Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Br.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Fc1ccc(CBr)c(Br)c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1ccc(CN2CCOCC2)c(Br)c1
Temperature: 81 °C
Yield: 95.5 %

Procedure:
Combine 2-bromo-1-bromomethyl-4-fluoro-benzene (4 g, 14.9 mmol), morpholine (2.6 mL, 29.8 mmol), and diisopropylethylamine (5.2 mL, 29.8 mmol) in acetonitrile (10.0 mL). Heat the reaction mixture at 81° C. for 2 h and cool to RT. Remove the solvent under reduced pressure. Dilute with DCM and wash with water and then aqueous saturated sodium chloride. Dry the organics over sodium sulfate. Filter and remove the solvent under reduced pressure to obtain the title compound (3.9 g, 95%). LCMS (ES) m/z 274 [M+1]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[NH:21]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=4)=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][N:19]=[N:20]1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2cccc(C(F)(F)F)c2)s1
Yield: 48 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and 3-trifluoromethylphenylboronic acid (11 mg, 0.06 mmol). The title compound was obtained in 48% yield (10.8 mg). MS (ESI+) calcd mass for C18H12F3N5O2S2 451.038451, found 451.038591.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]>C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]([C:2]2[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=2)[OH:20])[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cccc(Br)c1)c1cnc(Cl)nc1Cl
Reaction time: 1 h

Procedure:
To the solution of 5-bromo-2,4-dichloropyrimidine (22.8 g, 0.10 mol) in dry THF (150 mL), i-PrMgCl (50 mL, 0.10 mol, 2M in THF) was added dropwise at −35° C. under N2 atmosphere. After addition, the mixture was stirred for another one hour. Then 3-bromobenzaldehyde (18.5 g, 0.10 mol) was added in one portion. The resulting mixture was stirred for another two hours at −35° C. The reaction was quenched by water (10 mL), and filtered. The filtrate was extracted with ethyl acetate (3×300 mL). The combined organic phase was washed with water (300 mL), brine (200 mL) and dried over Na2SO4. The drying agent was removed by filtration and the residue was evaporated to give (3-bromo-phenyl)-(2,4-dichloro-pyrimidin-5-yl)-methanol as yellow oil. (Yield 33 g, 98.8%).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.C(N(CC)C(C)C)(C)C.[CH:36](O)=[O:37]>C(Cl)Cl>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH:36]=[O:37])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: O=CO
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccn2c(C3CCN(C=O)CC3)nc(-c3cc4ccccc4[nH]3)c12
Reaction time: 8 h
Yield: 432.5 %

Procedure:
To a solution of 1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30.00 mg, 0.0068 mmol) in DCM (0.5 mL, 0.008 mol) was added N-(3-dimethylaminopropyl)-N-ethylcarbodihnide hydrochloride (0.0195 g, 0.102 mmol), N,N-diisopropylethylamine (0.047 mL), 1-hydroxbenzotriaxole hydrate (0.0104 g, 0.0679 mmol) and formic acid (4.7 mg, 0.10 mmol). The reaction was stirred at it overnight then diluted with DCM, washed with saturated NaHCO3 (2×25 mL) and brine (2×25), then dried over Na2SO4 and concentrated in vacuo. The material thus isolated was crystallized from EtOAc to afford 10.6 mg of desired product. 1H NMR (400 MHz, CDCl3): δ 2.04-2.12 (m, 4H), 2.99-3.00 (m, 1H), 3.27-3.32 (m, 2H), 3.85 (m, 1H), 4.49 (m, 1H), 5.70 (br, 2H), 6.80 (s, 1H), 7.13-7.24 (m, 4H), 7.45 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 8.10 (s, 1H), 8.97 (br, 1H). MS (ES+): m/z 361.16 [MH+].
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6]CN(CC)CC.[Cl-].[CH2:14]1[CH2:18][O:17][CH2:16][CH2:15]1>>[CH2:1]([N:3]([CH2:4][CH3:5])[C:16]([CH:15]1[CH2:14][CH2:18][CH2:6]1)=[O:17])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCNCC
Reactant: C1CCOC1
Agent: [Cl-]
Product: CCN(CC)C(=O)C1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of diethyl amine (2.19 g, 30 mmol) and Et3N (3.33 g, 33 mmol) in THF (50 ml) was added dropwise cyclobutanecarboxyl chloride (3.56 g, 30 mmol) at 0° C. The reaction mixture was stirred at RT for 1 h and the precipitate was filtered out and THF was removed by in vacuo. The resulting oil was dissolved into EtOAc (100 mL), washed with 0.2 N HCl (100 mL), 5% NaHCO3 (100 mL), brine (100 mL), dried (MgSO4) and concentrated in vacuo to afford the title compound (4.4 g, 95% yield) as light yellow oil used in the next step without purification. 1H NMR (CDCl3) δ 1.1 (m, 6H), 1.7-2.3 (m, 6H), 3.2 (m, 3H), 3.3 (q, J=7.32 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([N+:18]([O-])=O)=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[O:7])=[C:4]([O:21][CH3:22])[CH:3]=1.C1COCC1.CCO>[Fe].CC(O)=O>[NH2:1][C:2]1[C:17]([NH2:18])=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[O:7])=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc(Br)cc1
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(N)c(N)cc1C(=O)Nc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-amino-N-(4-bromophenyl)-2-methoxy-5-nitrobenzamide (1.30 g; 3.55 mmol), THF (80 mL) and EtOH (50 mL) was treated with AcOH (3 mL) and stirred for 15 min at 100° C. To the warm mixture, Fe (1.30 g; 23.3 mmol) was carefully added in portions and the resulting mixture was heated for 2 h at 100° C. The mixture was cooled, filtered through celite and concentrated to give the crude sub-title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CO.[BH4-].[Na+]>O>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([OH:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: COc1c(C(C)=O)cc(Cl)c(F)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C(C)O)cc(Cl)c(F)c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanone (3.8 g, 14 mmol) in methanol (30 mL, 800 mmol) was added sodium tetrahydroborate (0.83 g, 22 mmol) at 0° C. The mix was stirred at 0° C. for 1 hour. Water (10 mL) was added to the mixture. The mixture was concentrated to about 30 mL. The residue was diluted with EtOAc, washed with water and brine, dried over magnesium sulfate and evaporated to yield the desired compound (3.9 g, 100%). LCMS calculated for C9H8BrClFO (M−OH)+: m/z=264.9, 266.9. found: 265.0, 267.0.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([CH2:15][C:16](=[O:24])[CH2:17][CH2:18]1)=[CH:13][C@H:12]3[CH3:25])(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>O1CCCC1.C(O)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)=[CH:13][C@H:12]3[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](C)C=C4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](C)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -3 °C

Procedure:
Add slowly a solution of 7α-methylandrost-5-en-3-on-17β-ol 17 acetate (L74a, 6.3 g, 18.9 mmol) in tetrahydrofuran (50 mL) to a solution of sodium borohydride (0.72 g, 18.9 mmol) in 95% ethanol (200 mL) cooled to −3° C. in a salt/ice bath with stirring. Stir at this temperature for 3 hours and decompose the excess reagent by cautious addition of acetic acid (10 mL). Remove the solvents and purify the resulting crude product by flash chromatography to give 7α-methylandrost-5-ene-3β,17β-diol 17 acetate (L75a) as a white solid. Similarly prepare the following analogs:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.CS[C:11]1[NH:16][C:15](=[O:17])[N:14]2[N:18]=[CH:19][CH:20]=[C:13]2[N:12]=1>C1(C)C(C)=CC=CC=1>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][CH:11]2[NH:16][C:15](=[O:17])[N:14]3[N:18]=[CH:19][CH:20]=[C:13]3[NH:12]2)[N:8]=[CH:7]1
Reactant: NCCc1c[nH]cn1
Reactant: CSc1nc2ccnn2c(=O)[nH]1
Solvent: Cc1ccccc1C
Product: O=C1NC(NCCc2c[nH]cn2)Nc2ccnn21
Yield: 49.1 %

Procedure:
A mixture of 135 mg of free histamine and 180 mg of 2-methylthio-4-oxo-3H-pyrazolo(1,5-a)-1,3,5-triazine in 10 ml of xylene is refluxed for 22 hrs. After evaporation of the solvent in vacuo, the pale pink residue is triturated with water and alcohol, filtered, washed with ether and dried to yield 120 mg of purified product. TLC (silica gel CHCl3 /MeOH/triethylamine=3:1:0-5) Rf=0.14.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][N:11]=[N:10]1.[Cl:21][C:22]1[C:23]([F:40])=[C:24]([N:28]2[C:32]([C:33]3[C:34]([NH2:39])=[N:35][CH:36]=[CH:37][CH:38]=3)=[N:31][N:30]=[N:29]2)[CH:25]=[CH:26][CH:27]=1>>[C:33]([NH:20][C:15]1[C:14]([C:13]2[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])[N:10]=[N:11][N:12]=2)=[CH:19][CH:18]=[CH:17][N:16]=1)([CH3:34])([CH3:38])[CH3:32].[C:14]([NH:39][C:34]1[C:33]([C:32]2[N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[C:23]=3[F:40])[N:29]=[N:30][N:31]=2)=[CH:38][CH:37]=[CH:36][N:35]=1)([CH3:15])([CH3:19])[CH3:13]
Reactant: Nc1ncccc1-c1nnnn1-c1cccc(Cl)c1F
Reactant: Nc1ncccc1-c1nnnn1-c1cccc(Cl)c1Cl
Product: CC(C)(C)Nc1ncccc1-c1nnnn1-c1cccc(Cl)c1Cl
Product: CC(C)(C)Nc1ncccc1-c1nnnn1-c1cccc(Cl)c1F

Procedure:
Crude N-tert-butyl-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine was dissolved in MeOH (10 mL), treated with 6N HCl (20 mL), and heated to reflux for 2 hours. The mixture was subsequently cooled to RT and neutralized with 6N NaOH. The resulting precipitate was collected, washed with water, and dried in vacuo to give 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine as white solid. Using the same procedure, 3-(1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine and 3-(1-(3-chloro-2-fluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine can be produced from N-tert-butyl-3-(1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine and N-tert-butyl-3-(1-(3-chloro-2-fluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine, respectively.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][N:16]([C:29]1[S:30][C:31]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)=[N:32][N:33]=1)[C:17](=[O:28])[CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C>ClCCl>[NH2:20][CH2:19][CH2:18][C:17]([N:16]([CH3:15])[C:29]1[S:30][C:31]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)=[N:32][N:33]=1)=[O:28]
Reactant: CN(C(=O)CCNC(=O)OC(C)(C)C)c1nnc(-c2cccnc2)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)CCN)c1nnc(-c2cccnc2)s1
Temperature: 23 °C
Yield: 49.5 %

Procedure:
Triethylsilane (530 μL, 3.3 mmol, 5.0 equiv) and trifluoroacetic acid (4.9 mL, 66 mmol, 100 equiv) were sequentially added to a stirred solution of tert-butyl 3-(methyl(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)amino)-3-oxopropylcarbamate (240 mg, 0.66 mmol, 1.0 equiv) in dichloromethane (8.8 mL) at 23° C. The resulting colorless solution was stirred at 23° C. for 30 m. The reaction mixture was concentrated by rotary evaporation. The residue was diluted with a saturated solution of sodium bicarbonate (80 mL) and extracted with dichloromethane (8×50 mL). The combined organic layers were dried (Na2SO4), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a tan powder (86 mg, 49%): mp 110-112° C.; IR (KBr thin film) 3047 (w), 2926 (w), 1682 (s), 1591 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ 9.15 (d, J=2 Hz, 1H), 8.69 (dd, J=5, 2 Hz, 1H), 8.28 (dt, J=8, 2 Hz, 1H), 7.43 (dd, J=8, 5 Hz, 1H), 3.86 (s, 3H), 3.17 (m, 2H), 2.86 (t, J=6 Hz, 2H); ESIMS m/z 264 ([M+H]+).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:27]([O:31][C:32]([N:34]1[CH2:43][CH2:42][C:41]2[C:36](=[C:37]([C:44](O)=[O:45])[CH:38]=[CH:39][CH:40]=2)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[N:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][N:17]([C:44]([C:37]4[CH:38]=[CH:39][CH:40]=[C:41]5[C:36]=4[CH2:35][N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:43][CH2:42]5)=[O:45])[CH2:16][CH2:15]3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)c2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(Pyridin-4-yl)-3,9-diazaspiro[5.5]undecane dihydrochloride (F-09) (0.49 g, 1.62 mmol) was dissolved in DMF and triethylamine (0.45 g, 3.25 mmol), and 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (0.45 g, 1.62 mmol) (available commercially from Ennova, for example) was added, followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.93 g, 2.11 mmol) and 4-methylmorpholine (0.53 g, 4.87 mmol). The reaction mixture was stirred for 15 h at RT, and then the solvent was removed in vacuo. The residue was taken up in ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with sat. sodium hydrogen carbonate solution and sat. sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol 20:1+ammonia solution (25% aq.)). Yield: 0.78 g (98%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1O)c1ccccc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
188 (1 mole) g of 2-amino-4-chloro-5-nitrophenol and 79 g (1 mole) of pyridine were added to 500 ml of N-dimethylacetamide, followed by dropping 140 g (1 mole) of benzoyl chloride at about 5° C. in about 30 minutes and agitating for further 30 minutes. The resulting crystals were filtered and washed with 500 ml of methanol to obtain 260 g (yield 89%) of an isomer of exemplified compound [IV]-(1) (2-benzamido-4-chloro-5-nitrophenol). From the melting point of below 250° C. and an IR spectrum (νC=O, 1654 cm-1), this compound was found to be 2-benzamide compound.
Reaction SMILES: Cl[Si:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[CH2:3][CH3:4].C(=O)=O.Br[C:13]([F:16])([F:15])[F:14].C(N(CC)P(N(CC)CC)N(CC)CC)C>CC(C)=O.ClCCl>[CH2:3]([Si:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:13]([F:16])([F:15])[F:14])[CH3:4]
Reactant: FC(F)(F)Br
Reactant: CC[Si](Cl)(CC)CC
Agent: CCN(CC)P(N(CC)CC)N(CC)CC
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC[Si](CC)(CC)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A flask equipped with a dry ice condenser was flame dried under a nitrogen stream, and charged with 25g (0.17 mol) of chlorotriethylsilane and 40 mL of dichloromethane. After cooling the resulting solution to -78° C. and charging the condenser with dry ice and acetone, 40 mL (0.43 mol) of bromotrifluoromethane (Freon 13Bl) that had been condensed into a graduated tube was warmed to room temperature and allowed to distill into the flask. The cold solution was treated dropwise with 66mL (0.24 mol) of hexaethylphosphorous triamide, allowed to stir at -78° C. for two hours, and allowed to stir at room temperature overnight. Low boiling components were then short path distilled into a cold (-78° C.) receiving flask at >1 torr with the pot temperature kept at <50° C. The distillate was further fractionated by removal of the dichloromethane (40°-45° C. at atmospheric pressure) and short path distillation to give 22.0 g of 98% pure (69% yield) triethyltrifluoromethylsilane: bp 52°-54° C. at 10 torr; 1H NMR (CDCl3)δ0.59-1.16 (m); 19F NMR (CDCl3 , relative to CFCl3) -61.3 ppm (s); IR (neat) 2960, 2915, 2882, 1458, 1413, 1206, 1055 1020, 734, 693 cm-1 ; mass spectrum (70 eV) m/z (relative intensity) 115 (66, M-CF3), 105 (46), 87 (85), 77 (100), 59 (56), 49 (41), 47 (37), 41 (38). Anal. Calcd. for C7H15F3Si: C, 45.62; H, 8.20. Found: C, 47.53; H, 8.56.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([NH:41][C:42]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:47]2[CH:48]=[CH:49][C:44]([C:42]([NH:41][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:43])=[CH:45][CH:46]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(C)(C)NC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 56.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (522 mg, 1 mmol), [4-(tert-butylaminocarbonyl)phenyl]boronic acid (442 mg, 2 mmol), and dichlorobis(triphenylphosphine)palladium (II) (70.2 mg, 0.1 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 1.25 mL, 2.5 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) to afford 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-N-tert-butyl-benzamide (300 mg, 56.9%) as a light yellow solid: LC/MS m/e calcd for C31H33N3O3S [M+H]+ 528.69, observed 528.0.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH2:10]([O:12][P:13]([C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([Cl:28])[CH:22]=2)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:11]>>[CH2:10]([O:12][P:13]([C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([N+:1]([O-:4])=[O:2])=[C:23]([Cl:28])[CH:22]=2)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CCOP(=O)(OCC)c1cc2ccc(Cl)cc2[nH]c1=O
Agent: O=S(=O)(O)O
Product: CCOP(=O)(OCC)c1cc2cc([N+](=O)[O-])c(Cl)cc2[nH]c1=O
Reaction time: 0.25 h

Procedure:
55 ml of nitric acid are added dropwise to a solution of 55 ml of 96% sulphuric acid cooled in an ice bath, and then (7-chloro-2-oxo-1,2-dihydro-3-quinolyl)phosphonic acid diethyl ester (14.7 g, 46.6 mmol) is added in portions whilst maintaining the temperature at less than or equal to 5° C. When the addition is complete, stirring is continued for 15 minutes and then the ice bath is withdrawn and the reaction mixture is brought to ambient temperature over a period of about 1 hour 30 minutes. The solution is poured into ice and the precipitate is stirred to obtain a filterable solid. Filtration is carried out, followed by washing with water to neutrality and drying in vacuo. The solid is suspended in 210 ml of ethanol at reflux; the batch is left to cool and, after drying, filtered to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH:21]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:21]=[C:20]([CH:19]=[C:4]([CH:5]=[C:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH:3]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cc(F)cc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(C=C2CCNCC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 133.1 %

Procedure:
To a solution of tert-butyl 4-(3-fluoro-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (585 mg, 0.001 mol) in dry CH2Cl2 (7 mL) cooled to 0° C. was added trifluoroacetic acid (0.99 mL, 0.012 mol). The reaction mixture was stirred for 30 min at 0° C. and then for 1 h at RT. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (469 mg, 100%). 1H NMR (500 MHz, CDCl3): δ 9.82 (m, 1H), 8.43 (s, 1H), 7.95 (d, J=8 Hz, 1H), 7.07 (d, J=9 Hz, 1H), 6.83 (q, J=13.5 Hz, 2H), 6.43 (s, 1H), 3.29 (s, 1H), 3.17 (s, 1H), 2.85 (m, 1H), 2.72 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@@H:25]([C:27]3[CH:36]=[CH:35][C:30]([C:31](OC)=[O:32])=[CH:29][CH:28]=3)[CH3:26])[CH:24]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@@H:25]([C:27]3[CH:28]=[CH:29][C:30]([CH2:31][OH:32])=[CH:35][CH:36]=3)[CH3:26])[CH:24]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc([C@@H](C)n2cc(C[C@@H]3C(=O)NC=CN3S(=O)(=O)c3ccc(Cl)c(Cl)c3)nn2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@H](c1ccc(CO)cc1)n1cc(C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)nn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Methyl 4-((R)-1-(4-(((R)-1-(3,4-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-pyrazin-2-yl)methyl)-1H-1,2,3-triazol-1-yl)ethyl)benzoate (1.38, 2.51 mmol) was dissolved in CH2Cl2 (200 mL) and cooled to −78° C. under N2. Dibal (1.5M solution in toluene, 8.4 mL, 12.6 mmol) was then added over 10 min. After 30 min, the cold bath was removed and the reaction was stirred for 4 h. To the solution was added MeOH (20 mL), followed by Na2SO4 (25.1 g) and saturated NH4Cl (2.5 mL). The reaction mixture was stirred overnight. The solids were removed by filtration, and washed with CH2Cl2/MeOH (10/1). The filtrate was concentrated and the residue was chromatographed on silica (100% CH2Cl2 to 5% MeOH in CH2Cl2) to yield the title compound.