form of white crystals which melt at 236° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C(=O)C)[C:13](=[O:21])[C:12]23[CH2:23][CH2:22]2)[CH:5]=[C:4]([F:24])[C:3]=1[C:25]([F:28])([F:27])[F:26].OS(O)(=O)=O>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:21])[C:12]23[CH2:22][CH2:23]2)[CH:5]=[C:4]([F:24])[C:3]=1[C:25]([F:28])([F:27])[F:26]
Reactant: CC(=O)N1C(=O)C2(CC2)c2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc2C12CC2

Procedure:
A mixture of 5'-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-1'-acetyl-spiro [cyclopropane-1,3'-indolin]-2'-one (0.60 g, 1.95 mmol), 5 mL of 1 N H2SO4 and tetrahydrafuran is heated at reflux for about 24 hours (until reaction is complete by gas chromatographic analysis). The reaction mixture is diluted with ethyl acetate and water and the phases are separated. The organic phase is dried (MgSO4) and concentrated in vacuo to give a residue. The residue is chromatographed using silica gel and ethyl acetate/hexane 25/75 to give the title product as a white solid, 0.41 g, (76%), mp 168°-170° C. identified by H1NMR.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[C:10]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=4)[N:9]=[CH:8][C:7]=3[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[Br:27]N1C(=O)CCC1=O>CN(C)C=O.[Cl-].[Na+].O>[Br:27][C:6]1[C:7]2[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:26])[C:15]3[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=3)=[CH:11][C:12]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(ccn3C3CC3)cn2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3C2CC2)cc1
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
In a 250 ml round bottom flask was added (R)—N-(1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (17, 3.2 g, 9.2 mmol) in N,N-dimethylformamide (31 ml). The mixture was cooled in ice bath, followed by addition of N-bromosuccinimide (1.477 g, 8.30 mmol) in portions. The mixture was stirred in ice bath for 30 min, at which point about ˜10% starting material remained. Another 0.1 equivalence (160 mg) of N-bromosuccinimide was added to the reaction mixture, which was stirred in an ice bath for another 30 min. Brine (200 ml) was added, followed by extraction with EtOAc (2×200 mL). Organic layers were combined. After drying and filtering, a suspension was obtained upon concentration. The solid was collected on a filtered, and then washed with 10 ml EtOAc. The resulting 2 g of filtrated solid was purified by silica gel column chromatography, eluting with 5-10% MeOH in EtOAc. Product-containing fractions were combined and concentrated to yield a solid which was washed twice with EtOAc (2×10 ml). The title compound (22, 0.62 g, 16%) was obtained as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.04 (m, 2H) 1.05-1.13 (m, 2H) 1.42 (s, 3H) 3.42-3.54 (m, 3 H) 4.71 (t, J=5.81 Hz, 1H) 4.99 (s, 1H) 7.58 (d, J=8.59 Hz, 2H) 7.62 (s, 1H) 8.01 (d, J=8.59 Hz, 2H) 8.48 (d, J=0.76 Hz, 2H) 8.51 (d, J=0.76 Hz, 2H) 10.63 (s, 1H); ESI-MS: m/z 432 (M+H)+. Additional amounts of the title compound were obtained by combining filtrates and re-purifying them by silica gel column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]=[CH:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[CH3:28]I>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:14])=[O:15])[CH3:28])=[CH:26][CH:27]=1
Reactant: CI
Reactant: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Solvent: ClC(Cl)Cl
Product: CN(CC=Cc1ccc(Cl)cc1)CCNS(=O)(=O)c1cccc2cnccc12
Reaction time: 0.67 h

Procedure:
1.50 g of the product of Example 172 was dissolved in 10 ml of chloroform, to the solution was added 3 ml of methyl iodide at a room temperature, and the mixture was stirred for 40 minutes. Excess methyl iodide was immediately evaporated off under a reduced pressure, and resulting residue was purified on a silica gel column (silica gel 50 g, eluant: 5% methanol in chloroform), to obtain 720 mg of the title compound in a colorless amorphous form.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[CH:7][N+:8]([O-:10])=[O:9].[C:11]1([CH3:23])[CH:16]=[CH:15][C:14]([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl.CCOCC>[CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[C:7]([N+:8]([O-:10])=[O:9])[C:21]([NH:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:23])=[CH:12][CH:13]=1)(=[O:19])=[O:18])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CN1CCNC1=C[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NC(=O)C(=C2NCCN2C)[N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
A solution of 1.43 g of 1A in 20 ml of methylene chloride was treated with 1.99 g of p-tolylsulfonyl isocyanate at room temperature. After a brief period of exothermicity, the mixture was held at room temperature overnight. The mixture then was diluted with 20 ml of dry ether and filtered to give 1, as a white powder, m.p.: 155°- 157°.
Reaction SMILES: [C:1]1([CH2:7][C@:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([OH:21])[CH2:9]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]1([CH2:7][C@:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([OH:21])[CH2:9][N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@](O)(Cc2ccccc2)c2ccccc2)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O[C@@](Cc1ccccc1)(Cn1cncn1)c1ccccc1
Yield: 50.6 %

Procedure:
A mixture of 87 g (0.23 mol) of (2R)-1,2-diphenyl-2-hydroxy-3-tosyloxy-propane, 70 g (1 mol) of 1,2,4-triazole, 70 g (0.5 mol) of potassium carbonate and 800 ml of acetonitrile is refluxed for 16 hours with stirring. The reaction mixture is then poured into water, and the product which precipitates out is filtered off under suction. In order to remove any undesired biproducts which are still present, the product is dissolved in chloroform and filtered through a silica gel column, a mixture of chloroform/ethyl acetate=1:1 being used as eluent. The eluate is evaporated under reduced pressure. In this fashion, 32.5 g (51% of theory) of (2R)-1,2-diphenyl-2-hydroxy-3-(1,2,4-triazol-1-yl)-propane are obtained in the form of a solid of melting point 134° C. [α]D20 =-2.7° (c=2.75/CHCl3)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH3:10][C:11]1[C:12]([N:16]=[C:17]=[S:18])=[CH:13][S:14][CH:15]=1>C1COCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:17]([NH:16][C:12]1[C:11]([CH3:10])=[CH:15][S:14][CH:13]=1)=[S:18]
Reactant: Cc1cscc1N=C=S
Reactant: Nc1ccc(F)cc1N
Solvent: C1CCOC1
Product: Cc1cscc1NC(=S)Nc1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.02 mol of 4-fluoro-1,2-diaminobenzene is added to a solution of 0.02 mol of 4-methyl-3-thienyl isothiocyanate in 60 ml of anhydrous THF. The reaction mixture is stirred at room temperature for 2 hours and then allowed to stand overnight, and the solvent is then distilled off under reduced pressure using a rotary evaporator and the oily residue is purified on a silica gel column using a mixture of identical proportions of toluene and ethyl acetate.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])OC4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.[CH3:34][O:35][CH2:36][CH2:37][CH2:38][NH2:39]>>[CH3:34][O:35][CH2:36][CH2:37][CH2:38][NH:39][C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:6]2[N:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])[C:9]3[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=3[N:5]=2)=[CH:23][CH:22]=1)=[O:33]
Reactant: COCCCN
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Product: COCCCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C)C3)cc1

Procedure:
Method as described for example 51 using intermediate 10 and 3-methoxypropylamine as starting materials. Purified by prep. LCMS (high pH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])=[O:25])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:34]([F:36])[F:35]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH:34]([F:36])[F:35])=[O:25])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)Cl
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3O)co2)cc1OCc1ccccc1
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3OC(F)F)co2)cc1OCc1ccccc1

Procedure:
Using the compound obtained in Example 266 and chlorodifluoromethane, white powdery 3-[2-(3-benzyloxy-4-methoxy phenyl)oxazol-4-yl]-1-(2-difluoromethoxyphenyl)propan-1-one was obtained following the procedure of Example 19.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Br[C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>CS(C)=O>[Br:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:22]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(Br)ccc2[N+](=O)[O-])sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate, 2,4-dibromonitrobenzene and dimethyl sulfoxide, ethyl 2-(5-bromo-2-nitroanilino)benzo[b]thiophene-3-carboxylate is obtained.