Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[OH-].[K+].Cl[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12](=[O:21])[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20]>C(O)C>[CH3:10][N:9]1[C:5]([OH:1])=[C:6]([C:12](=[O:21])[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[C:7]([CH3:11])=[N:8]1
Reactant: Cc1nn(C)c(Cl)c1C(=O)c1c(Cl)cccc1Cl
Reactant: O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C)c(O)c1C(=O)c1c(Cl)cccc1Cl
Yield: 48 %

Procedure:
In 5 ml. of water is dissolved 0.56 g. of potassium hyroxide and a solution of 1.52 g. of 5-chloro-4-(2,6-dichlorobenzoyl)-1,3-dimethylpyrazole in 10 ml. of ethanol is added thereto. The mixture is heated under reflux for 12 hours. After completion of the reaction, the reaction mixture is allowed to cool and extracted with benzene. An aqueous layer is separated and 2N HCl solution is added to adjust the pH to 3-4, whereby crystalline substance is separated out. The resulting crystalline substance is recovered by filtration and recrystallized from ethanol to give 0.68 g. of the desired product as colorless needles melting at 249.5°-250.5° C. Yield 48.0%.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[BrH:27].[S:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:27].[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([O:19][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:31]3[CH2:30][CH2:29][S:28][CH2:33][CH2:32]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCSCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCSCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-[4-(thiomorpholino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrobromide is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-thiomorpholinobutyric acid hydrobromide in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[S:9][C:10]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)=[CH:11][C:12]=1[CH3:13])=[O:7])C.Cl>C1COCC1.O>[Cl:30][C:25]1[CH:24]=[C:23]([C:17]2([C:19]([F:20])([F:22])[F:21])[O:16][N:15]=[C:14]([C:10]3[S:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([CH3:13])[CH:11]=3)[CH2:18]2)[CH:28]=[C:27]([Cl:29])[CH:26]=1
Reactant: CCOC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(=O)O
Temperature: 50 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
LiOH (3.2 g) is added to a solution of 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid ethyl ester (9.88 g) in a mixture of THF and water (240 ml, 9:1). After 16 hours at room temperature, LiOH (1.05 g) and THF (150 ml) was added. The reaction mixture was heated at 50° C. for 10 hours. HCl (2N) was added to the reaction mixture until pH 1-2 was obtained. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, washed with water and a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo to yield 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid (9.3 g) as brown resin. The crude product is used without further purification.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:10](=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>>[OH:12][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][C:10]([NH:16][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: O=C1CCC(c2ccccc2)O1
Reactant: CC(C)N
Product: CC(C)NC(=O)CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 100.4 %

Procedure:
A mixture of γ-phenyl-γ-butyrolactone (10.0 g, 61.7 mmol) and isopropylamine (50 ml, 587 mmol) was stirred at room temperature for approximately 26 hours. The solvent was removed under reduced pressure to give 4-hydroxy-N-isopropyl-4-phenyl-butyramide (13.71 g, 100%) as a yellow solid, mp 131-135° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:25][C:26](=[O:34])[C@H:27]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([NH:28][C@H:27]([C:26]([O:25][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
N-(tert-Butoxycarbonyl)-D-leucine (230 mg, 1.0 mmol) and benzyl-3-tert-butyl-L-alaninate hydrochloride (300 mg, 1.10 mmol) (John X. He, Wayne L. Cody, Annette M. Doherty, J. Org. Chem., 1995, 60, 8262-8266) are reacted by general procedure 6. The crude product is purified (workup method 2) by preparative HPLC (method 16), resulting in 362 mg (80% of theory) of product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:30]([CH:27]4[CH2:29][CH2:28]4)=[O:31])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)C5CC5)c4)CC3)cccc2n1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5quinolinyl)-1-perazinyl]ethyl}aniline (D6) and cyclopropanecarbonyl chloride.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([NH:17][C:18]2[N:19]=[C:20]([OH:35])[C:21]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[CH:25]=[CH:24][C:22]3[N:23]=[C:18]([NH:17][C@@H:15]([C:12]4[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=4)[CH3:16])[N:19]=[C:20]([OH:35])[C:21]=3[N:27]=2)=[CH:33][CH:32]=1
Reactant: C[C@@H](Nc1nc(O)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Nc1nc(O)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A mixture of crude (R)—N-tert-butyl-4-(1-(6-(4-fluorophenyl)-4-hydroxypyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide (670 mg), TFA (5 ml) and dichloromethane (1 ml) was stirred at room temperature overnight. Solvents were removed under vacuum. To the residue was added a mixture of acetonitrile (5 ml) and water (50 ml) with vigorous stirring whereupon some oily material was formed. The mixture was diluted by EtOAc, neutralized by adding sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried and concentrated. The residue was dissolved in EtOAc (40 ml) and dichloromethane (20 ml) was added slowly, followed by hexanes (5 ml). The resulting solid was collected to give 328 mg (R)-4-(1-(6-(4-fluorophenyl)-4-hydroxypyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide. The filtrate was concentrated and purified by reverse phase HPLC (eluting by ACN/H2O+0.1% TFA) to give 200 mg (R)-4-(1-(6-(4-fluorophenyl)-4-hydroxypyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][OH:19])[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH:18]=[O:19])[C@@H:12]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCO)[C@H]1Oc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CC=O)[C@H]1Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a solution of tert-butyl((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carbamate (250 mg, 0.613 mmol) in CH2Cl2 (6.1 mL) at 0° C. was added Dess-Martin periodinane (286 mg, 0.675 mmol). The resulting mixture was stirred at 0° C. for 2 h, quenched with sat. aqueous sodium thiosulfate (Na2S2O3; 3 mL) and sat. aqueous NaHCO3 (3 mL) solution, and then removed from the cold bath and stirred vigorously for 10 min. The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×6 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide the title compound as a fluffy white foam (255.4 mg, 98%): 1H NMR (400 MHz, CDCl3) δ 9.65 (t, J=1.7 Hz, 1H), 7.29 (dd, J=8.7, 7.4 Hz, 2H), 7.02-6.93 (m, 1H), 6.88 (d, J=7.9 Hz, 2H), 5.23-5.08 (m, 2H), 4.30-4.10 (m, 2H), 2.60 (dd, J=16.0, 5.4 Hz, 1H), 2.44 (d, J=6.4 Hz, 1H), 2.38-2.21 (m, 2H), 1.73 (ddd, J=19.5, 13.8, 9.2 Hz, 3H), 1.44 (s, 9H), 1.37-1.22 (m, 5H); 13C NMR (101 MHz, CDCl3) δ 200.78, 173.29, 158.65, 154.90, 129.80, 129.73, 121.59, 115.23, 80.63, 79.98, 74.23, 53.28, 46.09, 36.71, 33.64, 31.78, 28.33, 19.72, 18.18; ESIMS m/z 428.2 ([M+Na]+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:6]([CH:26]=1)[C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1)=[O:8].Cl.[F:33]C(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=NC=1.FC1C(N2N=CC=N2)=C(C=CC=1)C(O)=O>>[F:33][C:4]1[C:5]([N:27]2[N:28]=[CH:29][CH:30]=[N:31]2)=[C:6]([CH:26]=[CH:2][CH:3]=1)[C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][N:17]=1)=[O:8]
Reactant: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1
Agent: Cl
Agent: O=C(O)c1cccc(F)c1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cccc(F)c1-n1nccn1

Procedure:
Prepared according to the procedure for 5-chloro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 97) from (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 50 mg, 0.20 mmol) and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1293284-51-1; 42 mg, 0.20 mmol) to afford the title compound.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].ClCCl.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](Cl)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(N(CC)CC)C>[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32]([N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cl
Reactant: O=C(OCc1ccccc1)[C@@H]1CC2=C(CCCC2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 litres of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 107 ml of triethylamine and then 162 g of (2S)-2-[(tert-butoxycarbonyl)amino]propionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]propionyl}-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: C(C1C([C:9]2[N:14]=[C:13]([CH3:15])[C:12]([C:16]([C:18]3[C:19]([CH3:32])=[N:20][C:21](C4C(CC)=NC=NC=4)=[N:22][CH:23]=3)=[O:17])=[CH:11][N:10]=2)=CN=CN=1)C.[BH4-].[Na+].[CH3:35]COC(C)=O>CCO>[CH2:32]([C:19]1[C:18]([CH:16]([C:12]2[C:13]([CH3:15])=[N:14][CH:9]=[N:10][CH:11]=2)[OH:17])=[CH:23][N:22]=[CH:21][N:20]=1)[CH3:35]
Reactant: CCc1ncncc1-c1ncc(C(=O)c2cnc(-c3cncnc3CC)nc2C)c(C)n1
Reactant: CCOC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCc1ncncc1C(O)c1cncnc1C
Reaction time: 0.5 h

Procedure:
To a solution of 63 mg of (4-ethylpyrimidin-5-yl)-4-methylpyrimidin-5-yl ketone in 1 ml EtOH chilled in an ice bath was added 7.4 mg of sodium borohydride. After stirring the solution for 30 minutes, 1 ml of EtOAc was added followed by 1 ml NaH2PO4 (pH=3.0). The mixture was stirred vigorously and the aqueous extracted with EtOAc (3 times). The organic layers were combined, dried (MgSO4) and filtered through silica gel with EtOAc. The solvent was evaporated to yield 52 mg of pure 1-(4-ethylpyrimidin-5-yl)-1-(4-methylpyrimidin-5-yl)methanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:17]([NH2:19])[CH3:18]>>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[N:19][O:17][CH3:18])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CON
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: Cl
Product: CON=Cc1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
Reaction of 4-formyl-benzoic acid tert-butyl ester with methoxylamine hydrochloride as described in the preparation of compound 1-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate, 96:4) (79% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.60 (9H, s, t-Bu), 4.00 (3H, s, OCH3), 7.62 (2H, d, J=8.0 Hz, aromatics), 7.97 (2H, d, J=8.0 Hz, aromatics), 8.08 (1H, s, CH).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21]C)=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl>[Br:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: COc1cc2c(cc1Br)C(c1ccccc1Cl)=NCC(=O)N2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C1CN=C(c2ccccc2Cl)c2cc(Br)c(O)cc2N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 7.3 %

Procedure:
A solution of 1.00 g (0.0263 mole) of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Id) in 85 mL of 1,2-dichloroethane was stirred overnight with 1.053 g (0.0079 mole) of aluminum trichloride. An additional 1.00 g of aluminum trichloride was added, and the mixture stirred overnight, after which time the mixture was poured into ice water. The mixture was extracted with dichloromethane-methanol, and the organic layer washed twice with water and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to provide 0.700 g of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-hydroxy-2H-1,4-benzodiazepin-2-one (Ipp) (MH+/Z=465), which was of sufficient purity to be used in the next step.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1.CN(C=O)C.[NH2:17][C:18]1[C:19]([F:25])=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][N:28]=1>ClCCl>[CH3:38][O:37][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][C:33]=1[O:39][CH3:40])[N:30]=[CH:29][N:28]=[C:27]2[O:24][C:20]1[C:19]([F:25])=[C:18]([CH:23]=[CH:22][CH:21]=1)[NH2:17]
Reactant: Nc1cccc(O)c1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(N)c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a stirred slurry of cesium carbonate (10.25 g, 31.47 mmol) in a 9:1 mixture of THF/DMF (100 mL) at rt, was added 3-amino-2-fluorophenol (2.00 g, 15.74 mmol) in one portion. After stirring for 30 min at rt, 4-chloro-6,7-dimethoxyquinazoline (3.54 g, 15.74 mmol) was added and the reaction mixture was heated at 50° C. for 18 h. The reaction was cooled to rt, then diluted with dichloromethane. The solution was washed with water, then brine, and dried over MgSO4. Filtration followed by concentration under reduced pressure gave a solid that was triturated with a mixture of 10% dichloromethane in ethyl acetate. Filtration afforded 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (2.10 g, 42%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 6.93 (dd, J=8.4, 8.4 Hz, 1H), 6.71 (dd, J=8.4, 8.4 Hz, 1H), 6.53 (m, 1H), 5.37 (brs, 2H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:37](=[N:39]O)[NH2:38]>>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:37]1[N:39]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:27][N:38]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1ccc(F)cc1F
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccc(F)cc3F)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 47.3 (0.275 mmol) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 52.1 mg (38% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH:11]=[C:10]([CH2:13]O)[C:9]3[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[BrH:20]>>[Br:20][CH2:13][C:10]1[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[O:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:12]=2[CH:11]=1
Reactant: OCC1=Cc2c(Cl)cccc2Oc2ccccc21
Reactant: Br
Solvent: O
Product: Clc1cccc2c1C=C(CBr)c1ccccc1O2
Yield: 38.7 %

Procedure:
4.58 g (17.70 mmol) of (1-chloro-dibenz[b,f]oxepin-10-yl)-methanol are heated under reflux in 50 ml of 48% hydrobromic acid for 2 hours. The mixture is cooled, water is added and the mixture is extracted 3× with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate and concentrated. 5.57 g of crude product are obtained which becomes solid on being left to stand (3 days). Recrystallisation from tert-butyl methyl ether/hexane yields 2.205 g (6.86 mmol)=38.7% of 10-bromomethyl-1-chloro-dibenz[b,f]oxepine in the form of light-beige crystals; TLC (silica gel; ethyl acetate; UV): Rf =0.73; 1H-NMR (CDCl3, 200 MHz): 4.60 (s, 2H); 7.15-7.58 (m, 8H).
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][CH:3]=[N:2]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:45])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[C:34]([NH2:44])[CH:33]=1>CN(C=O)C.O.C(Cl)CCl>[CH3:29][O:30][C:31](=[O:45])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]([CH2:40][CH3:41])[CH2:42][CH3:43])=[C:34]([NH:44][C:7](=[O:9])[CH2:6][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:33]=1
Reactant: O=C(O)Cn1cccn1
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1N
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cn1cccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
To a solution of 1.76 g of Pyrazol-1-yl-acetic acid in 20 ml of dry DMF 2.09 g of HOAT, 3.75 g of EDC and 6.9 ml of DIPEA were added at 0° C. After 30 min 3.3 g of 3-amino-4-(1-ethyl-propylamino)-benzoic acid methyl ester were added and the reaction was stirred at rt for 16 h. The reaction was then poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. The crude product was purified by precipitation from heptane to yield 2.28 g (47%) of 4-(1-Ethyl-propylamino)-3-(2-pyrazol-1-yl-acetylamino)-benzoic acid methyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:18])[CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[C:7]([N+:19]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([NH2:19])[C:8]([N:11]([CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH3:18])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CN(C)CCCN(C)c1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCN(C)c1ccc(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(4-tert-Butyl-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (Step 2, 200 mg, 0.682 mmol) was dissolved in 7 mL MeOH. Palladium (66 mg, 0.062 mmol, 10% w/w on carbon) was added, a balloon containing hydrogen was inserted, and the reaction was stirred at RT for 18 h. The solution was then filtered through a pad of Celite and concentrated, yielding the title compound as a dark brown solid. MS (M+H)+=264; Calc'd 263.42 for C16H29N3.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH2:7].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12]>O.OC1CC(C)(C)[NH+]([O-])C(C)(C)C1>[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH:7][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: COC(CN)OC
Reactant: C=C(C)C(=O)Cl
Agent: CC1(C)CC(O)CC(C)(C)[NH+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)C(=O)NCC(OC)OC
Temperature: -10 °C
Yield: 82.4 %

Procedure:
220 g (5.5 mol) of sodium hydroxide are dissolved in 300 g of water and 700 g of ice in a 3-liter reactor having a stirrer and a cooling system. The sodium hydroxide solution is cooled to 10° C. and 526 g (5.0 mol) of aminoacetaldehyde dimethylacetal and 50 mg of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxide (radical inhibitor) are added. 548.6 g (5.5 mol) of methacrylic acid chloride are slowly added at 10° C. to the solution over a period of 3.5 hours. When the addition is complete, the pH value drops slowly to 7.2 and amine can no longer be detected by GC. The reaction mixture is extracted with 500 ml of petroleum ether, and in order to remove impurities, the aqueous phase is saturated with sodium chloride and extracted three times with 500 ml of tert-butyl methyl ether. The organic phase is dried with magnesium sulfate, filtered and concentrated using a rotary evaporator. The resulting 882.2 g of yellowish oil are slowly stirred into 2000 ml of petroleum ether at −10° C. by means of an Ultraturax. The product crystallises, and is isolated by filtration and dried. 713.8 g of methacrylamidoacetaldehyde dimethylacetal (86% of theory), melting point 30-32° C., are obtained; the product is 99.7% according to GC.