Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=4)[C:17](=[O:28])[CH:16]=3)=[CH:14][C:9]=2[O:8][CH2:7]1.CCN(CC)CC>CO>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=4)[C:17](=[O:28])[CH2:16]3)=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: CCCOc1ccc2c(c1)C(=O)C=C2c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCOc1ccc2c(c1)C(=O)C[C@H]2c1ccc2c(c1)OCO2
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A 250 mL three-necked flask equipped with air driven stirrer and 250 mL addition funnel was charged with anhydrous THE (50 mL) and (R)-MeCBS (1.6 mL, 1 M, 1.6 mmol). The solution was cooled to -15° C. and BH3 -THF (32.4 mL, 1 M, 32.4 mmol) added in a steady stream. Charge the 250 mL addition funnel with 3-(1,3-Benzodioxol-5-yl)-6-propoxy-1H-inden-1-one (10 g, 32.4 mmol) and anhydrous TEF (50 mL) and add the solution dropwise over 1.5 h period while maintaining the internal reaction temperature between -10 to -15° C. Upon complete addition, stir the reaction mixture for 0.5 h at -15° C., cool the solution to -25° C. and add CH3OH (20 mL) dropwise over 20 minutes while maintaining the internal reaction temperature below -15° C. Warm the solution to 20° C. over 0.5 h and stir the solution for an additional 0.5 h at ambient temperature. Cool the solution to 0° C. and add Et3N (11 mL, 81 mmol) to the reaction mixture dropwise over 15 minutes while maintaining the internal reaction temperature below 5° C. Add 1,1-bis(triphenylphosphine) nickel(II) chloride (211 mg, 3.24 mmol) and warm the reaction mixture to 60° C. for 4 h. Concentrate the solution to 1/4 volume, cool to room temperature, add Celite (12 g) and then hexanes (85 ml). Stir the mixture vigorously for 10 min and filter through a SiO2 (10 g) and Celite (10 g) pad. Wash the filter pad with THF/hexane (45 mL/120 mL), combine the filtrates, and transfer to a 500 mL round-bottomed flask. Concentrate the solution in vacuo until a precipitate forms, add hexane (40 mL) and cool the solution to -15° C. for 8 h. Filter the precipitate, wash the filter cake with cold (0° C.) hexane solution and dry under vacuum to afford (S)-3-(1,3-Benzodioxol-5-yl)-2,3-dihydro-6-propoxy-1H-inden-1-one as a light yellow solid (8.1 g, 81%, 88% e.e.): mp 68.0-69.5° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH:13]1[CH:14]=[CH:15][N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[NH:19][CH2:18][C:17]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:19]2[C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[CH2:22][N:16]3[CH:15]=[CH:14][CH:13]=[C:17]3[CH2:18]2)=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1cc(I)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(I)ccc1C(=O)N1Cc2cccn2Cc2ccccc21
Reaction time: 2 h
Yield: 90 %

Procedure:
A suspension of 4-iodo-2-methoxybenzoic acid of Step B (2.5 g, 9.0 mmol) in thionyl chloride (10 mL) was heated at reflux for 1 hour. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a brown solid. The acid chloride was then dissolved in dichloromethane (10 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.75 g, 9.5 mmol) and N,N-diisopropylethyl amine (3.4 mL, 19.5 mmol) in dichloromethane (20 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography on silica gel using a solvent gradient of 15 to 25% ethyl acetate in hexane provided 3.6 g of title product as a white foam, which was redissolved in dichloromethane and evaporated to dryness prior to use in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.C(Cl)(Cl)Cl>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(N)cn1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)Cc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a suspension of 5-amino-2-cyanopyridine (0.500 g, 4.2 mmol) in dry dichloromethane (20 mL) was added triethylamine (0.637 g, 6.3 mmol) and the mixture was stirred at 0° C. To the reaction mixture phenylacetyl chloride (0.973 g, 6.3 mmol) was added dropwise and stirred at 0° C. for 1 hour and then at room temperature for 24 hours. The reaction mixture was diluted with chloroform (100 mL) and washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified using column chromatography (silica gel, 20% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[N:12][C:13]([OH:16])=[N:14][CH:15]=1)([O-:3])=[O:2].[I-].C[N+]1C=CN([C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)C=1.C(N(CC)CC)C>C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[N:14][C:13]([O:16][C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:12][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1-c1cnc(O)nc1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1ncc(-c2ccccc2[N+](=O)[O-])cn1)c1ccccc1
Yield: 31.9 %

Procedure:
A solution of 5-(2-nitrophenyl)-pyrimidin-2-ol (0.35 g, 1.61 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (0.55 g, 1.61 mmol) and triethylamine (0.22 ml, 1.61 mmol) in acetonitrile (15 ml) was heated at 50° C. for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.18 g, 32% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]2[CH2:9][CH2:8]2)=[N:5][N:6]=1.[Cl:10][C:11]1[C:16]2[O:17][C:18]3[C:27]([CH3:28])=[CH:26][C:25]([C:29]([OH:31])=[O:30])=[CH:24][C:19]=3[S:20](=[O:23])(=[O:22])[CH2:21][C:15]=2[CH:14]=[C:13]([S:32](Cl)(=[O:34])=[O:33])[CH:12]=1.N1C=CC=CC=1>C(OCC)(=O)C>[Cl:10][C:11]1[C:16]2[O:17][C:18]3[C:27]([CH3:28])=[CH:26][C:25]([C:29]([OH:31])=[O:30])=[CH:24][C:19]=3[S:20](=[O:23])(=[O:22])[CH2:21][C:15]=2[CH:14]=[C:13]([S:32](=[O:33])(=[O:34])[NH:1][C:2]2[S:3][C:4]([CH:7]3[CH2:9][CH2:8]3)=[N:5][N:6]=2)[CH:12]=1
Reactant: Nc1nnc(C2CC2)s1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Nc3nnc(C4CC4)s3)cc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Amino-5-cyclopropyl-1,3,4-thiadiazole (0.236 g, 0.126 mmol) was added to a mixture of Example 49j (0.3 g, 0.68 mmol) and pyridine (8 mL) in ethyl acetate (10 mL). The reaction mixture was stirred at room temperature for 15 h, concentrated, treated with water and extracted with n-butanol. The organic extract was washed with water, dried concentrated and purified using flash chromatography (silica gel, 4% methanol/chloroform) to obtain the title compound. Yield: 0.03 g, (8%); 1H NMR (DMSO-d6): δ 0.98 (m, 2H, CH2), 1.12 (d, 2H, CH2), 2.3 (m, 1H, CH), 2.7 (s, 3H, CH3), 5.46 (s, 2H, CH2), 7.95 (d, 1H, Ar,), 8.06 (s, 1H, Ar), 8.14 (s, 1H, Ar), 8.16 (s, 1H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)=[C:22]([CH:35]3OCCC[O:36]3)[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.Cl.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:42])[CH2:4][CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=3)=[C:22]([CH:35]=[O:36])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[CH:35]([C:22]1[CH:21]=[C:20]([O:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:42])=[O:2])=[O:41])=[CH:9][CH:10]=2)[CH2:15][CH:16]([CH3:17])[CH3:18])[CH:25]=[CH:24][C:23]=1[C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1)=[O:36]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)C)cc3)c(C3OCCCO3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CC(Oc1ccc(-c2ccc(C(C)C)cc2)c(C=O)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)C)cc3)c(C=O)c2)cc1

Procedure:
3-{4-[1-(2-[1,3]Dioxan-2-yl-4′-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (570 mg) is taken into THF (10 ml), treated with 5N HCl for 5 h, neutralfied with 5N NaOH, extracted with ethyl acetate, dried over MgSO4 and concentrated. The residue is purified by column chromatography to afford 3-{4-[1-(2-formyl-4′-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (36 mg) and 3-{4-[1-(2-formyl-4′-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic acid (228 mg). MS (ES): 502.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: Cc1ccccc1-c1cc2c(N3CCOCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C23H20ClN5O3, 449.9
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:33])[O:30][CH2:31][CH3:32]>C(Cl)Cl>[CH2:31]([O:30][C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])=[O:33])[CH3:32]
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (110 mg, 0.33 mmol) in DCM (5 ml), were added triethylamine (138 μl, 0.99 mmol) and ethyl carbonochloridate (38 μl, 0.40 mmol). The reaction was stirred at RT for 4 hours, and then solvent was evaporated. EtOAc was added, and the organic phase was washed with water and brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-(ethoxycarbonylamino)-2-phenylacetate (60 mg; 55% yield). The product was used as such in the next step.
Reaction SMILES: [CH2:1]([C:11]1[CH:31]=[CH:30][C:14]([C:15]([NH:17][C:18]2([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19]2)=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:32][I:33]>>[I-:33].[CH2:1]([C:11]1[CH:31]=[CH:30][C:14]([C:15]([NH:17][C:18]2([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:21][N+:20]([CH3:32])([CH3:23])[CH2:19]2)=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(C(=O)NC2(CC(=O)OCC)CCN(C)C2)cc1
Reactant: CI
Product: CCCCCCCCCCc1ccc(C(=O)NC2(CC(=O)OCC)CC[N+](C)(C)C2)cc1
Product: [I-]

Procedure:
According to the method described in example 2a, ethyl 2-(3-(4-decylbenzamido)-1-methylpyrrolidin-3-yl)acetate (35 mg, 0.08 mmol) was reacted with methyl iodide to give the title compound as a white solid (46 mg, quantitive). MS ESI 445.3 [M]+, calcd for [C27H45N2O3+] 445.34.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)=[O:8])=[CH:5][CH:4]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH:7]([OH:8])[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[N:20]2[CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: C1CNC1
Reactant: O=C1CCCCC1C(=O)c1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: OC(c1ccc(C(F)(F)F)cc1)C1CCCCC1N1CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-[4-(trifluoromethyl)benzoyl]cyclohexanone, 5.4 g, 0.02 mole, with 2.28 g, 0.04 mole of azetidine and 25 mg of p-toluenesulfonic acid in 50 ml of benzene was refluxed for 17 hr using a Soxhlet device containing 50 g of 3 A molecular sieves. The resulting solution was evaporated, the residue was dissolved in 75 ml of ethanol and hydrogenated in the presence of 0.5 g of platinum dioxide (PtO2) at an initial pressure of 54 psig for 1.5 hr. The mixture was filtered, cooled in ice and treated with 5.4 g of sodium borohydride (NaBH4) and stirred at room temperature for 16 hr. The mixture was then evaporated, the residue taken up in a water/diethyl ether mixture, the ether extract being separated and washed with saturated sodium chloride solution, dried with magnesium sulfate and evaporated. Trituration of the residue with diethyl ether gave 0.76 g (plus filtrate) of the N-[2-[[4 -(trifluoromethyl)phenyl](hydroxy)methyl]cyclohexyl]azetidine as a colorless solid, mp 163°-165° C., which was raised to 167°-168° C. on recrystallization from methanol. The UV λmax(ε)216-(9,550), 252(382), 258(442), 263(411), 258(307). The IR and Mass spectral analyses were consistent. The NMR (CDCl3) indicated that the product contained a mixture of two diastereoisomers. δ7.6-7.4 (m, 5H, aromatic) 5.1 (m, 1H, HC--O) 2.7 (m, 1H, CH--N) 2.2-1.9 (m, 3H, CH'C--O and C--CH2 --C of azetidine) 1.9-0.9 (m, 8H, CH2 's).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:8][CH2:7][CH2:6]2.[N+:21]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)([O-:23])=[O:22].[N+]([CH2:35][CH3:36])([O-])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:27]([C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)=[C:35]([CH3:36])[N:8]1[CH2:7][CH2:6]2
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=C1NCCc2cc(OC)c(OC)cc21
Reactant: CC[N+](=O)[O-]
Product: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2

Procedure:
Following the procedure described in Example 1, ethyl (6,7-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoate (Example III.1), 3-nitro-benzaldehyde, and nitroethane were reacted to give ethyl 8,9-dimethoxy-3-methyl-2-(3-nitrophenyl)-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylate.
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C:19](=[O:29])[CH:20]=[CH:21]3)[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.CCCCCC>CC(C)=O>[O:29]=[C:19]1[CH:20]=[CH:21][C@@:22]2([CH3:23])[C:17]([CH:16]=[CH:15][C@@H:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH:5]=[O:4])[CH3:9])=[CH:18]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.9 %

Procedure:
In 100 ml of acetone was dissolved 0.410 g (1.0 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-1,4,6-trien-3-one, followed by addition of 10 mg (0.05 mmole) of p-toluenesulfonic acid. The mixture was stirred at room temperature for 12 hours. From the reaction mixture thus obtained, the solvent was distilled off under reduced pressure and the residue was diluted with methylene chloride. The methylene chloride solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:5, v/v) to recover 0.243 g of 3-oxopregna-1,4,6-triene-20-carbaldehyde (yield: 75%).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.Cl.[Cl:9][C:10]1[CH:11]=[C:12]([OH:30])[CH:13]=[C:14]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][CH2:27][NH:28][CH2:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:15]=1.[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][O:38][CH3:39]>>[CH3:31][O:32][CH2:33][CH2:34][N:35]([CH2:36][CH2:37][O:38][CH3:39])[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:28]1[CH2:27][CH2:26][C:25]2[C:18]3[C:17]([NH:16][C:14]4[CH:13]=[C:12]([OH:30])[CH:11]=[C:10]([Cl:9])[CH:15]=4)=[N:22][CH:21]=[N:20][C:19]=3[S:23][C:24]=2[CH2:29]1)=[O:7]
Reactant: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Reactant: O=C(O)/C=C/CBr
Reactant: COCCNCCOC
Agent: Cl
Product: COCCN(C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cc(O)cc(Cl)c4)c23)C1)CCOC

Procedure:
In analogy to Example 130, the title compound was prepared from (2E)-4-bromobut-2-enoic acid (84 mg, 0.41 mmol), 3-chloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 65A (100 mg, 0.27 mmol) and bis(2-methoxyethyl)amine (58 mg, 0.43 mmol) to yield 42 mg (29%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].C(N(CC)CC)C.O>ClCCl>[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)=[O:17]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A mixture of 43.42 g (0.26 mol) of ethyl 4-aminobenzoate and 40.8 g (0.26 mol) of 2-methylbenzoyl chloride in 150 ml of dichloromethane is cooled in an ice bath and 26.56 g (0.26 mol) of triethylamine is added dropwise. After the addition, the solution is stirred at room temperature overnight. The mixture is poured into water and the organic layer separated. The organic layer is washed with water, 1N HCl, 1M NaHCO3 and dried (Na2SO4). The solvent is removed and the solid slurried with ethyl acetate and filtered to give 57 g of ethyl 4-[(2-methylbenzoyl)amino]benzoate as crystals, m.p. 110°-115° C.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13]([O:15]CC)=O)[C:9]([CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([OH:26])[CH:20]=1>C1(C)C(C)=CC=CC=1>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=[O:15])[NH:25][C:24]3[CH:19]=[CH:20][C:21]([OH:26])=[CH:22][CH:23]=3)[C:9]([CH3:18])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(O)cc1
Reactant: CCOC(=O)C1C(=O)N(c2ccccc2)N=C1C
Solvent: Cc1ccccc1C
Product: CC1=NN(c2ccccc2)C(=O)C1C(=O)Nc1ccc(O)cc1

Procedure:
The solution of 2.2 g of 1-phenyl-3-methyl-4-carbethoxy-2-pyrazolin-5-one and 1.1 g of p-aminophenol in 120 ml xylene is refluxed for one hour, and 15 ml of the solvent are distilled off gradually to remove water. The cooled mixture is filtered and evaporated, the residue crystallized from warm methanol and recrystallized from ethyl acetate, to yield the 1-phenyl-3-methyl-4-(p-hydroxyphenylcarbamoyl)-2-pyrazolin-5-one melting at 135°-140° and remelting at 225°; it contains half a mole of ethyl acetate as solvate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17](=[NH:20])[NH:18][OH:19])=[N:9]2)=[N:6][CH:7]=1.Cl.NO.[C:24]([O-:27])([O-])=O.[Na+].[Na+].[CH2:30](O)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:14])([F:16])[F:15])=[CH:11][C:10]([C:17]3[N:20]([CH3:30])[C:24](=[O:27])[O:19][N:18]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: N=C(NO)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Reactant: O=C([O-])[O-]
Reactant: CCO
Agent: Cl
Agent: NO
Agent: [Na+]
Product: Cn1c(-c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)noc1=O
Temperature: 85 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
Step-3: 1-(5-Bromopyridin-2-yl)-N-hydroxy-5-(trifluoromethyl)-1H-pyrazole-3-carboximidamide: A mixture of step-2 intermediate (150 mg, 0.473 mmol), hydroxylamine hydrochloride (82 mg, 1.183 mmol) and Na2CO3 (125 mg, 1.183 mmol) in ethanol (10 mL) was stirred at 85° C. for 6 h. Reaction mixture was cooled to room temperature and the solvent was evaporated under vacuum. Water (10 mL) was added to the obtained residue and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford 106 mg (64%) of the title compound as a white solid. 1HNMR (400 MHz, DMSO- d6) δ 9.96 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.37 (dd, J=2.0 & 8.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.23 (s, 1H), 5.93 (s, 2H); ESI-MS (m/z) 350, 352 [(MH)+, Br79,81].
Reaction SMILES: [CH3:1][C:2]1[S:6][N:5]=[N:4][C:3]=1[C:7]([O:9]CC)=O.C(Cl)(=O)C([Cl:15])=O>>[CH3:1][C:2]1[S:6][N:5]=[N:4][C:3]=1[C:7]([Cl:15])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1nnsc1C
Product: Cc1snnc1C(=O)Cl

Procedure:
Hydrolysis of ethyl 5-methyl-1,2,3-thiadiazole-4-carboxylate (D. L. Pain and R. Sleck, J. Chem. Soc., 5166 (1965)) and subsequent treatment of the acid with oxalyl chloride according to the method of Example 3 provides 5-methyl-1,2,3-thiadiazole-4-carbonyl chloride.