Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][O:28][CH3:29])[CH:21]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([C:21]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][O:28][CH3:29]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COCOc1ccc(C=O)cc1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCOc1ccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1CCO
Temperature: 150 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A mixture of 2-amino-4,6-dimethoxy-benzamide (0.25 g, 1.27 mmol), 3-(2-hydroxy-ethyl)-4-methoxymethoxy-benzaldehyde (0.268 g, 1.27 mmol), sodium hydrogensulfite (0.146 g, 1:4 mmol) and p-toluenesulfonic acid (0.025 g, 0.127 mmol) in N,N-dimethyl acetamide (8 mL) was stirred at 150° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solvent evaporated under reduced pressure. Water (70 mL) was added to obtain a solid. The yellow solid was filtered off, washed with water and dried under vacuum to provide crude 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.182 g, 36.7%) which was used as such in the next step. A solution of 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.18 g), 50% acetic acid solution (4 mL) and catalytic amount of concentrated sulfuric acid (0.02 mL) was heated at 70° C. for 2.5 h. After cooling to room temperature the reaction mixture was diluted with water (30 mL) to obtain a solid. The solid was filtered off, washed with water and dried under high vacuum to provide crude solid (0.135 g, 85%). The crude was purified by flash column chromatography to give pure 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.035 g. 8% over 2 steps). Selected data: MS (ES) m/z: 343.0; MP 249-250.3° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl.CCOC(C)=O>[C:26]([Si:23]([CH3:25])([CH3:24])[O:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])([CH3:29])([CH3:28])[CH3:27]
Reactant: CON(C)C(=O)c1cc(O)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
To an ice-cold suspension of 3-hydroxy-5-trifluoromethyl-benzoic acid (1.0 mg, 4.85 mmol) and N,O-dimethylhydroxylamine hydrochloride (520 mg, 5.33 mmol) in CH2Cl2 (20 mL) was added N-methylmorpholine (586 μl, 5.33 mmol). The mixture was stirred for 5 minutes, to which were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.05 g, 5.33 mmol). The mixture was stirred for 3 hours at room temperature, and then diluted with EtOAc. The organic layer was washed with 1N HCl, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was vacuum-dried to give the 3-hydroxy-N-methoxy-N-methyl-5-trifluoromethyl-benzamide. To a suspension of 3-hydroxy-N-methoxy-N-methyl-5-trifluoromethyl-benzamide (13.7 g, 44.8 mmol) and imidazole (495 mg, 7.27 mmol) in CH2Cl2 (20 mL) was added portionwise tert-butyldimethylsilyl chloride (877 mg, 5.82 mmol) at 0° C. The mixture was stirred for 3 hours at room temperature, and then diluted with EtOAc. The organic layer was washed with 1N HCl, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 3-(tert-butyl-dimethyl-silanyloxy)-N-methoxy-N-methyl-5-trifluoromethyl-benzamide (1.71 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[NH:7][CH:8]=[CH:9][C:10]=2[CH:11]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[N:7][C:6]=2[Cl:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2cc(Br)cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1nccc2cc(Br)cnc12
Temperature: 130 °C
Yield: 67.8 %

Procedure:
3-Bromo-7H-[1,7]naphthyridin-8-one (1.5 g, 6.67 mmol) was suspended in toluene (20 ml). DIPEA (3.5 ml, 20 mmol) and POCl3 (1.8 ml, 20 mmol) were added and the reaction mixture was heated to 130° C. for 36 h. The reaction mixture was cooled to rt and partitioned between water (75 ml) and EtOAc (150 ml). The phases were separated and the aq phase was extracted twice with EtOAc (25 ml). The combined organic layer was washed with NaHCO3 solution and brine, treated with MgSO4 and filtered. The filtrated was concentrated to give the desired product as a beige solid (1.1 g, 4.52 mmol).
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])[CH:15]=[CH:14]3)=[N:3][CH:2]=1.Br[CH2:34][C:35]([NH2:37])=[O:36]>CN(C=O)C>[F:32][C:29]([F:31])([F:30])[C:25]1[CH:24]=[C:23]([NH:22][C:20]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:4]4[C:5]5[CH2:9][N:8]([CH2:34][C:35](=[O:36])[NH2:37])[CH2:7][C:6]=5[N:1]=[CH:2][N:3]=4)=[CH:19][CH:18]=3)[CH:14]=[CH:15]2)=[O:21])[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CNC4)ccc21
Reactant: NC(=O)CBr
Solvent: CN(C)C=O
Product: NC(=O)CN1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2C1
Reaction time: 1 h

Procedure:
5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide (217 mg, 0.494 mmol) is dissolved in DMF (5 mL) and TEA (160 μl, 1.15 mmol) is added followed by 2-bromoacetamide (250 mg, 1.81 mmol). The solution is stirred at it for 1 h. The reaction is concentrated and the residue absorbed onto silica gel and separated via FCC (0-10%, 10% NH4 in MeOH:DCM) to obtain 5-(6-carbamoylmethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 497.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 10.38 (br. S., 1H) 8.58 (s, 1H) 8.27 (d, J=8.84 Hz, 1H) 8.09-8.13 (m, 2H) 7.96 (s, 1H) 7.65 (t, J=8.08 Hz, 1H) 7.48-7.51 (m, 2H) 7.38 (br. S., 1H) 7.09-7.17 (m, 2H) 6.80 (d, J=3.03 Hz, 1H) 4.12 (dd, J=10.61, 2.02 Hz, 4H) 3.38 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Reactant: COc1ccc(B(O)O)cc1
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3)cccc2c1N
Yield: 70.2 %

Procedure:
Using method F, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (178 mg, 0.50 mmol) and 4-methoxyphenylboronic acid (303 mg, 2.00 mmol) were reacted (reflux 14 hours) to afford the title compound (118 mg, 70% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.58 (bm, 1H), 7.69-7.83 (m, 3H), 7.62 (d, J=8.9 Hz, 2H), 7.05 (d, J=8.9 Hz, 2H), 3.87 (s, 3H), 3.45 (apparent q, J=6.6 Hz, 2H), 1.65 (apparent sextet, J=7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH:12]=[C:11]([Cl:24])[C:10]=1[F:25])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH:12]=[C:11]([Cl:24])[C:10]=1[F:25]
Reactant: CN1CCN(C(=O)c2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cc(Cl)c(F)c(CN)c2)CC1

Procedure:
was prepared according to Scheme C3 (step B) from [3-chloro-2-fluoro-5-(4-methyl-piperazine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester (165 mg, 0.43 mmol) and TFA (2 mL) in CH2Cl2. MS (LC-MS): 286.0 [M]+; tR (HPLC conditions c): 1.47 min.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C(OCC)(=O)C>C1COCC1>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][O:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)=[CH:20][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(C#N)cc2)CC1
Temperature: 25 °C

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil; 490 mg, 12.2 mmol) in THF (10 mL) was added a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.46 g, 12.2 mmol) in THF (2 mL) at rt. The reaction mixture was stirred at rt for several minutes and then heated to reflux for 15 min. After cooling to rt 4-(bromomethyl)benzonitrile (2.00 g, 10.2 mmol) was added, and the reaction mixture was stirred at rt over night. Ethyl acetate was added and the mixture was washed with water. The organic layer was dried with anhydrous magnesium sulfate and filtered. The solvent was removed and the crude product was used as such for Step 2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10]
Reactant: Cc1cc(O)cc(C)c1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(OC(=O)C(C)(C)C)cc(C)c1O
Yield: 61 %

Procedure:
By using 6.90 g of 2,6-dimethylbenzene-1,4-diol, 6.63 g of pivaloyl chloride, 11.85 g of pyridine and 60 ml of dichloromethane, reaction and purification were carried out in a similar manner to that described in Reference Example 9, whereby 6.77 g of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7](=O)[N:6]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[C:5]2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:4]=2[O:3]1.B.CO.Cl>O1CCCC1>[OH:11][CH:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][N:6]1[C:5]2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:4]=2[O:3][C:2]([CH3:25])([CH3:1])[CH2:7]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2N(CC(=O)c2ccccc2)C1=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CN(CC(O)c2ccccc2)c2cc([N+](=O)[O-])ccc2O1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 115.4 %

Procedure:
In an argon gas stream, 1.5 g of 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-4-phenacyl-2H-1,4-benzoxazine was added to 30 ml of a 1.0 M solution of borane in tetrahydrofuran at 0°-10° C. The above solution was stirred at 70° C. for 1 hour, at the end of which time 5.6 ml of methanol was gradually added. After stirring at 70° C. for 15 minutes, 5.6 ml of concentrated hydrochloric acid was added and the mixture was further stirred at 70° C. for 1 hour. The solvent was then distilled off and the residue was diluted with 30 ml of water, made alkaline with potassium carbonate, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-n-hexane) to give 1.67 g of 3,4-dihydro-4-(2-hydroxy-2-phenylethyl)-2,2-dimethyl-6-nitro-2H- 1,4-benzoxazine as oil.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH:34]1[CH:39]=[N:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[N:38]1[CH:39]=[CH:34][CH:35]=[C:36]([CH2:40][NH:41][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([C:21]3[CH:20]=[CH:19][C:18]4[N:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:33])[F:32])=[O:6])[CH:9]=5)[CH:15]=[N:16][C:17]=4[CH:22]=3)=[CH:31][CH:30]=2)[CH:37]=1
Reactant: NCc1cccnc1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4ccc(C(=O)O)cc4)ccc32)c1
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4ccc(C(=O)NCc5cccnc5)cc4)ccc32)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 7 starting from 4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl)-amino)phenyl]-1H-benzimidazol-5-yl}benzoic acid and picolamine (Aldrich Cat. No. A65409). LCMS (M+H)+: m/z=545.2.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][CH:12]([C:17]1[C:18]([CH:36]([CH3:38])[CH3:37])=[N:19][C:20]2[C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][CH2:24][C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:13]([O:15][CH3:16])=[O:14])([CH3:10])([CH3:9])[CH3:8].[C:39]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:39]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:44]=[CH:43][C:42]([N:23]2[CH2:22][C:21]([CH3:35])([CH3:34])[C:20]3[N:19]=[C:18]([CH:36]([CH3:38])[CH3:37])[C:17]([CH:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[C:13]([O:15][CH3:16])=[O:14])=[C:26]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:25]=3[CH2:24]2)=[CH:41][CH:40]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(c1ccc(-c3ccccc3)cc1)CC2(C)C
Reaction time: 0.08 h
Yield: 84.8 %

Procedure:
A mixture of Cu(OAc)2 (16.42 mg, 0.090 mmol) and pyridine (7 μl, 0.09 mmol) in CH2Cl2 (1 mL) was stirred for 5 min. Added to this were methyl 2-(tert-butoxy)-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 5) (20 mg, 0.045 mmol), 4-biphenylboronic acid (17.90 mg, 0.09 mmol) and 34 mg molecular sieves. After stirring uncovered for 18 h, the mixture was adsorbed directly onto silica gel and was purified by flash column chromatography (Biotage; 0%-50% EtOAc/hexane) to give methyl 2-(6-([1,1′-biphenyl]-4-yl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetate (22.7 mg, 84% yield) as a colorless oil. LCMS (M+H) calcd for C38H44FN2O3: 595.33. found: 595.4. 19F NMR (500 MHz, Methanol d4) δ ppm: −113.055.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)NC
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (0. 19 g ;0.80 mmol) was dissolved in methylene chloride (1 0 mL). 1-Hydroxy-7-azabenzotriazole (0.108 is g; 0.795 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.17 g; 0.87 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3(1-naphthyl)propionamide (0.32 g; 0.80 mmol) was dissolved in methylene chloride (10 mL) and added. Diisopropylethylamine (0.14 mL; 0.80 mmol) was added. The reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (5 mL) was added. The reaction mixture was washed with water (30 mL), an aqueous solution of sodium hydrogen sulfate (10%; 30 mL), an aqueous solution of sodium hydrogen carbonate (saturated; 30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3×30 cm) using ethylacetat/methylene chloride 1:1 as eluent to afford 0.26 g of ((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert butylester.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:9](=O)[CH2:10][CH2:11][CH2:12][CH3:13]>C(O)(=O)C>[CH:9](=[C:2]1/[C:1](=[O:6])[CH2:5][CH2:4][CH2:3]/1)\[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C1CCCC1
Reactant: CCCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCC/C=C1\CCCC1=O
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A stirred solution of 42.0 grams (g) (0.5 mole) of cyclopentanone in 80 milliliters (ml) of 1 percent (%) NaOH was treated with 21.5 g (0.25 mole) of n-pentanal at about 30 degrees Celsius (°C.). After stirring for about 2 hours, the solution was neutralized with 36% acetic acid, then extracted with three 30 ml portions of benzene. Then 1.0 ml of phosphoric acid was added to the combined extracts. After the resulting mixture was refluxed through a condenser equipped with a Dean-Stark trap for about 2 hours, the solvent was removed on a rotary evaporator to give an oil residue, which was subjected to distillation to give 28.5 g of 2-(E)-pentylidene cyclopentanone as a yellowish liquid. The boiling point of this intermediate compound was determined to be 98°-102° C. at a pressure of 6 millimeters (mm) mercury (Hg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].Cl.[N:20]1([C:26]2[O:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[N:20]1[CH2:21][CH2:22][N:23]([C:8]([C:7]2[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:10])[CH2:24][CH2:25]1
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3ccccc3o2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example 2.4) and 2-piperazin-1-yl-benzoxazole hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate) to yield the title compound as a slightly yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[C:18](OC)(OC)(OC)[CH:19]([CH3:21])[CH3:20]>C(O)(=O)C>[CH3:11][N:10]1[CH:9]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:18]1[CH:19]([CH3:21])[CH3:20]
Reactant: COC(OC)(OC)C(C)C
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Solvent: CC(=O)O
Product: Cc1ccsc1C1Cc2ccccc2N=C(C(C)C)N1C
Yield: 26.5 %

Procedure:
A solution of 5.86 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 19.56 g of trimethyl orthoisobutyrate was treated rapidly with 7.94 ml of glacial acetic acid. The solution was refluxed for 8 hours under nitrogen and concentrated on a rotary evaporator at 40° C. The residual oil was acidified with 10% hydrochloric acid solution and extracted with ether (3×100 ml). The aqueous phase was basified with 10% sodium hydroxide solution and extracted with dichloromethane (3×100 ml). The organic phases was dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Purification was accomplished by HPLC (Water's Associates Prep LC/System 500A, silcia gel, utilizing methanol followed by 2% triethylamine in methanol as successive eluents). Concentration of the appropriate fractions yielded 1.88 g of 4,5-dihydro-3-methyl-2-(1-methylethyl)-4-(3-methyl-2-thienyl)-3H-1,3-benzodiaze pine as an oil. The oil was treated with ethereal hydrogen chloride and the resulting precipitate was triturated with ether to yield 1.80 g of 4,5-dihydro-3-methyl-2-(1-methylethyl)-4-(3-methyl-2-thienyl)-3H-1,3-benzodiazepine hydrochloride, mp 240.5°-241.0° C.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.O>[C:21]1([CH2:27][C:28]([O:20][C:9]2[CH:8]=[CH:7][C:6]3[C@@H:5]4[C@H:14]([C@H:15]5[C@@:2]([CH2:3][CH2:4]4)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]5)[CH2:13][CH2:12][C:11]=3[CH:10]=2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Solvent: c1ccncc1
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(OC(=O)Cc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O

Procedure:
Oestrone (2 g.) in pyridine (10 ml.) was treated for three days at room temperature with phenylacetyl chloride (3 ml.). The mixture was diluted with water (50 ml.) and the product extracted with ether (50 ml.) containing a little chloroform. The extract was washed with water (50 ml.) then 2N-sulphuric acid (25 ml.) then water again (50 ml.) and the solvent was evaporated in vacuo. Filtration of the residue in methylene chloride through a short Florisil column and crystallisation from light petroleum (b.p. 40°/60°)-ether gave the title compound in two crops (total 1.54 g., 54%), m.p. 114°-116°.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19](O)=[O:20])=[O:5].[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:16])([CH3:17])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([NH:34][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:20])=[O:5]
Reactant: CC(C)CN
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Product: CC(C)CNC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 45A and commercially available isobutylamine using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 0.85 (d, J=6.8 Hz, 6H), 1.45 (s, 6H), 1.48 (s, 6H), 1.76 (sept, J=6.8 Hz, 1H), 2.99 (t, J=6.4 Hz, 2H), 7.67-7.81 (m, 3H), 8.05 (t, J=5.9 Hz, 1H), 11.49 (br s, 1H). MS (ESI+) m/z 487 (M+H)+. Anal. calcd. for C23H26F4N2O3S: C, 56.78; H, 5.39; N, 5.76. Found: C, 57.06; H, 5.57; N, 5.68.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([NH:15][NH2:16])[CH:8]=1)(=[O:6])=[O:5])[CH3:2].[CH2:19]([CH2:21][CH2:22][CH2:23][C:24](CC([O-])=O)=[O:25])[CH3:20]>>[CH2:17]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([N:15]2[C:24](=[O:25])[CH2:23][C:22]([CH2:21][CH2:19][CH3:20])=[N:16]2)[CH:8]=1)(=[O:5])=[O:6])[CH3:18]
Reactant: CCCCCC(=O)CC(=O)[O-]
Reactant: CCN(CC)S(=O)(=O)c1ccc(OC)c(NN)c1
Product: CCCC1=NN(c2cc(S(=O)(=O)N(CC)CC)ccc2OC)C(=O)C1

Procedure:
From the reaction of N,N-diethyl-3-hydrazino-4-methoxybenzenesulfonamide and ethylbutyrylacetate, N,N-diethyl-3-(4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-4-methoxybenzenesulfonamide is obtained. Subsequent reaction with 2-ethylaniline yields N,N-diethyl-3-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-4-methoxybenzenesulfonamide, oil