Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[C:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[C:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:19]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1C(=O)CBr
Product: CCOC(=O)n1c(C(=O)c2ncccc2CO[Si](C)(C)C(C)(C)C)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 employing 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromoacetyl-3-(tert-butyldimethylsilyloxymethyl)pyridine (step 2).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])[N:16]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:17]1[N:16]=[C:15]([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[C:24]2[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
tert-Butyl(S)-pyrrolidin-3-ylcarbamate (245 mg, 1.31 mmol) was dissolved in 1.8 mL of anhydrous CH2Cl2 and cooled to 0° C. 2-(4-Chloro-7-methylquinazolin-2-yl)phenol (300 mg, 1.1 mmol) dissolved in 1.8 mL of anhydrous CH2Cl2 was added dropwise to the mixture followed by triethylamine (134 mg, 184 μL, 1.32 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. Purification via silica gel chromatography using 10-100% ethyl acetate/hexanes gave tert-butyl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate. LC/MS: m/z 421.0 (M+H)+ at 2.84 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C([Li])CCC.F[Si:22]([CH3:25])([CH3:24])[CH3:23]>ClC1C=CC=CC=1>[CH3:23][Si:22]([CH3:25])([CH3:24])[N:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]([Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:9][CH2:8][N:7]([Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:6][CH2:5]1
Reactant: C[Si](C)(C)F
Reactant: C1CCNCCNCCNCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: Clc1ccccc1
Product: C[Si](C)(C)N1CCCCCN([Si](C)(C)C)CCN([Si](C)(C)C)CC1
Reaction time: 5.8 h

Procedure:
1,4,7-Tris(trimethylsilyl)-1,4,7-triazacyclododecane was prepared from 1,4,7-triazacyclododecane trishydrochloride with six equivalents of n-butyllithium essentially by the procedure of Example 1 (A). In a 50 ml flask a solution of 0.675 g of the tris silyl compound (distilled bulb-to-bulb at 95°-125°/0.1 mm) in 2.5 ml of chlorobenzene was frozen, evacuated, and pressured with 40 ml of phosphorus oxyfluoride gas. The flask was sealed and the mixture heated overnight at 100°. Then the mixture was refluxed under a nitrogen atmosphere for 4 hours. A sample indicated (by nmr) that two-thirds of the silyl groups had reacted. Refluxing was continued for 5.8 hours under a nitrogen pressure of 960- 1040 mm of mercury. A sample at this time showed almost complete displacement of the silyl groups as fluorotrimethylsilane. The mixture remaining (about 80-85% of the original) was concentrated under vacuum and distilled bulb-to-bulb under vacuum (0.1 mm). The fraction collected at 80°-100° oven temperature consisted of solidified condensate in the mouth of the receiver, mp 78°-86.5°. This sample (~30 mg) was used for ir and mass spectroscopy which identify this material as 13-oxo-1,4,7-triaza-13-phosphatricyclo[5.5.1.04,13 ]-tridecane. It was recrystallized in part from cyclohexane giving needles, mp 86°-87.5°.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:17][C:18]([OH:20])=O)[CH3:2].[CH:21]([NH:24][NH:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:29][CH:28]=1)([CH3:23])[CH3:22].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH2:17][C:18]([N:24]([CH:21]([CH3:23])[CH3:22])[NH:25][C:26](=[O:38])[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:31][CH:32]=2)=[O:20])=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[CH:14]=1
Reactant: CCc1ccccc1-c1cc(F)ccc1OCC(=O)O
Reactant: COCCOc1ccc(C(=O)NNC(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccc(OCCOC)cc1)C(C)C
Yield: 7.8 %

Procedure:
A solution of (2′-ethyl-5-fluoro-biphenyl-2-yloxy)-acetic acid (38 mg, 0.1395 mmol), and 4-(2-methoxy-ethoxy)-benzoic acid-N′-isopropyl hydrazide (32 mg, 0.1268 mmol) in DMF (5 mL), was treated with triethylamine (0.053 ml, 0.38 mmol), HOBT (20 mg, 0.152 mmol), and EDCI (29 mg, 0.152 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 50-100% ethyl acetate/hexanes gradient to afford the product as a white solid (5 mg, 7%). MS m/e 509.42 (M+H+)
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:33][C:34]1([C:41]2[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[CH2:35][CH2:36][CH:37]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=4)[N:18]([CH3:31])[N:17]=3)[CH2:9]2)[CH2:38][CH2:39]1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(O)C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(O)C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 60, Step B) and 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[Cl:19][CH2:20][C:21]1[C:22]([NH:34][CH2:35][CH3:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH2:32][CH3:33])=[CH:26][CH:25]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:19].[ClH:18].[CH2:32]([O:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([NH:34][CH2:35][CH3:36])[C:21]([CH2:20][C:6]1[C:7]3[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=3)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=1[OH:17])=[CH:30]2)[CH3:33]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CCNc1nc2ccc(OCC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1nc2ccc(OCC)cc2cc1Cc1c(O)nc(CC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 10 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (140 mg, 0.60 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-ethoxy-N-ethylquinolin-2-amine hydrochloride SLA 41042 (181 mg, 0.60 mmol) at RT followed by a 2 N aq. LiOH solution (0.60 mL, 1.20 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided after evaporation 33 mg of 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.05 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 41 as a yellow solid (31.4 mg, 10% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:21][C:20]2[C:19]([F:18])=[CH:26][CH:25]=[CH:24][C:23]=2[F:27])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncc(Cl)cc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
33 g of 5-chloro-2-nitropyridin-3-ol (Example 15A; 189 mmol, 1 equivalent) and 61.6 g of caesium carbonate (189 mmol, 1 equivalent) were initially charged in 528 ml of DMF, 40.4 g of 2,6-difluorobenzyl bromide (189 mmol, 1 equivalent) were added and the mixture was stirred at RT overnight. The reaction mixture was stirred into water/1N aqueous hydrochloric acid and the solid was filtered off, washed with water and air-dried. This gave 54.9 g (97% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:13]C.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1>CCOC(C)=O>[OH:13][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a vigorously stirred suspension of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (47.0 g, 238 mmol) in EtOAc (450 mL) at room temperature, anhydrous aluminum chloride (38.1 g, 286 mmol) was added in one portion. Then pyridine (77 mL, 954 mmol) was added dropwise at 45-50° C. for 30 minutes. The reaction mixture was refluxed for 2 hours and allowed to cool down to 60° C. The reaction mixture was carefully poured into ice/concentrated HCl mixture (265 mL). After stirring at 50° C. for 1 hour, the reaction mixture was cooled to 0° C. The formed precipitate was separated by filtration, washed with water, and vacuum-dried to afford 3,4-dihydroxy-5-nitrobenzaldehyde (29.4 g, 161 mmol, 67.3% yield).
Reaction SMILES: [OH:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH3:27][O:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate in DMF (2 mL) was added dropwise to a suspension of NaH (50 mg, 1.98 mmol) in DMF (5 mL) at 0° C. A solution of methyl iodide (700 mg, 5 mmol) in DMF (1 mL) was then added dropwise. The reaction mixture was stirred at 0° C. for 1 hour. The reaction was quenched with ice/saturated NH4Cl, extracted with DCM (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated to afford tert-butyl 4-((5R,7R)-7-methoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate as an oil, which was used without purification. MS (APCI+) [M+H]+ 349.0. This material was used to prepare the title compound as described analogously in Example 3, Steps 12-14, substituting the appropriate starting materials. m/z 504.3; 1H NMR (400 MHz, D2O) d ppm 8.49 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 5.16 (t, J=7.6 Hz, 1H), 4.49-3.61 (m, 10H), 3.47 (s, 3H), 3.38-3.33 (m, 3H), 2.37-1.78 (m, 6H), 1.36-1.32 (m, 2H), 1.08 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N+:17]([O-])[CH:18]=[C:19]([Cl:21])[CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([N:25](CC)CC)C.C[Si](C#N)(C)C.[OH-].[Na+]>C(#N)C.C(OCC)(=O)C>[Cl:21][C:19]1[CH:20]=[C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]([C:23]#[N:25])=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(Cl)c[n+]([O-])c1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(Cl)cnc1C#N
Temperature: 80 °C
Reaction time: 15 h
Yield: 58.1 %

Procedure:
To a stirred solution of (R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-5-chloropyridine 1-oxide (610 mg, 1.855 mmol, EXAMPLE 29 Step 2) and triethylamine (1.56 mL, 11.13 mmol) in acetonitrile was added trimethylsilyl cyanide (TMSCN) (1.24 mL, 9.28 mmol) at ambient temperature and the mixture was heated at 80° C. After being stirred at 80° C. for 15 h, the mixture was cooled to room temperature. 1.24 mL of TMSCN (9.28 mmol) and 1.56 mL of triethylamine (11.13 mmol) were added to the mixture and the mixture was heated at 80° C. further 6 h. After cooling to room temperature, the mixture was concentrated in vacuo to give a dark brown oil. The residual oil was dissolved with ethyl acetate and 2 N aq. sodium hydroxide. The mixture was extracted with ethyl acetate twice and washed with water, 2 N hydrochloric acid, and brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by silica gel column chromatography (hexane to ethyl acetate/hexane 1:4) to afford 364 mg (58%) of the title compound as a waxy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C@@H:8]([OH:10])[CH3:9].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:10][C@H:8]([C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:11])[CH3:9])(=[O:22])=[O:21]
Reactant: C[C@H](O)c1c(Cl)cncc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](OS(C)(=O)=O)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dissolve (S)-1-(3,5-dichloropyridin-4-yl)ethanol (5.02 g, 26.14 mmol) in dichloromethane (DCM, 100 mL) and cool the flask in an ice bath. Add triethylamine (TEA, 3.5 mL, 25.11 mmol) followed by the dropwise addition of methanesulfonyl chloride (2.2 mL, 28.42 mmol). Remove the ice bath and allow the reaction to warm to RT. After 4 hours, quench the reaction with water (100 mL) and separate layers. Extract the aqueous layer with DCM (50 mL) followed by 20% isopropyl alcohol (IPA)/chloroform (50 mL). Combine the organic extracts, dry over anhydrous sodium sulfate, filter and concentrate in vacuo. Yield: 7.15 g, (100%). MS (ES) m/z 270 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[C:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:25]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[C:15]3[CH2:16][CH2:17][N:18]([C:31](=[O:32])[CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH2:19][CH2:20]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: Clc1ccc2c(c1)OCc1cccnc1C2=C1CCNCC1
Reactant: O=C(O)Cc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3OCc3cccnc32)CC1

Procedure:
The title compound was prepared according to the method of Example 4 from 4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-piperidine, 3-pyridine-acetic acid hydrochloride, HOBT, EDCl and NMM in DMF. 4-(8-Chloro-5,11-dihydro[1]benz-oxepino[4,3-b]pyridin-11-ylidene)-1-(3-pyridine-acetyl)piperidine was obtained as a white foam; MS (CI, M+H)=432; anal.: found: C, 68.85; H, 5.53; N, 9.49; C25H22ClN3O2 requires: C, 69.52; H,5.13; N,9.73.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.C(=O)([O-])O.[Na+].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](ON3C(=O)CCC3=O)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl>O.O1CCCC1>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]3)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NC1CCCC(C(=O)O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CCCC(C(=O)O)C1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
3-Aminocyclohexanecarboxylic acid (10 g, 70 mmol) was added to a solution of sodium hydrogen carbonate (7.6 g, 91 mmol) in water (100 mL). A solution of 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy-2,5-pyrrolidinedione (Fmoc-OSu; 28.3 g, 84 mmol) in tetrahydrofuran (200 mL) was added. The solution was stirred at room temperature overnight and then poured into 3 M HCl (200 mL). The mixture was extracted with ethyl acetate (100 mL then 50 mL) and the combined organic layers were washed with saturated brine (3×100 mL), dried (Na2SO4), filtered, and concentrated to approximately 200 mL. Crystallization occurred on concentration. The mixture was allowed to stand overnight, then the solid was filtered off, washed with ethyl acetate and dried in a vacuum oven at 55° C. to give 3-[N-[(9H-fluoren-9-ylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid (14.66, 57%) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH3:33])[C:6]([C:8]1[S:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11](=[O:30])[C:10]=2[C:9]=1[O:31][CH3:32])=[O:7].C(N(CC)CC)C.[CH3:41][O:42][CH2:43][C:44](Cl)=[O:45]>C1COCC1.C(=O)([O-])O.[Na+]>[CH3:32][O:31][C:9]1[C:10]2[C:11](=[O:30])[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[S:20][C:8]=1[C:6]([N:5]([CH2:4][CH2:3][NH:2][C:44](=[O:45])[CH2:43][O:42][CH3:41])[CH3:33])=[O:7]
Reactant: COCC(=O)Cl
Reactant: COc1c(C(=O)N(C)CCN)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)NCCN(C)C(=O)c1sc2c(c1OC)c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a solution of the compound of Example 103 (100 mg, 0.21 mmol) and triethylamine (46 mg, 0.45 mmol) in THF (10 mL) was added methoxyacetyl chloride (25 mg, 0.23 mmol) under ice-cooling. After stirring at room temperature for 2 hr, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate; ethyl acetate to ethyl acetate/methanol=50/1) to give a white solid. Recrystallization of the white solid from ethyl acetate-hexane gave the title compound (61 mg, 56%) as a white powder.
Reaction SMILES: [N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH:17]1([Mg]Br)[CH2:19][CH2:18]1>O1CCCC1>[C:13]([O:12][C:10]([N:1]([CH:17]1[CH2:19][CH2:18]1)[NH:2][C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: Br[Mg]C1CC1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C1CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
A solution of di-tert-butyl azodicarboxylate (115 g, 500 mmol) in tetrahydrofuran (1000 mL) was added to a cooled (−78° C.) solution of cyclopropylmagnesium bromide (2 M, 1000 mL, 500 mmol) in tetrahydrofuran. The reaction mixture was stirred at −78° C. for 10 minutes, After which time it was quenched onto acetic acid (30 mL) and allowed to warm to room temperature. This mixture was partitioned between water (2000 mL) and ethyl acetate (1500 mL). The organic extract was dried over sodium sulphate, filtered, and evaporated under reduced pressure to give a solid, which was purified by column chromatography eluting with 3.33% ethyl acetate in pentane to give the title compound as a white solid (45 g, 33%). 1H-NMR (400 MHz, CDCl3): δ 0.65 (m, 4H), 1.30-1.50 (m, 18H), 2.70 (m, 1H).
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]>[Cu]Cl.O>[NH2:3][C:5]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: N
Agent: Cl[Cu]
Solvent: CO
Solvent: O
Product: Nc1c(Cl)cccc1C(=O)O
Temperature: -70 °C
Reaction time: 20 h
Yield: 80.9 %

Procedure:
70 ml of methanol was added to an autoclave, and cooled to −70° C., and 16 g (942 mmol) of a generated ammonia gas was added. 30 g (157 mmol) of 2,3-dichlorobenzoic acid and 0.78 g (7.85 mmol) of copper(I) chloride were added. The autoclave was sealed, and heated in an oil bath at 130° C. and 30 atmospheres for 20 hours. After the completion of the reaction, the autoclave was cooled to room temperature, and the reaction mixture was transferred into a reaction flask. 100 ml of water was added to the reaction solution, and the reaction solution was heated in an oil bath to 100° C. to remove the ammonia and the methanol. Then, the reaction solution was cooled to room temperature, and hydrochloric acid was added to adjust the pH value to 3. The precipitated crystals were filtered and dried to obtain 21.8 g of 2-amino-3-chlorobenzoic acid as white crystals with a yield of 81%.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:23])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(C)C.CC(OC)(C)C>[CH3:22][O:21][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:33]3[CH2:34][CH2:35][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH2:32]3)[C:9](=[O:23])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc(OC)c2c(C)c(CCOS(C)(=O)=O)c(=O)oc2c1
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4ccccc4)CC3)c(=O)oc2c1
Yield: 50 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 35) and 1-phenylpiperazine; yield 50%; m.p. 112°-114° C. (from isopropanol/TBME).