Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]2[C:15](=[O:33])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([F:32])[CH:20]=3)[O:18][C:13]=2[C:12]([F:34])=[CH:11][C:10]=1[F:35])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>O1CCCC1>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]2[C:15](=[O:33])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[C:21]([F:32])[CH:20]=3)[O:18][C:13]=2[C:12]([F:34])=[CH:11][C:10]=1[F:35]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCN=[N+]=[N-])c(F)cc(F)c3o2)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCN)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 82.6 %

Procedure:
332 mg (0.682 mmol) of the above 5-(4-azidobutylamino)-6, 8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one was dissolved in 20 mL of tetrahydrofuran, 272 mg (1.02 mmol) of triphenylphosphine and 20 mL of water were added and the mixture was stirred at room temperature for 22 hours. Ethyl acetate was added to the reaction solution, and the organic layer was separated, washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1-chloroform:methanol:aqueous ammonia=9:1:1) to give 260 mg of 5-(4-aminobutylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.CO[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1OC)[C:24](Cl)=[O:25].[CH2:32]([Cl:34])Cl>>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([CH2:32][Cl:34])[CH:22]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: ClCCl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COC(=O)c1cc(Br)ccc1NC(=O)c1cccc(CCl)c1
Reaction time: 1 h

Procedure:
Methyl 2-amino-5-bromobenzoate (compound A) (3.0 g) was dissolved in anhydrous methylene chloride (40.0 ml). Subsequently, pyridine (2.1 ml) and 4-(chloromethyl)benzoyl chloride (compound B) (2.2 ml) were added to the solution at room temperature, and the mixture was stirred at that temperature for one hr. After the completion of the reaction, distilled water was added, followed by separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated to give methyl 5-bromo-2-[3-(chloromethyl)benzoyl]aminobenzoate as a useful intermediate (4.90 g, yield 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C.[Cl:32][C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.ClC(Cl)C.Cl>O1CCOCC1>[ClH:32].[O:35]=[C:33]1[NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N:10]1[CH:11]1[CH2:12][CH2:13][N:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:15][CH2:16]1
Reactant: N#Cc1ccc(N)c(NC2CCN(C3CCOCC3)CC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: N#Cc1ccc2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1
Reaction time: 0.08 h

Procedure:
4-Amino-3-{[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}benzonitrile (D59, 240 mg, 0.0008 mol, 1 eq), diisopropylethylamine (140 mg, 0.00104 mol, 1.3 eq), triphosgene (70 mg, 0.00024 mol, 0.3 eq), and dichloroethane (20 ml) were combined. After 5 min, 4 ml of 4M HCl in dioxane were added, the reaction evaporated, the residue dissolved in methanol and purified exactly as in Example 1, where A=H2O and B=CH3CN to produce the title compound as a white solid. MS (ESI): 327 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C2C=CC=C(C(Cl)=O)C=2C=CC=1.[CH3:27][O:28][CH2:29][CH2:30][N:31]1[C:35]([CH3:36])=[C:34]([CH3:37])[S:33][C:32]1=[NH:38].CCN(CC)CC>C1COCC1>[CH3:27][O:28][CH2:29][CH2:30][N:31]1[C:35]([CH3:36])=[C:34]([CH3:37])[S:33]/[C:32]/1=[N:38]\[C:11]([C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(O)c1cccc2ncccc12
Agent: O=C(Cl)c1cccc2ncccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc2ncccc12
Yield: 48.2 %

Procedure:
The quinoline-5-carboxylic acid (Lancaster, 0.25 g, 1.4 mmol) was converted to quinoline-5-carbonyl chloride using 5 mL SOCl2 using the method described in Example 134A. The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and quinoline-5-carbonyl chloride in 30 mL THF were processed as in Example 134B to afford the title compound (0.18 g, 0.53 mmol, 49% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.30 (d, J=0.7 Hz, 3H), 2.34 (s, 3H), 3.31 (s, 3H), 3.80 (t, J=5.1 Hz, 2H), 4.49 (t, J=5.3 Hz, 2H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.83 (dd, J=8.5, 7.1 Hz, 1H), 8.15 (dt, J=8.5, 1.0 Hz, 1H), 8.40 (dd, J=7.3, 1.2 Hz, 1H), 8.87 (dd, J=4.1, 1.7 Hz, 1H), 9.55 (ddd, J=8.8, 1.7, 0.7 Hz, 1H); MS (DCI/NH3) m/z 342 (M+H)+; Anal. calculated for C18H19N3O2S: C, 63.32; H, 5.61; N, 12.31. Found: C, 63.44; H, 5.05; N, 12.10.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[CH3:17][O+:18](C)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>ClCCl.O>[C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:17][OH:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc[n+]([O-])cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccnc(CO)c1
Yield: 73 %

Procedure:
4-t-Butyl-pyridine N-oxide (11.0 g, 72.9 mmole) is dissolved in 200 ml dichloromethane in a 500 ml one neck round bottom flask under nitrogen. The solution is treated with trimethyloxonium tetrafluoroborate (10.8 g, 72.9 mmole), is stirred 1h at room temperature, and the volatiles are removed in vacuo. The solid residue is dissolved in 200 ml methanol in a 500 ml one neck round bottom flask. The solution is heated to reflux, is treated with ammonium persulfate (3.3 g, 14.5 mmole) in 15 ml water, and the reaction mixture is vigorously refluxed for 30 min. The reaction is treated with a second lot of ammonium persulfate (1.65 g, 7.2 mmole) in 7 ml water and is refluxed for an additional 1 h. The reaction is cooled and the bulk of the methanol is removed in vacuo. The residue is diluted with 300 ml conc ammonium hydroxide and the mixture is extracted with 4×100 ml dichloromethane. The combined organics are dried over potassium carbonate and are concentrated in vacuo to a yellow oil. The crude material is chromatographed over 400 g silica gel (230-400 mesh), eluting with 40% acetone/hexane, while collecting 50 ml fractions. Fractions 26-52 are combined and concentrated to afford 8.79 g (73%) of 4-t-Butyl-2-hydroxymethyl-pyridine as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][O:3]1.[Br:10]N1C(=O)CCC1=O.C([O-])(=O)C.[NH4+]>CCOCC.C(OCC)(=O)C>[Br:10][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[CH2:7][C:6]1=[O:8]
Reactant: CC1(C)CC(=O)CCO1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1(C)CC(=O)C(Br)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
Into around-bottom flask, was placed a solution of 2,2-dimethyloxan-4-one (1.00 g, 7.80 mmol, 1.00 equiv) in ether (20 mL). N-Bromosuccinimide (1.50 g, 25.5 mmol, 3.26 equiv) was added in portions, followed by the addition of ammonium acetate (60.0 mg, 0.78 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 25° C., then diluted with ethyl acetate (20 mL). The resulting mixture was washed brine (2×40 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:30) as the eluent to obtain the title compound as a yellow oil (508 mg, 31%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[N:16]=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>CC(C)=O>[C:30]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][C:3]=1[N:16]=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=S(=O)(O)c1cc(N=Nc2ccccn2)c(O)c2ccccc12
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(Oc1c(N=Nc2ccccn2)cc(S(=O)(=O)O)c2ccccc12)c1ccccc1

Procedure:
4-Hydroxy-3-(2-pyridylazo)-1-naphthalenesulfonic acid (110 g) was added to pyridine (350 ml) followed by benzoyl chloride (250 ml). Triethylamine (100 ml) was added slowly and the reaction mixture got warm. After 1 hour the mixture was diluted with five times its volume of acetone and filtered. The product was washed with acetone and allowed to suck dry. It was dissolved in water (minimum volume) and neutralized with hydrochloric acid. After filtration, the product was washed with acetone and ether. Yield 120 g (83 percent).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>CS(C)=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([O:15][CH2:18][CH:20]2[CH2:21][O:22]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(OCC2CO2)C1
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 81.3 %

Procedure:
To a solution of 8 (30 g, 0.15 mol) in DMSO (250 mL) was slowly added a solution of NaOH (9.9 g, 0.25 mol) in water (195 mL) at 15-25° C. Epichlorohydrin (93.8 g, 1.01 mol) was added and the mixture was stirred at 20-25° C. for 24 h. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layer was washed with water (2×50 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate-heptanes 3:2, yielding 9 as a clear oil (32.1 g, 84%). 1H NMR (300 MHz, CDCl3): δ 2.60 (1H, dd, J=4.8, 2.6 Hz), 2.81 (1H, dd, J=4.9, 4.2 Hz), 3.09-3.16 (1H, m), 3.25 (1H, dd, J=11.4, 6.2 Hz), 3.68 (1H, dd, J=11.5, 2.5 Hz), 3.89-3.97 (2H, m), 4.15-4.24 (2H, m), 4.29-4.37 (1H, m), 5.09 (2H, s), 7.28-7.36 (5H, m); 13C NMR (75 MHz, CDCl3): δ 44.2, 50.4, 56.7, 56.9, 66.7, 68.6, 70.0, 128.0, 128.1, 128.5, 136.6, 156.5; IR: (film) 2951, 1709, 1420 cm−1; ES-HRMS m/z: (M++1H) calcd. for C14H18NO4 264.1230. found 264.1230.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[C:6]([CH3:21])[N:5]=[C:4](N)[CH:3]=1.[I:23]CI.C(ON=O)(C)(C)C>CC#N>[I:23][C:4]1[N:5]=[C:6]([CH3:21])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[C:2]([CH3:1])[CH:3]=1
Reactant: ICI
Reactant: Cc1cc(N)nc(C)c1Oc1ccnc(-c2cnn(C)c2)c1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Cc1cc(I)nc(C)c1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.2 %

Procedure:
4,6-Dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.41 g, 1.4 mmol), KI (2.30 g, 13.9 mmol), and diiodomethane (4 mL, 49.6 mmol) were combined and stirred at RT. The suspension was treated with tert-butylnitrite (1.0 mL, 8.3 mmol) and the reaction mixture was stirred at RT for 12 h. The mixture was diluted with MeCN (10 mL), additional tert-butylnitrite (1.0 mL, 8.3 mmol) was added and stirring was continued at RT for 24 h. The reaction mixture was partitioned between EtOAc (120 mL) and sat. NaHCO3 (aq) (20 mL). The aqueous phase was collected and the organic phase was washed with sat. NaHCO3 (aq) (2×20 mL), 10% Na2S2O3(aq) (2×20 mL), and brine (2×20 mL). The combined aqueous washes were back-extracted with EtOAc (2×20 mL) and the combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc/DCM) to afford 6-iodo-2,4-dimethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.24 g, 43%) as an off white solid that was used in the next step without further purification. MS (ESI) m/z: 407.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light brown substance (231 mg, 50%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:15](=[O:18])[N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:13](=[O:25])[N:12]([CH2:26][C:27]4[O:31][N:30]=[C:29]([CH2:32][O:33][CH3:34])[N:28]=4)[C:11]=3[CH:10]=2)=[C:5]([O:35][CH3:36])[CH:4]=1.[CH2:37]([O:39][C:40]1[C:49]([O:50][CH3:51])=[CH:48][C:47]2[C:46]([C:52]3[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=3)[C:55](O)=[O:56])=[N:45][C@@H:44]3[CH2:61][CH2:62][S:63][CH2:64][C@@H:43]3[C:42]=2[CH:41]=1)[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:37]([O:39][C:40]1[C:49]([O:50][CH3:51])=[CH:48][C:47]2[C:46]([C:52]3[CH:53]=[C:54]([C:55]([N:22]4[CH2:23][CH2:24][CH:19]([N:14]5[C:15](=[O:18])[C:16]6[S:17][C:9]([C:6]7[CH:7]=[CH:8][C:3]([F:2])=[CH:4][C:5]=7[O:35][CH3:36])=[CH:10][C:11]=6[N:12]([CH2:26][C:27]6[O:31][N:30]=[C:29]([CH2:32][O:33][CH3:34])[N:28]=6)[C:13]5=[O:25])[CH2:20][CH2:21]4)=[O:56])[CH:58]=[CH:59][CH:60]=3)=[N:45][C@@H:44]3[CH2:61][CH2:62][S:63][CH2:64][C@@H:43]3[C:42]=2[CH:41]=1)[CH3:38]
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Reactant: COCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6OC)cc5n(Cc5nc(COC)no5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(4-fluoro-2-methoxyphenyl)-1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (415 mg; compound B84) is reacted with 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (408 mg; compound C8) and HBTU (322 mg) in DCM (10 ml) in the presence of DIPEA (498 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc, 100/0 to 0/100 (v/v)] and by preparative HPLC as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[N:11](C3CCCCO3)[N:10]=2)=[CH:5][CH:4]=1.O1CCOCC1.Cl.O>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1
Temperature: 65 °C
Yield: 68.7 %

Procedure:
A mixture of 251 mg (0.753 mmol) of 3-(4-methoxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile, 5.0 mL of dioxane, and 5.0 mL of 6.0 N aq. HCl was heated at 65° C. for 22 h. The reaction mixture was added to a mixture of 10.0 mL of H2O and 20.0 mL of EtOAc with stirring. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were added to 60 mL of sat. aq. NaHCO3 with rapid stirring. The layers were separated, and the organic layer was washed with sat. aq. NaHCO3, and dried (Na2SO4). Purification of the crude material by silica gel chromatography using 30-50% EtOAc in hexanes afforded the title compound (129 mg, 71% yield): ES-MS (m/z) 250 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][N:12]2[CH:16]=[CH:15][CH:14]=[C:13]2[CH:17]=O)=[C:5]([N+:19]([O-])=O)[CH:4]=1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>[Pd].C(OCC)(=O)C>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:19][CH2:17][C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:6]=2[CH:7]=1
Reactant: COc1cc(Cn2cccc2C=O)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)NCc1cccn1C2
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of the 1-[(4,5-dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde of Step A (4.97 g), acetic acid (0.5 mL), magnesium sulfate (0.5 g) and 10% palladium on charcoal (0.5 g) in ethyl acetate (50 mL) was hydrogenated overnight at atmospheric pressure. The reaction was then filtered through Celite and the solvent removed in vacuo to give the crude title compound as an amber foam (3.2 g) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](O)=O>>[F:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(F)c(F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3,4-difluorobenzoic acid: MS (APCl): m/z 405 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.[CH3:11][O:12][CH2:13][C:14](OCC)=[O:15].Cl>C1C=CC=CC=1.O>[CH3:11][O:12][CH2:13][C:14]([CH:6]1[CH2:5][CH:4]([CH3:3])[CH2:9][CH2:8][C:7]1=[O:10])=[O:15]
Reactant: CCOC(=O)COC
Reactant: CC1CCC(=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COCC(=O)C1CC(C)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
In 50 ml of benzene was suspended 2.5 g of 60% sodium hydride. While cooling the suspension, a mixture of 5.6 g of 4-methylcyclohexanone and 5.4 g of ethyl methoxyacetate was dropwise added thereto. After stirring at room temperature for 2 hours, 20 ml of water was added thereto and the pH was rendered 3 with concentrated hyrochloric acid. The benzene phase was separated and the aqueous phase was extracted with ether. The benzene solution and the ether solution were combined with each other followed by washing with a sodium chloride aqueous solution. After drying, the mixture was concentrated to give 7.4 g of crude 2-methoxyacetyl-4-methylcyclohexanone. The crude product was used at the following step. (2) 4-Cyano-2,3,5,6,7,8-hexahydro-1-methoxymethyl-7-methyl-3-oxoisoquinoline
Reaction SMILES: [NH2:1][C:2]([CH3:10])([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].C([N:13]([CH2:16][CH3:17])CC)C.O1CCCC1.ClC([C:26]1[CH:41]=[CH:40][CH:39]=C[C:27]=1[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=O>C(Cl)Cl>[CH3:10][C:2]([NH:1][C:16]1[C:17]2[CH:39]=[CH:40][CH:41]=[CH:26][C:27]=2[C:28](=[O:29])[O:30][N:13]=1)([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C(Cl)c1ccccc1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Reactant: COC(=O)C(C)(N)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C(C)(Nc1noc(=O)c2ccccc12)C(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 40 %

Procedure:
A solution of methyl 2-amino-2,3-dimethylbutyrate (2.76 g, 0.019 mol), and triethylamine (1.97 g, 0.0195 mol) and tetrahydrofuran is added dropwise to a 5° C. mixture of benzyl o-(chloroformyl)benzoate, o-oxime(6.0 g, 0.02 mol) (which is prepared following the procedure in examples 1 and 2) and tetrahydrofuran under a nitrogen stream. The reaction mixture is stirred at room temperature for 21 hours, filtered to remove solids and the filtrate is concentrated in vacuo to give a yellow oil. The oil is dissolved into methylene chloride. The methylene chloride solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow oil. Crystallization of the oil from a benzene/hexanes/methylene chloride solution yields a white solid. The solid is chromatographed using neutral alumina and 4% ethyl acetate in methylene chloride as eluent to give the title compound as a white solid (2.41 g, 40%), mp 132°-134°, identified by IR and NMR spectral analyses.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][NH:13][OH:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]=[C:17]=[O:18].C(OCC)C.O>O1CCCC1>[OH:14][N:13]([CH2:12][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=1)[C:17]([NH:16][CH3:15])=[O:18]
Reactant: ONCc1ccc(-c2ccccc2)o1
Reactant: CN=C=O
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N(O)Cc1ccc(-c2ccccc2)o1
Yield: 89.2 %

Procedure:
To a solution of N-(5-phenylfur-2-yl)methyl hydroxylamine (0.5 g, 2.64 mmol) in tetrahydrofuran (30 mL) was added methylisocyanate (0.24 mL, 3.97 mmol) dropwise at room temperature under nitrogen while stirring. The reaction was stirred for 20 h and ethyl ether (100 mL) and water (100 mL) was added. The organic layer was separated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated in vacuo, to give a solid (0.58 g). Purification by chromatography (silica gel, 2% methanol in dichloromethane) gave the desired product (0.28 g), mp 135°-139° C.; NMR (300 MHz, DMSO-d6): 2.63 (3H, d, J=5.4 Hz), 4.53 (2H, s), 6.38 (1H, d, J=3.3 Hz), 6.87 (1H, d, J =3.3 Hz), 7.03 (1H, q, J=5.4 Hz), 7.24-7.30 (1H, m), 7.38-7.45 (2H, m), 7.38-7.45 (2H, m), 7.62-7.68 (2H, m), 9.40 (1H, s); MS (CI-NH3): M+H=247; Analysis Calculated for C13H14N2O3 : C, 63.40; H, 5.73, N, 11.38; Found C, 63.29; H, 5.76; N, 11.34.