Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](Cl)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].C(N(CC)CC)C.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:24]3[CH2:25][CH2:26][N:21]([C:18](=[O:20])[CH3:19])[CH2:22][CH2:23]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: CC(=O)N1CCNCC1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Yield: 64.1 %

Procedure:
A mixture of 1.98 g (7.50 mmole) of 8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 1.16 g (9.05 mmole) of N-acetylpiperazine, and 2.0 mL of triethylamine in 20 mL of dry THF was refluxed under a nitrogen atmosphere for 16 hr. It was then poured into 5% aqueous sodium hydroxide and extracted three times with methylene chloride. The combined organic portions were dried over MgSO4, filtered and concentrated in vacuo to yield a product which was purified by flash chromatography (5% CH3OH in CHCl3) to afford 1.71 g of the title compound as a glass.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][CH:29]([CH2:34][C:35](OCC)=[O:36])[C:28]=3[CH:27]=[N:26]2)[CH:21]=[CH:22][C:23]=1[Cl:24].O>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][CH:29]([CH2:34][CH2:35][OH:36])[C:28]=3[CH:27]=[N:26]2)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CCOC(=O)CC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: OCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of DIBALH (1 M) in toluene (13 mL, 13.0 mmol) is slowly added, maintaining the reaction temperature under −65° C., to a solution of ethyl 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)acetate (1.83 g, 5.2 mmol) in 20 mL of dried Cl2CH2 cooled at −75° C. under N2 atmosphere. The resulting mixture is maintained under stirring at −70° C. during 30 minutes, effecting a follow-up of the reaction by TLC. Next, the temperature is raised to 0° C., and 10 mL of cold water are added, while the temperature is maintained at 0° C. A precipitate is formed, which is filtered and washed with Cl2CH2. The organic phase is washed twice with water, dried, and evaporated under reduced pressure. The resulting crude is purified by silica-gel chromatography, giving 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethanol (1.06 g, 3.41 mmol, 66%, oil).
Reaction SMILES: [C:1](OC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C2CC(COC)OC=2C=1)=O)(C)(C)C.[C:31]([O:35][C:36]([C:38]1[CH:49]=[C:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]([N:59]3[CH2:62][CH2:61][CH2:60]3)=[O:58])=[C:53]([F:63])[CH:52]=2)[C:41]2[CH2:42][C:43]([CH2:46][OH:47])([CH3:45])[O:44][C:40]=2[CH:39]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32].CI>>[C:31]([O:35][C:36]([C:38]1[CH:49]=[C:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]([N:59]3[CH2:62][CH2:61][CH2:60]3)=[O:58])=[C:53]([F:63])[CH:52]=2)[C:41]2[CH2:42][C:43]([CH2:46][O:47][CH3:1])([CH3:45])[O:44][C:40]=2[CH:39]=1)=[O:37])([CH3:32])([CH3:33])[CH3:34]
Reactant: COCC1Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)c2c(c1)OC(C)(CO)C2
Solvent: CI
Product: COCC1(C)Cc2c(Oc3ccc(C(=O)N4CCC4)c(F)c3)cc(C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 201a, from 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (240a) and methyl iodide. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.84 Hz, 2 H) 7.22 (s, 1 H) 7.07 (d, J=8.84 Hz, 2 H) 3.41-3.52 (m, 2 H) 3.40 (s, 3 H) 3.11 (d, J=16.67 Hz, 1 H) 2.76 (d, J=16.67 Hz, 1 H) 2.48 (td, J=7.89, 4.67 Hz, 1 H) 1.56 (s, 9 H) 1.46 (s, 3 H) 1.32-1.43 (m, 2 H) 1.00-1.12 (m, 2 H); LCMS for C26H30FNO6 m/z 472.20 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][C:5](OC)=[O:6].[CH2:11]1COC[CH2:12]1.C([Mg]Br)C>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.C(OCC)C.O>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][C:5]1([OH:6])[CH2:12][CH2:11]1
Reactant: C1CCOC1
Reactant: COC(=O)CC(OC)OC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: O
Product: COC(CC1(O)CC1)OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 1.0 L RBF containing methyl 3,3-dimethoxypropanoate (17.6500 g, 119 mmol) was added THF (150 ml) and diethyl ether (150 ml), and the mixture was allowed to stir at 0° C. for 15 min. At this time, tetra-isopropoxy titanium (6.98 ml, 23.8 mmol) was added in one portion before the dropwise addition of ethylmagnesium bromide (99.3 ml, 298 mmol) via syringe. The reaction was allowed to warm to 23° C. and stir for 14 hours before being re-chilled to 0° C. After 5 min at this temp, water (15 ml) was added and a solid formed. Diethyl ether (200 ml) was added and the quenched reaction was stirred for 10 min before filtering through a plug of magnesium sulfate. The filtrate was dried with additional magnesium sulfate, filtered and concentrated to give a colorless oil. The crude material was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl.CC(OC)(C)C>[CH3:21][O:22][CH2:23][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: COCCl
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
A solution of 2-(trifluoromethyl)phenol (12.0 g, 74.0 mmol) in dichloromethane (49 mL) was cooled to 5° C., and N,N-diisopropylethylamine (25.9 mL, 148 mmol) and methoxymethyl chloride (8.43 mL, 111 mmol) were added dropwise, keeping the internal temperature≦15° C. After stirring for 15 min at ambient temperature, the reaction mixture was diluted with MTBE (250 mL) and washed with 2N HCl (2×50 mL), water (50 mL), 2N NaOH (2×30 mL), water (30 mL), and brine (30 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (14.1 g, 68.4 mmol, 92%) which was used without further purification. MS (DCI/NH3) m/z 207 (M+H)+.
Reaction SMILES: C([CH:9]([O:16][C:17]([NH:19][CH2:20][C:21]1([CH2:27][C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[CH:31]1[CH:36]=[C:35](Cl)[CH:34]=[C:33]([C:38]([O:40]O)=[O:39])[CH:32]=1.C([O-])(O)=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:38]([O:40][CH:9]([O:16][C:17]([NH:19][CH2:20][C:21]1([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:31][CH:32]=1
Reactant: O=C(O)CC1(CNC(=O)OC(C(=O)c2ccccc2)c2ccccc2)CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 1-{[(α-benzoylbenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid (61) (1.89 g, 4.6 mmol) in 40 mL of CH2Cl2 was added 77% mCPBA (2.07 g, 9.2 mmol) and NaHCO3 (0.78 g, 9.2 mmol), respectively, at room temperature and the resulting mixture was stirred at room temperature overnight. The reaction mixture was acidified with 10% citric acid and extracted with CH2Cl2. The organic extract was washed with brine and dried over Na2SO4. After removing the solvent under reduced pressure, the residue was purified by reverse phase preparative HPLC (acetonitrile-water, 0.1% formic acid) to afford 960 mg (49%) of the title compound (59). 1H NMR (CDCl3, 400 MHz): δ 1.58-1.35 (m, 10H), 2.34 (s, 2H), 3.26 (dd, J=6.8, 0.8 Hz, 2H), 5.38 (t, J=6.8 Hz, 1H 7.46-7.26 (m, 5H), 7.63-7.55 (m, 3H), 7.89 (s, 1H), 8.08 (dd, J=8.8, 1.2 Hz, 2H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][NH:6][C:7]1[C:8]([O:14][CH2:15][C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:20][C@H:19]2[CH3:33])=[O:17])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)C.CO.O1CCCC1.O.[OH-].[Li+]>[Cl-].[Na+].O.O>[Cl:13][C:11]1[CH:12]=[C:7]([NH:6][CH2:5][C:4]([OH:34])=[O:3])[C:8]([O:14][CH2:15][C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:20][C@H:19]2[CH3:33])=[O:17])=[N:9][CH:10]=1
Reactant: CCOC(=O)CNc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1NCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-ylamino)-acetic acid ethyl ester (0.080, 0.16 mmol) in 2:2:1 methanol:tetrahydrofuran:water (1.5 mL) was added lithium hydroxide monohydrate (0.015 g, 0.36 mmol). The reaction was stirred at ambient temperature for 3 hours. The pH of the solution was adjusted to ˜4 by the addition of 0.2 M hydrochlroric acid, then diluted with brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by anion exchange chromatography to give the title compound as its acetic acid addition salt (0.058 g, LRMS: 465.1, 467.2).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[CH:14]1([CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15]1.[H-].[Na+]>CS(C)=O.C(OCC)C.[Cl-].[Na+].O>[CH:14]1([C:17]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:10][NH:11][CH:12]=2)[CH2:16][CH2:15]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C=CC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: COC(=O)c1c[nH]cc1C1CC1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 86.1 %

Procedure:
A solution of 8.77 g of p-toluenesulphonylmethyl isocyanide and 5.67 g of methyl 3-cyclopropylacrylate in 72 mL of dimethyl sulphoxide and 145 mL of diethyl ether is added dropwise over 1.5 hours and under an argon atmosphere to a suspension of 1.73 g (54 mmol) of sodium hydride (at 75% by weight in liquid petroleum jelly) in 90 mL of diethyl ether. The reaction is exothermic. After the reaction mixture has been stirred at room temperature for 2.75 hours, 180 mL of brine are added cautiously, and the mixture is extracted twice with 100 mL of diethyl ether. The organic phase is washed with water, dried and then concentrated to dryness under reduced pressure (2.7 kPa), giving 6.39 g of 4-cyclopropyl-3-methoxycarbonyl-1H-pyrrole in the form of a yellow solid melting at 107° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.O.[NH2:14][NH2:15]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:14][NH2:15])=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1
Reactant: Clc1cc(C2CCC2)c(Cl)nn1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(C2CCC2)c(Cl)nn1

Procedure:
3,6-Dichloro-4-cyclobutylpyridazine (22.5 g, 0.11 mol) and hydrazine hydrate (34 ml, 0.66 mol) were heated at reflux in dioxane (280 ml) for 24 hours. Upon cooling the desired isomer crystallized from the reaction and was collected by filtration (13.3 g, 64%). 1H NMR (250 MHz , d6-DMSO) 1.68-1.86 (1H, m), 2.00-2.11 (3H, m), 2.29-2.38 (2H, m), 3.52-3.61 (1H, m), 4.35 (2H, br), 6.99 (1H, s), 8.06 (1H, br); MS (ES+) m/e 198 [MH]+, 200 [MH]+.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=34)=[N:8][CH:9]=2)[N:4]1[C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.Cl[C:30]([O:32][CH3:33])=[O:31].CCN(C(C)C)C(C)C>CN(C=O)C>[C:21]([C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[CH:13][C:12]([C:7]3[N:6]=[C:5]4[C:10]([NH:11][C:3](=[O:2])[N:4]4[C@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:30]([O:32][CH3:33])=[O:31])[CH2:24]4)=[CH:9][N:8]=3)=[C:16]2[CH:17]=1)#[N:22]
Reactant: COC(=O)Cl
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a solution of example 6 (200 mg, 0.26 mmol) in DMF (2.6 mL), methyl chloroformate (27 mg, 0.28 mmol) and DIPEA (0.068 mL, 0.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, dissolved in CH2Cl2, and washed thrice with saturated NaHCO3 aqueous solution. The combined organic phases were dried over MgSO4 and concentrated to dryness. The crude residue was chromatographed on a silica gel flash system (ISCO Combiflash) using CH2Cl2/MeOH mixtures of increasing polarity as eluent to afford 36 mg of the desired product (32% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH:16]([C:20]([OH:22])=O)[CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[NH2:30][CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33]>C(Cl)Cl.O>[O:33]=[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][NH:30][C:20]([CH:16]1[O:17][CH2:18][CH2:19][N:14]([CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:15]1)=[O:22]
Reactant: NCC(=O)c1ccccc1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
Oxalyl chloride (1.187 mL, 13.56 mmol) was added to a suspension of 4-(phenylmethyl)-2-morpholinecarboxylic acid (2.0 g, 9.04 mmol) in CH2Cl2 (70 mL) at 0° C. in 10 minutes, and the resulting mixture was stirred at 25° C. for 2 hours. The mixture was concentrated, and the resulting residue was treated with CH2Cl2 (70 mL), triethylamine (2.77 mL, 19.89 mmol) and 2-amino-1-phenylethanone (1.551 g, 9.04 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 3 hours. Water (150 mL) was added, and the resulting aqueous mixture was extracted with EtOAc (3×80 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography to afford the title compound (1.0 g) as a brown solid. LC-MS (ES) m/z=339 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.CS(C)=O>[F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(CO)cc1F
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(C=O)cc1F
Reaction time: 1 h

Procedure:
2-Fluoro-4-hydroxymethylbenzonitrile (Example 9, Step C) 10 g, 0,066 mol) and triethylamine (32.3 mL, 0.231 mol) were dissolved in CH2Cl2 (100 mL)-DMSO (20 mL) at <5° C. with stirring and treated dropwise with a solution of pyridine.SO3 complex (31.5 g, 0.198 mol) in DMSO (70 mL) maintaining the reaction mixture temperature at <10° C. The reaction mixture was stirred at 5° C. for 1 hr after the addition, then at 20° C. for 1 hr, then partitioned between CH2Cl2 and H2O. The organic layer was separated, washed well with H2O, brine, and dried (Na2SO4). Filtration and concentration gave the title compound after purification by chromatography (silica gel, hexane: EtOAc, 3:1). 1H NMR (CDCl3) δ 10.06 (d, 1H, J=2 Hz), 7.86 (dd, 1H, J=5, 8 Hz), 7.798 (dd, 1H, J=1, 8 Hz), 7.728 (dd, 1H, J=1, 8 Hz).
Reaction SMILES: C(N(C(C)C)C(C)C)C.C(N1CCCO[CH:19]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18]1)C1C=CC=CC=1.C(Cl)(=[O:35])CC.[OH-].[Na+]>C(Cl)Cl>[C:26]1([NH:25][C:24](=[O:35])[CH2:19][CH3:18])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC(=O)Cl
Reactant: c1ccc(CN2CCCOC(CNc3ccccc3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
iPr2EtN (4.72 mL, 27.1 mmol) was added to a solution of (4-benzyl-1,4-oxazepan-2-ylmethyl) phenyl amine (80) (27.1 mmol) in CH2Cl2. The solution was cooled to 0° C. in an ice bath, then propionyl chloride (5.17 mL, 59.6 mmol) was added dropwise. The reaction was allowed to warm slowly to room temperature, with stirring, overnight. CH2Cl2 and 10% aqueous NaOH was added. The organic layer was removed and the aqueous layer extracted with CH2Cl2 (2×). The organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The resulting oily residue was purified by silica gel chromatography (97:1:2::Hexanes:CH2Cl2:2N NH3 in EtOH) to obtain 4-benzyl-1,4-oxazepan-2-ylmethyl)-N-phenylpropionamide (81) as a pale yellow oil. 1H NMR (CDCl3, ppm) 7.36-7.19 (8H, m), 6.94 (2H, broad d, J=6.5 Hz), 3.89-3.38 (5H, m), 3.65 (1H, d, J=13.3 Hz), 3.54 (1H, d, J=13.3 Hz), 2.88-2.75 (2H, m), 2.55 (1H, ddd, J=12.5, 8.9, 4.2 Hz), 2.34 (1H, dd, J=13.5, 8.9 Hz), 1.98-1.68 (4H, m), 0.98 (3H, t, J=7.5 Hz). 13C NMR (CDCl3) 174.05, 143.19, 139.64, 129.60, 129.15, 128.46, 128.35, 127.79, 127.10, 76.80, 67.25, 62.61, 59.05, 54.43, 51.64, 30.42, 27.91, 9.70 ppm. LRMS: 352.72.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:12])[C:8]=1[CH2:9][O:10][CH3:11])[NH2:5].C(N(CC)C1C=CC=CC=1)C.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:25](=[O:26])[O:27][CH:28]([CH3:30])[CH3:29])[CH:6]=[C:7]([Cl:12])[C:8]=1[CH2:9][O:10][CH3:11]
Reactant: CC(C)OC(=O)Cl
Reactant: COCc1c(Cl)cc(N)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: COCc1c(Cl)cc(NC(=O)OC(C)C)cc1Cl
Temperature: 0 °C
Reaction time: 12 h
Yield: 89.7 %

Procedure:
3,5-Dichloro-4-methoxymethylaniline (2.06 g) and N,N-diethylaniline (1.49 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (1.24 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3,5-dichloro-4-methoxymethylphenyl)carbamate (Compound No. 1) (2.62 g) in a yield of 89.6% nD26.2 1.5283.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)#[N:25].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:24]#[N:25])[CH:27]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg (0.50 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 6 ml of DMF. 24 mg (0.60 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 137 mg (0.70 mmol) of 3-cyanobenzyl bromide was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=[O:4].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNCC1
Reactant: O=C(CBr)c1cccc(F)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCCCC1)c1cccc(F)c1

Procedure:
A mixture of 2-bromo-1-(3-fluoro-phenyl)-ethanone (5.0 g; 23.04 mmol; 1.0 eq.), piperidine (2.30 ml; 23.04 mmol; 1.0 eq.) and DIEA (4.89 ml; 27.65 mmol; 1.20 eq.) in CHCl3 (100 mL) was heated for reflux overnight. The mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The separated organic layer was dried over MgSO4, filtered and concentrated. The residue was purified through flash chromatography on silica gel to afford the title compound. LC-MS: 222 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[NH:6][CH2:5]1.I[C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[O:8][C:7](=[O:9])[N:6]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH:5]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: COCC1CNC(=O)O1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-n2cc(COC)oc2=O)cc1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 25 and using 1-amino-3-methoxypropan-2-ol (1 g), 5-methoxymethyloxazolidin-2-one (620 mg) was obtained. To a mixture of 5-methoxymethyloxazolidin-2-one (620 mg), ethyl 4-iodobenzoate (1.6 mL), potassium carbonate (2.6 g) and copper (I) iodide (552 mg) were added toluene (20 mL) and N,N′-dimethylethylenediamine (625 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (830 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+].I[C:56]1[N:72]=[C:59]2[CH:60]=[CH:61][CH:62]=[C:63]([C:64]3[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][CH:65]=3)[N:58]2[N:57]=1.N#N.C(O)(=O)C>CN(C)C=O>[CH3:71][O:70][C:67]1[CH:66]=[CH:65][C:64]([C:63]2[N:58]3[N:57]=[C:56]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([N:8]5[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]5)=[CH:6][CH:7]=4)[N:72]=[C:59]3[CH:60]=[CH:61][CH:62]=2)=[CH:69][CH:68]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: COc1ccc(-c2cccc3nc(I)nn23)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: N#N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc3nc(Nc4ccc(N5CCN(C)CC5)cc4)nn23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
A solution of 4-(4-aminophenyl)-1-methylpiperazine (163 mg, 0.86 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (54 mg, 0.11 mmol), sodium tert-butoxide (103 mg, 1 mmol), and 2-iodo-5-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (150 mg, 0.43 mmol) in dimethylformamide (4 mL) was degassed by evacuation of the reaction vessel followed by N2 purge (3×). To this mixture was added trisdibenzylideneacetone-bispalladium (52 mg, 0.06 mmol), and the reaction mixture was further degassed. The reaction mixture was heated to 100° C. After 2 h, acetic acid (60 mg, 1 mmol) was added, the resulting mixture was filtered and concentrated. Purification by reverse phase HPLC provided product (60 mg, 30%). 1H NMR (400 MHz, CD3OD), δ: 8.10 (d, 2H), 7.7 (m, 1H), 7.6 (d, 2H), 7.35 (t, 1H), 7.20 (m, 3H), 7.0 (d, 2H), 3.9 (s, 3H), 3.2 (t, 4H), 2.7 (t, 4H), 2.4 (s, 3H); ES-MS m/z 415.3.