Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>ClCCl>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:15]([C:10]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
34.1 g (0.12 mol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid chloride, dissolved in 300 ml of dichloromethane, are added dropwise at 15 to 20° C. to a solution of 22.43 ml (0.11 mol) of 4-amino-1-benzyl-piperidine and 42.97 ml (0.31 mol) of triethylamine in 600 ml of dichloromethane. The mixture is stirred for 14 hours at ambient temperature. The reaction solution is diluted with 300 ml of dichloromethane and extracted with a mixture of 1N sodium hydrogen carbonate solution and 1N sodium hydroxide solution. The organic phase is dried over sodium sulphate and the solvent is eliminated. The residue is recrystallised from 650 ml ethanol.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC(N(C)C)=O.CCOC(C)=O>[C:8]([C:7]1[C:2]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:3][C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:5][CH:6]=1)#[N:9]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(Cl)c(C#N)cn1)CCC2
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(N3CCOCC3)c(C#N)cn1)CCC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N-(4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2J, 60 mg, 0.155 mmol) and morpholine (500 μl, 5.74 mmol) were dissolved in DMA (1 ml) under argon. The mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature, diluted in EtOAc and washed 2× with NH4Cl aq sat and 1× with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) followed by reverse phase chromatography (4.3 g C18 cartridge, 0.1% TFA in water/acetonitrile 90:10 to 0:100) to give the title compound as a white solid. (UPLC-MS 3) tR 1.13 min; ESI-MS 439.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1)[NH2:5].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:20])[CH3:19])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1
Reactant: Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo-5-nitroaniline (6.45 g, 29.7 mmol) was dissolved in dichloromethane (149 mL) and pyridine (2.88 mL, 35.7 mmol). The solution was cooled to 0° C. and then, acetyl chloride (2.325 mL, 32.7 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour. The reaction was diluted with water and dichloromethane and the organic phase was dried over sodium sulfate and was concentrated to dryness. N-(3-bromo-5-nitrophenyl)acetamide was isolated as a beige powder (7.86 g, 30 mmol, 100%) and was of sufficient purity to carry forward without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].[O:19]1CCC[CH2:20]1.C([Li])(CC)C.CCCCCC>O.CN(C)C=O>[CH3:1][N:2]([CH3:18])[S:3]([N:6]1[C:10]([CH:20]=[O:19])=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:4])=[O:5]
Reactant: C1CCOC1
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CN(C)S(=O)(=O)n1c(C=O)cnc1[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Imidazole (1) (20.0 g, 0.29 mol), triethylamine (41.0 mL, 0.29 mol) and N,N-dimethylsulfamoyl chloride (31.6 mL, 0.29 mol) were added to 320 mL of benzene. The reaction was stirred for 48 h at room temperature (rt) and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude product (˜0.5 mmHg, 115°-118° C.) afforded 38.7 g (76%) of a clear and colorless oil. Upon cooling the product solidifies to give white crystals (2). 1-(Dimethylsulfamoyl) imidazole (2) (18.8 g, 0.11 mol) was added to 430 mL of tetrahydrofuran (THF). The solution was cooled to −78° C. A solution of n-butyl lithium (n-BuLi) in hexane (1.6M, 70.9 mL, 0.11 mol) was added dropwise to the reaction flask. Upon completion, the reaction was stirred for 1 h at −78° C. t-Butyldimethylsilylchloride (17.8 g, 0.12 mol) in 50 mL of THF was added via cannula to the reaction. After the addition was completed the reaction mixture was warmed slowly to rt and then stirred for 24 h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane as eluant) afforded a light yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals (3). 1-Dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (3) (5.0 g, 17.3 mmol) was added to 100 mL of THF. The solution was cooled to −20° C. A solution of secondary butyl lithium (s-BuLi) in hexane (1.3M, 14.6 mL, 19 mmol) was added dropwise to the reaction flask. Upon completion the reaction was stirred for 1 h at −20° C. 8 mL of dimethylformamide (DMF) was added to the reaction and then stirred at rt for 3.5 h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane) afforded a light yellow oil. Upon cooling the product solidifies to give yellow crystals of 1-dimethylsulfamoyl-2-t-butyldimethylsilyl -5-imidazolecarboxaldehyde (4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[CH:9]=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[N:20][OH:21])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.Cl[CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.COC1C=CC2C3C(N4CCNCC4)=NC4C(C=3C(=O)C=2C=1)=CC=CC=4.C(C1OC1)Cl>>[N:25]1([CH2:24][CH2:23][O:21][N:20]=[C:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[C:17]3[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][C:5]2=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc2c(c1)C(=NO)c1c-2cnc2ccccc12
Agent: COc1ccc2c(c1)C(=O)c1c-2c(N2CCNCC2)nc2ccccc12
Agent: Cl
Solvent: ClCC1CO1
Product: COc1ccc2c(c1)C(=NOCCN1CCCC1)c1c-2cnc2ccccc12

Procedure:
9-methoxy-11H-indeno[1,2-c]quinolin-11-one O-2-(pyrrolidin-1-yl)ethyl oxime (6aa) was prepared substantially according to the procedures as set forth in the above Synthesis Example 18, except that compound 6a and 1-(2-chloroethyl)pyrrolidine·HCl were used in place of compound 5x and epichlorohydrin, respectively, giving the title compound at a yield of 56%.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])=[O:6])[CH2:2][CH:3]=[CH2:4].[CH2:22](O)[CH:23]=[CH2:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:1]([S:5]([N:8]([CH2:24][CH:23]=[CH2:22])[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])=[O:6])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCS(=O)(=O)Nc1cc(CCC)cc(C(=O)OC)c1
Reactant: C=CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCCS(=O)(=O)N(CC=C)c1cc(CCC)cc(C(=O)OC)c1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of methyl 3-[(3-buten-1-ylsulfonyl)amino]-5-propylbenzoate (D134) (1.3 g, 4.2 mmol, 1 equiv), 2-propen-1-ol (280 μl, 4.2 mmol, 1 equiv) and triphenylphosphine (1.28 g, 4.9 mmol, 1.15 equiv) in toluene (20 ml) at room temperature was slowly added diisopropyl azodicarboxylate (964 ml, 4.9 mmol, 1.15 equiv). The resulting solution was stirred at this temperature for 30 min then concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 4:1) gave methyl 3-[(3-buten-1-ylsulfonyl)(2-propen-1-yl)amino]-5-propylbenzoate (D135) (1.1 g, 75%) as a yellow oil. [M+H]+=352.1, RT=3.63 min.
Reaction SMILES: I[C:2]1[CH:31]=[CH:30][C:5]2[N:6]([CH:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[CH3:11])[C:7]([NH2:9])=[N:8][C:4]=2[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:31]=[CH:30][C:5]3[N:6]([CH:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]5[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)=[C:14]([O:28][CH3:29])[CH:13]=4)[CH3:11])[C:7]([NH2:9])=[N:8][C:4]=3[CH:3]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc(COc2ccc(C(C)n3c(N)nc4cc(I)ccc43)cc2OC)cn1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2ccc(C(C)n3c(N)nc4cc(-c5ccc(F)cc5)ccc43)cc2OC)cn1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 152.9 %

Procedure:
To a stirred solution of 5-iodo-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-2-amine (Example 3-45-6) (0.195 g, 0.37 mmol), 4-fluorophenylboronic acid (0.064 g, 0.46 mmol), and potassium phosphate tribasic (0.413 g, 1.91 mmol) in tetrahydrofuran (5 mL)/water (4 mL) was added 2nd generation XPhos precatalyst (0.015 g, 0.018 mmol). The yellow solution was degassed under vacuum/backfilled with nitrogen (×3). The mixture was heated to 60° C. After 90 min, the mixture was treated with an additional portion of boronic acid (0.030 g) and precatalyst (0.014 g), and the temperature was increased to 75° C. After a total reaction time of 150 min, the brown mixture was allowed to cool to room temperature and was diluted with water (30 mL). The mixture was extracted with dichloromethane (3×25 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 0.282 g of a brown oil. Chromatographic purification (CombiFlash, 12 g SiO2 gold column, 1-5% 2M ammonia in methanol/dichloromethane elute) afforded 0.142 g (78%) of the product as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J=2.4, 0.8 Hz, 1H), 7.68 (dd, J=8.4, 2.5 Hz, 1H), 7.62-7.52 (m, 3H), 7.23 (dd, J=8.4, 1.7 Hz, 1H), 7.17-7.06 (m, 3H), 6.96-6.88 (m, 2H), 6.81-6.79 (m, 1H), 6.78-6.74 (m, 1H), 5.58 (q, J=7.0 Hz, 1H), 5.05 (s, 2H), 4.49 (s, 2H), 3.93 (s, 3H), 3.76 (s, 3H), 1.88 (d, J=7.0 Hz, 3H) ppm; (M+1)=499.
Reaction SMILES: [OH:1][CH:2]([CH3:26])[CH:3]([CH2:11][C:12]1[O:13][C:14]([C:17](=[O:25])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)[C:4](OC(C)(C)C)=[O:5].[BH4-].[Li+].Cl>O1CCCC1>[OH:5][CH2:4][CH:3]([CH2:11][C:12]1[O:13][C:14]([C:17](=[O:25])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)[CH:2]([OH:1])[CH3:26]
Reactant: CC(O)C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C(CO)Cc1ccc(C(=O)Nc2ccccc2)o1
Temperature: 0 °C
Yield: 64.6 %

Procedure:
3.0 g of tert-butyl (2RS,3SR)-3-hydroxy-2-{5-(phenylcarbamoyl)-2-furylmethyl}butanoate [the compound prepared in Reference Example 3(2)] in 30 ml of tetrahydrofuran was stirred together with 1.09 g of lithium borohydride at room temperature for 2 hours. The reaction solution was cooled to 0° C., mixed with 2N hydrochloric acid and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure to give 1.56 g of the title compound as a colorless oily substance.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH:21]=2)[NH:16][CH:15]=1.[H-].[Na+].[CH3:34]I>CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]([CH3:34])[S:25]([C:28]([F:30])([F:31])[F:29])(=[O:27])=[O:26])[CH:21]=2)[NH:16][CH:15]=1
Reactant: CI
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(CNS(=O)(=O)C(F)(F)F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)S(=O)(=O)C(F)(F)F

Procedure:
In a similar manner to that described in Example 10(i), N-[[3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indol-5-yl]methyl]-trifluoromethanesulphonamide (1.04 g), sodium hydride (80%, 0.72 g) and methyl iodide (0.6 ml) in dimethylformamide (15 ml) gave the title compound (0.51 g) as a yellow solid m.p. 131°-3° after column chromatography on kieselgel 60 (80 g) eluted with ether/cyclohexane (4:1).
Reaction SMILES: [O:1]1[C@@H:21]2[C@:2]31[C@H:11]([C@H:12]1[C@:19]([CH3:22])([CH2:20]2)[C@@:15]([OH:23])([C:16](=[O:18])[CH3:17])[C@H:14]([CH3:24])[CH2:13]1)[CH2:10][C@H:9]([F:25])[C:8]1[C@:3]3([CH3:27])[CH2:4][CH2:5][C:6](=[O:26])[CH:7]=1.[FH:28]>>[F:25][C@@H:9]1[C:8]2[C@:3]([CH3:27])([CH2:4][CH2:5][C:6](=[O:26])[CH:7]=2)[C@:2]2([F:28])[C@H:11]([C@H:12]3[C@:19]([CH3:22])([CH2:20][C@@H:21]2[OH:1])[C@@:15]([OH:23])([C:16](=[O:18])[CH3:17])[C@H:14]([CH3:24])[CH2:13]3)[CH2:10]1
Reactant: F
Reactant: CC(=O)[C@@]1(O)[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Product: CC(=O)[C@@]1(O)[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C

Procedure:
The epoxide ring of the 9β,11β-epoxy-6α-fluoro-17α-hydroxy-16α-methyl-4-pregnene-3,20-dione is opened by means of hydrogen fluoride, and 6α,9α-difluoro-11β,17 -dihydroxy-16α-methyl-4-pregnene-3,20-dione is obtained. The conditions under which this reaction step is performed are also conventional (J. Fried et al. Organic Reactions in Steroid Chemistry, van Nostrand Reinhold Co., New York et al., Vol. 1, 1972, 425 ff).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][O:6][C:7]([C:9]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC(C)C)=O)=C(C)[NH:13][C:14]=1[CH3:15])=[O:8].C(O)C>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][O:6][C:7](=[O:8])/[CH:9]=[C:14](\[NH2:13])/[CH3:15]
Reactant: CC1=C(C(=O)OCc2ccc(Cl)c(Cl)c2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Solvent: CCO
Solvent: CC(C)O
Product: C/C(N)=C/C(=O)OCc1ccc(Cl)c(Cl)c1
Yield: 75 %

Procedure:
Analogously to Example 1 eating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid isopropyl ester and 75 mmols of β-aminocrotonic acid 3,4-dichlorobenzyl ester in 120 ml of isopropanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3, 4-dichlorobenzyl ester of melting point 155° C (from ethanol).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CNCCN2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCNc2ccccc2C1
Temperature: 0 °C
Yield: 83 %

Procedure:
2,3,4,5-Tetrahydro-1H benzo[e][1,4]diazepine (5 g, 33.7 mmol) was dissolved in THF (168.5 mL and cooled to 0° C. with an ice bath. Hunig's base (8.81 mL, 50.6 mmol) and benzyl chloroformate (5.30 mL, 37.1 mmol) was added dropwise with stirring. After 7 hours stirring, THF was removed, and water and ethyl ether were added to the flask. The reaction mixture was extracted with diethyl ether (4×), and the combined organic extracts were washed with aqueous sodium bicarbonate (1×) and brine (1×). The organic extracts were then dried with magnesium sulfate, filtered and concentrated to give a yellow oil. Further purification (25:75 ethyl acetate/hexane, then 30:70 ethyl acetate/hexane) yielded 7.9 g of desired product (83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([N:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[Si]([C:25]#[N:26])(C)C.O>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:7][CH:8]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[C:25]#[N:26])=[CH:19][CH:20]=1
Reactant: COc1ccc(N=Cc2ccc(S(C)(=O)=O)cc2)cc1
Reactant: C[Si](C)(C)C#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(NC(C#N)c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 65.1 %

Procedure:
1.48 g (5.1 mmol) of 4-methoxy-N-(4-methylsulfonylbenzylidene)aniline [prepared as described in step (i) above] were suspended in 15 ml of anhydrous tetrahydrofuran, and 0.80 ml (6.0 mmol) of 95% trimethylsilyl cyanide and 0.85 g (6.0 mmol) of zinc chloride were added to the resulting suspension at 0° C., whilst stirring. The temperature of the reaction mixture was then allowed to return to room temperature, and the mixture was stirred overnight. At the end of this time, water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous sodium sulfate, after which it was concentrated by evaporation under reduced pressure and the crystals which precipitated were collected by filtration, to give 1.05 g (yield 65%) of the title compound as a slightly yellow powder.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH:5](=[O:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Cl-].[NH4+]>O1CCCC1>[CH2:1]=[CH:2][CH:5]([OH:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C=C[Mg]Br
Reactant: CCCCCCCCCCC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)CCCCCCCCCC
Reaction time: 6 h

Procedure:
To a solution of vinyl magnesium bromide in tetrahydrofuran (1M, 82.0 mL) at 0° C. was added a solution of undecanal i (7.00 g, 41.1 mmol) in tetrahydrofuran (25 mL) in about 10 min. After 6 h at 0° C., saturated ammonium chloride solution (50 mL) was added. The two layers were separated. The water layer was extracted with ether (2×50 mL). The combined organic solutions were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate in hexane) to give 7.94 g (98%) of i-a as a colorless oil: IR (neat) 3409, 3079, 1644, and 1463 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ5.80 (ddd, 1H, J=6.3, 10.7, and 17.2 Hz, CH=CH2), 5.55 (dd, 1H, J=17.2 and 1.4 Hz, CH=CH2), 5.05 (dd, 1H, J=10.7 and 1.4 Hz, CH=CH2), 3.99 (q, 1H, J=6.2 Hz, CHOH), 2.58 (br s, 1H, OH), 1.46-1.22 [m, 18H, C(4-12)H2 ], and 0.83 (t, J=6.4 Hz, CH2CH3); 13C NMR (CDCl3, 75.5 MHz) δ141.61, 114.50, 73.33, 37.24, 32.12, 29.83, 29.55, 25.57, 22.87, and 14.26.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]3[CH2:17][CH:18]([CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25]([C:28]5[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=5)[CH2:24][CH2:23]4)[O:19][C:14]4[C:15]3=[C:10]([C:11]([O:35]C)=[CH:12][CH:13]=4)[C:9]=2[CH3:37])=[CH:4][CH:3]=1.B(Br)(Br)Br>>[OH:35][C:11]1[C:10]2[C:9]([CH3:37])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[N:16]3[CH2:17][CH:18]([CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([C:28]5[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=5)[CH2:26][CH2:27]4)[O:19][C:14]([C:15]=23)=[CH:13][CH:12]=1
Reactant: COc1ccc2c3c1c(C)c(-c1ccc(O)cc1)n3CC(CCN1CCN(c3cc(C)ccn3)CC1)O2
Agent: BrB(Br)Br
Product: Cc1ccnc(N2CCN(CCC3Cn4c(-c5ccc(O)cc5)c(C)c5c(O)ccc(c54)O3)CC2)c1
Yield: 30.9 %

Procedure:
0.1 g of 2,3-dihydro-5-(4-hydroxyphenyl)-7-methoxy-6-methyl-2-[2-(4-(4-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrrolo[1,2,3-de]-1,4-benzoxazine (preparation according to Example 3) was demethylated by treatment with boron tribromide according to the method described in Example 2. 0.03 g of the title compound was obtained as a white powder having a melting point of 250° C. (decomposition).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH2:28])=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=23)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH:28][C:9](=[O:11])[CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=23)=[CH:15][CH:14]=1
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Product: O=C(Cc1ccccn1)Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Yield: 45.1 %

Procedure:
2-Pyridylacetic acid hydrochloride (44 mg, 0.25 mmol) and the product from Example 99A (62 mg, 0.25 mmol) were processed as described in Example 98 to afford 41 mg (45%) of the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 8.85 (dd, J=7.0, 1.7 Hz, 1H), 8.55 (dd, J=4.1, 1.7 Hz, 1H), 8.47-8.53 (m, 1H), 7.77-7.86 (m, 1H), 7.68-7.71 (m, 2H), 7.40-7.48 (m, 1H), 7.31-7.40 (m, 3H), 7.05 (dd, J=7.0, 4.1 Hz, 1H), 3.97 (s, 2H); MS (ESI) m/z 364 (M+H)+; Anal. calculated for C19H14ClN5O: C, 62.73; H, 3.88; N, 19.25. Found C, 62.65; H, 3.65; N, 19.19.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16](OCC)=[O:17])=[CH:13][C:12]=2[CH:21]=1.O.[OH-].[Na+]>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([CH2:16][OH:17])=[CH:13][C:12]=2[CH:21]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.0 mL (7.00 mmol) 1 M lithium aluminium hydride solution in THF is slowly added dropwise at −5° C. to a solution of 3.70 g (13.8 mmol) ethyl 5-bromo-benzofuran-2-carboxylate in 50 mL THF. The reaction solution is heated to RT and then cooled again to 10° C. Another 0.7 mL (0.70 mmol) 1 M lithium aluminium hydride solution in THF are added dropwise and the reaction is stirred for 1 h at RT. 1.0 mL water, 1.0 mL 15% NaOH and finally 3.0 mL water are added successively to the reaction mixture and the insoluble precipitate is filtered off. The organic phase is dried over MgSO4, filtered through activated charcoal and the solvent is eliminated i.vac.