Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.[C:24]([O:39][CH3:40])(=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O-])=[O:36]>CCOCC>[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:36])([O:39][CH3:40])=[O:38]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCC(=O)OC
Reaction time: 0.33 h
Yield: 83.1 %

Procedure:
To a stirred, ice-cold solution of 0.89 g (4.0 mM) amine (4) and dried triethylamine (1.2 mL) in dry ether (40 mL) is added dropwise over ca. 4 minutes a solution of acid chloride (7) (1.04 g, 4.6 mM) in 20 mL of dry ether. The resultant mixture is allowed to stir cold for 20 minutes, and then at room temperature overnight. After filtering off the triethylamine hydrochloride, the ether filtrate is concentrated in vacuo and the residue chromatographed on an 82 g silica gel column using 20% ethyl acetate/hexane as eluant to give 1.49 g (85%) of (8) as a waxy solid.
Reaction SMILES: Cl([O-])=O.[Na+].C(O)(=[O:7])C.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(OCC)(=O)C>[O:7]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 131.1 %

Procedure:
To a 1000 mL four-necked flask equipped with a mechanical stirrer, a dropping funnel and a thermometer, 496.8 g (1.37 mole) of 25% sodium chlorite aqueous solution, and then 26 mL (0.46 mole) acetic acid were slowly added. The pH in the reaction system was pH 4.4. Furthermore, 100 g (0.62 mole) of diethyl malonate was slowly added under room temperature, and then the mixture was stirred under room temperature for 3 hours, and then 490 mL ethyl acetate was added to the reaction system to separate the liquids. The organic layer was separated, and ethyl acetate was distilled off under reduced pressure. Toluene was added thereto to perform azeotropic dehydration and the toluene was distilled off under reduced pressure, to give 105 g of diethyl ketomalonate as an oily substance (97 yield rate).
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4](=[O:31])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].C(N[C:37]1[CH:42]=CC=[CH:39][CH:38]=1)C>>[CH2:32]([N:3]([C:1]1[CH:39]=[CH:38][CH:37]=[CH:42][CH:2]=1)[C:4](=[O:31])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:10])=[O:11])=[O:7])[CH3:33]
Reactant: CCN(CC)C(=O)C(Cc1ccc(OC)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CCNc1ccccc1
Product: CCN(C(=O)C(Cc1ccc(OC)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Yield: 75.2 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (550 mg) obtained in Example 112 (4) and N-ethylaniline (161 mg). This was purified by silica gel column chromatography to give the title compound (456 mg) as a white powder.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[F:34][C:35]1[C:43]2[CH:42]=[C:41]([C:44](=[O:47])[CH2:45][CH3:46])[S:40][C:39]=2[CH:38]=[CH:37][CH:36]=1>O1CCCC1>[Br:1][CH:45]([CH3:46])[C:44]([C:41]1[S:40][C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([F:34])[C:43]=2[CH:42]=1)=[O:47]
Reactant: [Br-]
Reactant: CCC(=O)c1cc2c(F)cccc2s1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(Br)C(=O)c1cc2c(F)cccc2s1
Temperature: 0 °C
Reaction time: 5 h
Yield: 154.4 %

Procedure:
Phenyltrimethylammonium tribromide (0.98 g) was added in portions under nitrogen at 0° C. over 10 minutes to a stirred solution of 1-(4-fluorobenzo[b]thiophen-2-yl)propan-1-one (0.54 g) in tetrahydrofuran (15 ml) then the mixture was stirred at 0° C. for 5 hours. Further phenyltrimethylammonium tribromide (0.49 g) was added, and the mixture was stirred at 0° C. for 3 hours then allowed to stand at ambient temperature for 12 hours. Further phenyltrimethylammonium tribromide (0.49 g) was added, the mixture was stirred at ambient temperature for 3 hours, then it was filtered through a bed of silica. The solvent was removed in vacuo to give 2-bromo-1-(4-fluorobenzo[b]thiophen-2-yl)propan-1-one (0.67 g) as a colourless solid which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[OH:23].[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH2:35][C:33]2[CH:32]=[CH:31][C:28]3[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=3[N:34]=2)[C@H:3]([OH:23])[CH2:4]1
Reactant: N[C@H]1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)C[C@H]1O
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C1COc2ccc(CN[C@H]3CCN(CCn4c(=O)ccc5c(F)cc(F)cc54)C[C@H]3O)nc2N1
Yield: 70.9 %

Procedure:
Cis(±)1-{2-[4-amino-3-hydroxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one (175 mg, 0.54 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (96 mg, 0.54 mmol) and sodium triacetoxy borohydride (344 mg, 1.6 mmol) were reacted as described for Example 1 to give 186 mg (71%) of the free base of the product as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([O:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[CH:5]=[CH:6][CH:7]=2)=[N:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C(Nc1cccc(O)c1)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1)c1cccc(C(F)(F)F)c1
Yield: 83.8 %

Procedure:
In the same method as in Example C1(v) and using N-(3-hydroxyphenyl)-3-(trifluoromethyl)benzamide (5.00 g, 17.7 mmol), 2-chloro-5-nitropyridine (2.81 g, 17.7 mmol), potassium carbonate (7.37 g, 30.6 mmol) and N,N-dimethylformamide (150 mL) as starting materials, the title compound (5.98 g, 83%) was obtained as a pale-brown powder.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:43])[CH2:15][C@@H:16]([C:22]1[CH:42]=[CH:41][C:25]([O:26][CH2:27][C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)C1C=CC=CC=1.[OH:44]O.[Li+].[OH-].Cl>C1COCC1.O>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][O:26][C:25]1[CH:41]=[CH:42][C:22]([C@@H:16]([C:17]2[CH:21]=[CH:20][O:19][N:18]=2)[CH2:15][C:14]([OH:44])=[O:43])=[CH:23][CH:24]=1)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: OO
Reactant: CC(C)(C)C(=O)Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cccc(COc2ccc([C@H](CC(=O)O)c3ccon3)cc2)c1
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To a solution of the oxazolidinone 30.1 (62.0 mg, 0.107 mmol) dissolved in THF (10 mL), was added a 30% hydrogen peroxide solution (0.120 mL, 1.07 mmol) followed by a 2M LiOH solution (0.266 mL, 0.533 mmol). The resulting slurry was stirred for five hours. The reaction mixture was diluted with water and acidified with hydrochloric acid to a pH ˜3. The mixture was then extracted with EtOAc (1×50 mL), and the organic layer was washed with acidic sodium sulfite solution (2×30 mL) and brine (1×30 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 30 (29.0 mg). MS ESI (pos.) m/e: 423.1 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.32 (1H, d, J=1.6 Hz), 7.92 (1H, br. s.), 7.61 (1H, s), 7.42 (1H, d, J=7.8 Hz), 7.22 (1H, t, J=7.8 Hz), 7.12 (2H, d, J=9.0 Hz), 7.05 (1H, d, J=7.4 Hz), 6.84 (2H, d, J=9.0 Hz), 6.15 (1H, d, J=1.6 Hz), 4.95 (2H, s), 4.43 (1H, t, J=7.8 Hz), 3.08 (1H, dd, J=16.6, 8.4 Hz), 2.83 (1H, dd, J=16.4, 7.4 Hz), 1.16 (9H, s).
Reaction SMILES: [CH3:1][CH:2]1[S:7][CH2:6][CH2:5][CH2:4][S:3]1.C([Li])CCC.[F:13][C:14]([F:21])([F:20])[C:15]([O:17]CC)=O.[Cl-].[NH4+]>C1COCC1>[F:21][C:14]([F:13])([F:20])[C:15]([C:2]1([CH3:1])[S:7][CH2:6][CH2:5][CH2:4][S:3]1)=[O:17]
Reactant: CC1SCCCS1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C(=O)C(F)(F)F)SCCCS1
Temperature: -20 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
2-Methyl-1,3-dithiane (1.50 g, 11.2 mmol) was dissolved in THF (50 mL), followed by cooling to −20° C. Then, n-butyllithium (1.58 M solution in hexane, 7 mL, 11.1 mmol) was added dropwise and the mixture was stirred for two hours. Ethyl trifluoroacetate (1.4 mL, 11.8 mmol) was added, and the mixture was heated to room temperature and stirred for 20 hours. Aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=100/0, 95/5, 85/15) to obtain 1.09 g of the title compound as a pale yellow solid (42%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([C:9]1[O:13][N:12]=[C:11]([C:14](Cl)=[O:15])[CH:10]=1)[CH2:7][CH3:8].O>ClCCl>[C:1]([NH:5][C:14]([C:11]1[CH:10]=[C:9]([CH2:6][CH2:7][CH3:8])[O:13][N:12]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(C(=O)Cl)no1
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: O
Product: CCCc1cc(C(=O)NC(C)(C)C)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
At 5° C., 9.3 g (126.8 mmol) of tert-butylamine in 20 ml of dichloromethane was dripped into 10.0 g (57.6 mmol) of 5-n-propyl-isoxazole-3-carboxylic chloride in 250 ml of anhydrous dichloromethane. The mixture was stirred for 12 hours at room temperature, 200 ml of water was added, the phases were separated, the organic phase was washed once with 150 ml of saturated sodium bicarbonate solution and once with 150 ml of saturated sodium chloride solution, followed by drying over magnesium sulfate and stripping off the solvent under reduced pressure. There was obtained 11.5 g (95%) of 5-n-propylisoxazole-3-carboxylic acid-tert-butylamide as a solid of melting point 34°-37° C.
Reaction SMILES: C=O.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[N:17]=1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>CO.C(Cl)Cl>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:30])[CH2:27][CH2:28]3)[CH:22]=2)[N:17]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)nc1-c1nc2ccccc2o1
Agent: C=O
Agent: N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)n3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
37% Aqueous formaldehyde (0.049 ml) was added to a stirred solution 3-(1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyrazin-2-amine (200 mg, 0.55 mmol) dissolved in methanol (2 ml) and DCM (2 ml) over a period of 5 minutes at 0° C. under an atmosphere of argon. The resulting solution was stirred at 0° C. for 5 minutes. Sodium triacetoxyborohydride (0.141 g) was added and the mixture was stirred for 5 minutes at ambient temperature. A solution of ammonia in methanol 7N (1 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel (eluting with 1 to 5% methanolic ammonia (7 N) in dichloromethane). The solvent was evaporated to dryness and there was thus obtained 3-(1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyrazin-2-amine (0.165 g); Mass Spectrum: M+H+ 376; NMR Spectrum (DMSOd6): 8.67 (s, 1H), 8.36 (s, 1H), 8.03 (s, 1H), 7.90 (d, 1H), 7.88 (d, 1H), 7.84 (bs, 2H), 7.51 (dd, 1H), 7.47 (dd, 1H), 4.13-4.24 (m, 1H), 2.82-2.94 (m, 2H), 2.21 (s, 3H), 1.95-2.12 (m, 6H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].N.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:13]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: N
Product: O=C(N[C@@H]1c2ccccc2C[C@H]1O)c1ccccc1

Procedure:
The trans amide can be made from the epoxide either (1) by treating the indene oxide with ammonia or a primary amine to produce a trans-1-amino-2-indanol and reacting the trans-1-amino-2-indanol with an acylating agent, or (2) by treating the epoxide with an amide anion to produce the trans hydroxy amide directly. In one embodiment the indene is oxidized with aqueous hypochlorite in the presence of a chiral salen catalyst to produce a partially resolved epoxide, which is converted to the partially resolved trans-1-amino-2-indanol by treating with ammonia or a primary amine followed by acylating with benzoyl chloride. The resulting benzamide is recrystallized to yield substantially optically pure trans-1-benzamido-2-indanol. In two preferred embodiments, the cis-1-amino-2-indanols are (1S,2R)-1-amino-2-indanol and (1R,2S)-1-amino-2-indanol, produced by oxidation of indene in the presence of an R,R or S,S-salen catalyst respectively.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a solution of 1-BOC-4-formyl-piperidine (210 mg) in dry 1,2-dichloroethane (10 mL), was added morpholine (86 mg) and glacial acetic acid (60 μL) and stirred for 1 h at room temperature. To the mixture was added sodium triacetoxyborohydride (272 mg) and the mixture stirred for 12 h. The reaction mixture was extracted into DCM (25 mL), washed with 50% sodium bicarbonate solution (10 mL), brine (10 mL), and dried (MgSO4). The solvents were removed in vacuo to give a residue which was purified by flash chromatography to give 4-morpholine-4-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester (120 mg). Treatment with TFA yielded the desired amine which was isolated as the TFA salt.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O>ClCCl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:22])=[O:15])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a suspension of 4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid of Step A (3.55 g, 0.0141 mmol) in dry dichloromethane (40 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (2 drops, cat.) followed by a 2.0 M solution of oxalyl chloride in dichloromethane (14.1 mL, 0.0283 mol) and the reaction mixture stirred at room temperature for 4.5 hours. The reaction mixture was then concentrated in vacuo to afford (4-chlorocarbonyl-benzyl)carbamic acid tert-butyl ester as a white solid. The crude acid chloride was dissolved in dry tetrahydrofuran (20 mL), added to a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (3 g, 9.42 mmol), and N,N-diisopropylethylamine (4.92 mL, 28.27 mmol) in dry tetrahydrofuran (20 mL), and the reaction mixture stirred at room temperature for 19 hours. The reaction was quenched by the addition of 2 M sodium hydroxide (20 mL) and then partitioned between ethyl acetate (200 mL) and 2 M sodium hydroxide (200 mL). The separated organic phase was washed with 2 M sodium hydroxide (200 mL), water (200 mL) and brine (200 mL), dried over magnesium sulfate, and concentrated in vacuo to afford an orange solid (3.95 g). Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in dichloromethane gave a colorless glass that was recrystallized from ethyl acetate/hexane to afford the title compound (1.29 g, 25%) as a cream crystalline solid, m.p. 171° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[C:24]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:23]=1.[C:37]1(=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](=[O:46])[NH:38]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[C:33]([C:24]1[CH:23]=[C:22]([C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2][N:38]2[C:39](=[O:46])[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:37]2=[O:47])[CH:27]=[CH:26][C:25]=1[N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])([CH3:36])([CH3:35])[CH3:34]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCBr)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(CCCN3C(=O)c4ccccc4C3=O)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
In a 50 mL three-necked flask under a nitrogen atmosphere, equipped with a magnetic stirrer, 1.0 g (1.82 mmol) of ethyl 4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate, 294 mg (2 mmol) of isoindole-1,3-dione and 276 mg of potassium carbonate (2 mmol) are placed in 20 mL of dimethylformamide. The reaction medium is heated at 100° C. for 3 hours and is then poured into water beforehand and acidified slightly with a 1 mol/L solution of hydrochloric acid, and extracted twice with ethyl acetate. The organic phases obtained are combined and washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to give a brownish oil. This oil is purified by chromatography on silica (eluent: 80/20 heptane/ethyl acetate) to give 950 mg of ethyl 3″-tert-butyl-4″-diethylamino-4′-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propyl]-[1,1′;3′,1″]terphenyl-4-carboxylate (yield=86%) in the form of a colorless oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:26]3[CH2:31][CH2:30][S:29][CH2:28][CH2:27]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: C1CSCCN1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCSCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and thiomorpholine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][CH:12]([C:14]1([CH2:18][CH2:19][CH3:20])[CH2:17][O:16][CH2:15]1)[CH3:13].N1C=CC=CC=1>CCOCC>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][CH:12]([C:14]2([CH2:18][CH2:19][CH3:20])[CH2:17][O:16][CH2:15]2)[CH3:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCCC1(C(C)O)COC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCC1(C(C)OC(=O)c2ccc(I)cc2)COC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-iodobenzoyl chloride (3.5 g) in dry ether (25 ml) was added to a stirred solution of 3-(1-hydroxyethyl)-3-n-propyloxetane (1.7 g) and pyridine (1.8 ml) in ether (50 ml) at 0° C. The resulting mixture was stirred for 24 hours at room temperature. After this time the mixture was washed with water and brine. The organic extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica (pre-eluted with 1% triethylamine in hexane) and eluted with hexane/ether mixtures. 3-[1-(4-Iodobenzoyloxy)ethyl]-3-n-propyloxetane was obtained as a colourless oil (1.8 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=3)=[N:9][N:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:5]2=[N:6][CH:7]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1.ClCCl>[NH2:19][C:13]1[C:14]([NH:18][C:29](=[O:30])[O:31][CH3:32])=[C:15]([NH2:17])[N:16]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:9]=2)[N:12]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1N
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
31.75 g (86.20 mmol) of the compound from example 30A were initially charged in pyridine (600 ml) under argon and cooled to 0° C. Then a solution of 6.66 ml (86.20 mmol) of methyl chloroformate in dichloromethane (10 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h. Thereafter, the reaction mixture was brought to RT, concentrated under reduced pressure and co-distilled repeatedly with toluene. The residue was stirred with water/ethanol and then filtered off with suction using a frit, and subsequently washed with ethanol and ethyl acetate. Subsequently, the residue was stirred again with diethyl ether, filtered off with suction and then dried under high vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C(O)C>[C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)ONCCC1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)ONCCC1CCN(c2ccncc2)CC1

Procedure:
N-t-butoxycarbonyloxy 2-(piperidin-4-yl)-ethylamine (prepared per Method K′ above) (14.4 g, 50 mmol), 4-chloropyridine HCl (1.0 eq., 8.0 g), TEA (2.2 eq.) were mixed in ethanol, and maintained under reflux overnight. The desired compound, N-t-butoxycarbonyloxy 2-[1-(pyrid-4-yl)piperidin-4-yl]-ethylamine, was isolated by column chromato-graphy, (silica gel) eluted with EtOAc and carried in the next step.