Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][NH2:19]>ClCCl>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:19][O:18][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[O:9])=[CH:10][CH:11]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1ccc(CO)cc1
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 4-(Hydroxymethyl)benzoic acid (0.75 g, 5 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.59 g, 5 mmol), and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (1.15 g, 6 mmol) in dichloromethane (50 mL) was stirred at room temperature for 2 h (monitored by TLC). The mixture was extracted with water and dried over magnesium sulfate. The residue was purified by chromatography (MeOH:DCM=1:50) to give the title compound (0.88 g, 70%). NMR (400 MHz in DMSO, Bruker AVANCE-400): δ 1.52 (m, 3H, OTHP), 1.72 (m, 3H, OTHP), 3.51 (m, 1H, OTHP), 4.04 (m, 1H, OTHP), 4.53 (s, 2H, CH2), 4.98 (s, 1H, OTHP), 5.28 (s, 1H, NH), 7.38 (d, 2H, J=10.0 Hz, Ar—H), 7.72 (d, 2H, J=5.0 Hz, Ar—H), 11.55 (s, 1H, OH).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=S>O1CCOCC1>[N:17]1([C:15]2[NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=3[S:11](=[O:14])(=[O:13])[N:12]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(C(=O)O)cc1S(N)(=O)=O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
4-Amino-3-sulfamoylbenzoic acid (6 g) and thiocarbonyldiimidazole (23.2 g) in dioxane (60 mL) was refluxed for 2 h. The solvent was removed by distillation under reduced pressure. The residue was dispersed in water (200 mL) and supplemented with a 10% aqueous solution of NaOH (40 mL). After stirring for 30 min. at room temperature, the solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 2 with 12N HCl. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound (yield: 4.5 g); m.p. >300° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[C:5](=[O:15])[N:4]=[C:3]1SC.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][CH3:33])=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:36]([F:39])([F:38])[F:37]>C(O)C>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:32]([CH3:33])[C:3]3[N:2]([CH3:1])[CH:7]=[C:6]([CH2:8][C:9]4[CH:10]=[N:11][CH:12]=[N:13][CH:14]=4)[C:5](=[O:15])[N:4]=3)=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:36]([F:37])([F:38])[F:39]
Reactant: CNCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CSc1nc(=O)c(Cc2cncnc2)cn1C
Solvent: CCO
Product: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)c1nc(=O)c(Cc2cncnc2)cn1C
Temperature: 130 °C
Reaction time: 48 h
Yield: 28.9 %

Procedure:
1-Methyl-2-methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (50 mg, 0.201 mmol, 1 eq) and {2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-methyl-amine (99.4 mg, 0.302 mmol, 1.5 eq) were dissolved in dry ethanol (300 μl) and stirred at 130° C. for 48 h. Reaction mixture was evaporated and crude residue was purified via Biotage SP-1 Snap Si 10 g; 15 ml/min; UV Wavelength (Collection: 254 nm; Monitor: 290 nm) in the gradient of MeOH in DCM: 0% for 1 CV, 0-8% for 25 CV. The appropriate fractions were combined and product was not pure enough and it was sent to HPLC/MS Purification. After HPLC/MS purification combined fractions of desired product were collected and put on lyophilisation to obtain 2-({2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-methyl-amino)-1-methyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.058 mmol; yield: 28.9%, HPLC-MS/UV: [M+H]+=530.95; rt: 12.13 min; purity: 99%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 1.38 (s, 3H), 2.81 (s, 3H), 2.87 (t, J=6.73 Hz, 2H), 3.38 (t, J=7.20 Hz, 2H), 3.50 (s, 2H), 7.02 (d, J=7.20, 2H), 7.18 (d, J=8.17, 1H), 7.31 (d, J=8.17, 2H), 7.37 (s, 1H), 7.50 (s, 1H), 7.67 (d, J=8.65, 1H), 8.67 (s, 2H), 8.97 (s, 1H)
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:30]3[CH:31]=[C:32]4[C:37](=[CH:38][CH:39]=3)[NH:36][C:35](=O)[CH:34]=[C:33]4[CH3:41])=[N:26][CH:27]=2)=[CH:18][CH:17]=1.[Br:42]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:42][C:35]1[CH:34]=[C:33]([CH3:41])[C:32]2[C:37](=[CH:38][CH:39]=[C:30]([C:29]#[C:28][C:25]3[CH:24]=[CH:23][C:22]([C:19]4[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=4)=[CH:27][N:26]=3)[CH:31]=2)[N:36]=1
Reactant: Cc1cc(=O)[nH]c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Reactant: ClBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Cc1cc(Br)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Temperature: 95 °C

Procedure:
478 mg (1.48 mmol) of tetrabutylammonium bromide and 493 mg (3.37 mmol) of phosphorus pentoxide are added to a suspension of 500 mg (1.21 mmol) of 6-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-4-methyl-1H-quinolin-2-one in 10 mL of toluene and the reaction mixture is heated to 95° C. for 1.5 hours. After cooling, the organic phase is decanted off, the residue is treated twice with toluene in the ultrasound bath, and the combined organic phases are washed with semisaturated sodium bicarbonate solution and water and dried over magnesium sulfate. After the desiccant and solvent have been eliminated, the residue is dried and reacted further without purification. Yield: 120 mg (18% of theoretical); C23H14BrClN2 (M=433.730); calc.: molpeak (M+H)+: 433/435/437 (BrCl); found: molpeak (M+H)+: 433/435/437 (BrCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)=[O:10].[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[NH2:17])=[O:10]
Reactant: COc1ccccc1S(=O)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1S(=O)c1cccc(N)c1
Temperature: 25 °C

Procedure:
1-Methoxy-2-(3-nitrophenylsulfinyl)benzene (217 mg, 0.78 mmol) was dissolved in ethyl alcohol (5.0 ml) and water (1.75 ml), to which was added iron powder (488 mg, 8.7 mmol) and ammonium chloride (77 mg, 1.4 mmol). This mixture was heated to reflux for four hours, cooled to room temperature and the supernatant decanted. The insoluble material was rinsed with methylene chloride, followed by aqueous 1M potassium carbonate. All decanted solutions were combined and the organic layer separated. The aqueous layer was extracted again with methylene chloride, and the combined organics washed once with brine. After drying over magnesium sulfate and concentration in vacuo, the title compound was obtained as a white solid (145 mg, 75%). 1H NMR(400 MHz): 3.89(3H,s), 6.69-6.74(1H,m), 6.86(1H,d,J=8.4), 7.03-7.09(2H,m), 7.10-7.20(2H,m), 7.38(1H,dt,J=8.3, 1.5), 7.86(1H,dd,J=7.8, 1.5).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[O:6][CH2:7][CH:8]3[N:13]([C:14]=2[N:15]=1)[CH2:12][CH2:11][O:10][CH2:9]3.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[N:16]1([C:4]2[C:5]3[O:6][CH2:7][CH:8]4[N:13]([CH2:12][CH2:11][O:10][CH2:9]4)[C:14]=3[N:15]=[C:2]([C:30]3[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=3)[N:3]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Clc1nc(N2CCOCC2)c2c(n1)N1CCOCC1CO2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2nc(N3CCOCC3)c3c(n2)N2CCOCC2CO3)cn1
Temperature: 120 °C
Yield: 5.6 %

Procedure:
A mixture of 3-chloro-1-morpholin-4-yl-5,6,8a,9-tetrahydro-8H-7,10-dioxa-2,4,4b-triaza-phenanthrene (45 mg, 0.144 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (60 mg, 0.271 mmol), PdCl2(PPh3)2 (10 mg, 0.014 mmol) and sodium carbonate (460 μL, 0.46 mmol, 1M aqueous solution) in acetonitrile (2 mL) was degassed and heated at 120° C. for 30 mins in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient acetonitrile 5-98%) affording 121 as a white solid (3 mg, 6%). LCMS (method B): RT=3.08 min, [M+H]+=372. 1H NMR (400 MHz, CDCl3): δ 9.11 (2H, s), 5.18 (2H, broad s), 4.55 (1H, dd, J=13.5, 2.4 Hz), 4.22 (1H, dd, J=10.8, 3.1 Hz), 4.05 (1H, dd, J=11.5, 3.5 Hz), 3.88 (2H, m), 3.81 (4H, m), 3.69-3.56 (6H, m), 3.29 (1H, t, J=11.5 Hz), 3.02 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=O)[CH:18]=[CH:19]N(C)C)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]([NH2:28])=[NH2+:27].C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([C:17]3[CH:18]=[CH:19][N:25]=[C:26]([NH2:28])[N:27]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NC(N)=[NH2+]
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)nn3ccccc23)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)pyrazolo[1,5-a]pyridine (60 mg, 0.19 mmol), guanidinium hydrochloride (36 mg, 0.38 mmol), and K2CO3 (105 mg, 0.76 mmol) in N,N-dimethylformamide (3 mL) was stirred in a 110° C. oil bath for 8 h. Additional guanidinium hydrochloride (36 mg, 0.38 mmol) was added, and the mixture stirred in a 110° C. oil bath for 16 h. The mixture was cooled to room temperature, and water (20 mL) added. The resulting tan precipitate was collected by filtration, washed with water, air-dried, the dried under high-vacuum to afford the title compound, 0.033 g (57%). 1H NMR (CDCl3) δ 8.57 (d, 1H, J=6.0 Hz), 8.51 (d, 1H, J=8.9 Hz), 7.98 (d, 2H, J=5.7 Hz), 7.64 (m, 2H), 7.46 (m, 1H), 7.22 (m, 2H), 7.04 (m, 1H), 6.47 (d, 1H, J=5.8 Hz), 5.76 (s. 2H). MS (+ve ion electrospray) 306 (100), (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]12[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH:20]C(=O)O[C:16]2=[O:17]>O1CCCC1.C(O)C>[NH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[C:16]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)=[O:17]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To an ice-cold solution of 28 ml (134 mmol) of 4-amino-1-(phenylmethyl)piperidine in 200 ml of tetrahydrofuran were added, batchwise, 21.9 g (134 mmol) of isatoic acid anhydride. The resulting suspension was stirred for 2½ hours at room temperature and 2½ hours at reflux temperature, then freed from solvent. The residue was dissolved in 100 ml of hot ethanol, the resulting solution was filtered whilst hot after the addition of 5 g of activated charcoal. The crystal mass precipitated after cooling was suction filtered, washed with diisopropylether and dried in vacuo at 50° C. 28.3 g of colourless crystals were obtained. A further 5.1 g of a product of the same quality were isolated from the combined mother liquors. Total yield: 33.4 g (80.6% of theory).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]([CH3:20])[N:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][N:5]1[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:7][C:3]([CH2:2][N:21]2[CH2:26][CH2:25][N:24]([CH2:2][C:3]3[CH:7]=[C:6]([C:8]4[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=4)[N:5]([CH3:20])[N:4]=3)[CH2:23][CH2:22]2)=[N:4]1
Reactant: C1CNCCN1
Reactant: COc1cc(-c2cc(CCl)nn2C)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)n(C)n4)CC3)nn2C)cc(OC)c1OC

Procedure:
3-Chloromethyl-1-methyl-5-(3,4,5-trimethoxy-phenyl)pyrazole (119 mg) and piperazine (17 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][C@@:2]12[C:17]([CH3:19])([CH3:18])[C@@H:5]([C:6]3[C:7](=[O:16])[N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[NH:9][C:10]=31)[CH2:4][CH2:3]2.Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:1][C@@:2]12[C:17]([CH3:19])([CH3:18])[C@@H:5]([C:6]3[C:7](=[O:16])[N:8]([CH2:11][C:12]([F:13])([F:14])[F:15])[N:9]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:10]=31)[CH2:4][CH2:3]2
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(CC(F)(F)F)c(=O)c12
Reactant: BrCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(CC(F)(F)F)n1CCc1ccccc1
Temperature: 100 °C
Yield: 11.5 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 47; 150 mg, 0.55 mmol), tetrabutylammonium iodide (220 mg, 0.60 mmol) and (2-bromoethyl)benzene (660 μL, 4.8 mmol) in dimethylformamide (2 mL) was heated in a pressure tube in an oil-bath at 100° C. for 24 h. Dichloromethane (75 mL) was added and the solution was washed with water (5×25 mL) and aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and purified using an ISCO 40 g column, eluting with 20-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated with methanol, and dried under high vacuum at 90° C. for 3 h to give (4S,7R)-7,8,8-trimethyl-1-phenethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (24 mg, 12%) as a yellow gum. ES(+)-MS (M+H) 379.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21](=[O:27])[C:22]#[C:23][CH2:24][O:25][CH3:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:28]#[N:29])[CH:5]=[CH:6][C:7]=1[F:8]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21](=[O:27])/[CH:22]=[CH:23]\[CH2:24][O:25][CH3:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:28]#[N:29])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: COC/C=C\C(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Reaction time: 5.5 h
Yield: 0.7 %

Procedure:
A mixture of 0.05 g (0.1 18 mmol) N-[4[(3-chloro-4-fluorophenyl)amino]-3-cyano-6-quinolinyl]-4-methoxy-2-butynamide and 6 mg of Lindlar catalyst in 15 mL of methanol was hydrogenated at room temperature for 5.5 hrs. The mixture was filtered through a pad of Celite. The solvent was removed to give 0.05 g (99.7%) yellow solid; HRMS m/z 410.0928 (M+.).
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.CC(C)=O.Cl.[CH2:24]([N+:28]([O-:30])=[O:29])/[CH:25]=N\O>O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[C:2](=[C:16]([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:1]=[CH:25][C:24]=1[N+:28]([O-:30])=[O:29]
Reactant: Cc1cc(C)c(N)c(C(=O)c2ccccc2Cl)c1
Reactant: O=[N+]([O-])C/C=N\O
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)c2ncc([N+](=O)[O-])c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-amino-2'-chloro-3,5-dimethylbenzophenone (1 g), acetone (50 ml), 20 % hydrochloric acid (20 ml) and methazonic acid (4.5 g, wet) was stirred for 2 hrs. at room temperature and refluxed for 4 hrs. The mixture was diluted with water, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by a column chromatography on silica gel to give 4-(2-chlorophenyl)-6,8-dimethyl-3-nitroquinoline as crystals, which was recrystallized from a mixture of methanol and chloroform. m.p. 130°-131° C. Yield 1.95 g (54.2 %).
Reaction SMILES: CS(O[C:6]1([CH3:23])[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].[ClH:29]>C(O)(C)C.CCOCC>[ClH:29].[C:24]([NH:28][C:6]1([CH3:23])[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)(C)NC1(C)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a solution of 1-benzhydryl-3-methylazetidin-3-yl methanesulfonate (2.00 g, 6.23 mmol) in iso-propanol (10 ml) was added tert-butyl amine (1.36 g, 18.63 mmol). The mixture was heated at 80° C. for 3 h. The reaction mixture was then allowed to cool to room temperature and concentrated. The residue was slurried with ethyl acetate and filtered, washing with further ethyl acetate and then concentrated to give a solid. The solid was slurried in ether and hydrochloric acid (20 ml, 2M in ether) was added, then stirred for 10 mins and filtered to provide the title compound as a tan solid (1.69 g, 74%). 1H NMR (DMSO) 1.40 (9H, s), 1.99 (3H, s), 3.85 (2H, brs), 4.11 (2H, brs), 4.71 (1H, brs), 7.35-7.50 (6H, m), 7.70-7.81 (4H, m), 10.23 (1H, s).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:15][C:3]=12.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1.[H-].[Na+]>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:14]=[CH:15][C:3]=23)(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1Cl
Reactant: COc1ccc(S(=O)(=O)NCc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Following the procedure of Example 53, the product of Example 47 is reacted with (4-methoxybenzenesulfonyl) (3-pyridinylmethyl) amine and sodium hydride to provide-ethyl 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 89°-91° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:48])[CH2:36][O:37][C:38](=[O:47])[C:39]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:46])[CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:48])[CH2:36][O:37][C:38](=[O:47])[C:39]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:46])[CH2:27][C:28]([OH:30])=[O:29])=[O:24])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c2c(Cl)cccc2Cl)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)O)C(=O)COC(=O)c2c(Cl)cccc2Cl)n(C)c2ccccc12
Yield: 60 %

Procedure:
Treatment of N-[(1-methyl-3-isobutyl-indole-2-cabonyl)leucinyl]-3-amino-5-(2,6-dichlorobenzoyl) oxy-4-oxo pentanoic acid, tert-butyl ester (63 mg, 0.089 mmol) with TFA as described in Example 80 gave the titled product (34.5 mg, 60%) as a white powder. MS C32H37Cl2N3O7, [M+H]+=646, [M−H]−=644. TLC (CH2Cl2/MeOH, 90/10): Rf=0.23.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:13][CH2:12][C@@H:11]([O:14]/[N:15]=[C:16]2\[CH2:17][CH:18]3[C@:31]([CH3:35])([CH2:32][C@H:33]\2[F:34])[C@@H:30]2[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]2)([CH3:27])[C@@H:25]([OH:36])[CH2:24][CH2:23]4)[CH2:20][C:19]3=O)[CH2:10]1.Cl.[NH2:39][OH:40]>>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:13][CH2:12][C@@H:11]([O:14]/[N:15]=[C:16]2\[CH2:17][CH:18]3[C@:31]([CH3:35])([CH2:32][C@H:33]\2[F:34])[C@@H:30]2[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]2)([CH3:27])[C@@H:25]([OH:36])[CH2:24][CH2:23]4)[CH2:20]/[C:19]/3=[N:39]\[OH:40])[CH2:10]1
Reactant: NO
Reactant: C[C@]12CC[C@H]3[C@@H](CC(=O)C4C/C(=N\O[C@@H]5CCNC5)[C@H](F)C[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Product: C[C@]12CC[C@H]3[C@@H](C/C(=N\O)C4C/C(=N\O[C@@H]5CCNC5)[C@H](F)C[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
The title compound was obtained in 74% yield following the procedure described in Example 34 starting from (E)-3-[3-(R)-pyrrolidinyl]oxyimino-2α-fluoro-17β-hydroxyandrostan-6-one fumarate (Example 35, 73 mg) and hydroxylamine hydrochloride (11 mg). After evaporation of the solvent the crude reaction mixture was purified by flash chromatography (SiO2, CHCl3/MeOH/26% NH4OH 90/10/1). To the concentrated fractions, a stoichiometric amount of fumaric acid in MeOH was added. The resulting precipitate was rinsed with heptane and filtered to give the title compound I-bj.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=2[CH:7]=[CH:6][C:5]=1[CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:2][CH3:3].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31].Cl>C(Cl)Cl>[CH3:29][S:30]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][C:5]1[CH:6]=[CH:7][C:8]2[C:9]([C:13]([F:15])([F:14])[F:16])=[N:10][O:11][C:12]=2[C:4]=1[CH2:1][CH2:2][CH3:3])(=[O:32])=[O:31]
Reactant: CCCc1c(CCCCO)ccc2c(C(F)(F)F)noc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(CCCCOS(C)(=O)=O)ccc2c(C(F)(F)F)noc12
Reaction time: 2 h

Procedure:
To a solution of 4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butan-1-ol, from this Example step 4, in CH2Cl2 (25 mL) was added Et3N (0.42 mL, 2.99 mmol) and methanesulfonyl chloride (0.17 mL, 2.2 mmol) at 0° C. The mixture was stirred from 0° C. to room temperature for 2 hours. 0.5N HCl was added and the mixture extracted 3 times with CH2Cl2. Combined organic extracts were washed with water and brine then dried over Na2SO4. The solvent was evaporated in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>O1CCCC1>[F:1][C:2]1[CH:9]=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C1COCCN1
Reactant: N#Cc1ccc(F)cc1F
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCOCC2)cc1F
Yield: 65 %

Procedure:
A solution of 2,4-difluorobenzonitrile (6.03 g, 43.35 mmol) and morpholine (8.3 ml, 95.17 mmol) in tetrahydrofuran (27 ml) was stirred at room temperature for 24 hr. The mixture was evaporated and the white solid purified by Biotage™ column (90 g, silica) eluting with cyclohexane:ethyl acetate: (4:1) to give 2-fluoro-4-(morpholino)-benzonitrile as a white solid (5.81 g, 65%).