Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH:32]4[CH2:35][NH:34][CH2:33]4)=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH:32]4[CH2:33][N:34]([C:1](=[O:3])[CH3:2])[CH2:35]4)=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OC4CNC4)ccc23)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CC(Oc2ccc3c(C4CCN(C(=O)OC(C)(C)C)CC4)ncnc3c2)C1
Reaction time: 8 h

Procedure:
Acetic anhydride (66 μL, 703 μmol) was added dropwise with stirring at rt to a mixture of 4-[7-(Azetidin-3-yloxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (180 mg, 469 μmol), as prepared in the previous step, in DCM (1.0 mL). The resulting homogeneous yellow solution was stirred overnight, and was then partitioned with DCM (3 mL) and IM NaHCO3 (1×4 mL). The organic layer was dried (Na2SO4), concentrated, and purified by silica flash chromatography (8:2 DCM/acetone/3% DMEA eluent) to afford the title compound as a white crystalline film (88.3 mg, 44% over two steps). LC/MS (ESI): calcd mass 426.2, found 426.9 (MH)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]2[CH2:21][CH:20]2[NH:22][C:23](OC(C)(C)C)=[O:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH2:46]1[O:50][C:49]2[CH:51]=[C:52]([CH2:55]C(O)=O)[CH:53]=[CH:54][C:48]=2[O:47]1.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C@H:19]2[CH2:21][C@@H:20]2[NH:22][C:23](=[O:24])[CH2:55][C:52]2[CH:53]=[CH:54][C:48]3[O:47][CH2:46][O:50][C:49]=3[CH:51]=2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)NC1CC1c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc2c(c1)OCO2)N[C@H]1C[C@@H]1c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-{2-[(tert-butoxycarbonyl)amino]cyclopropyl}phenyl 4-(trifluoromethyl)benzenesulfonate (0.09 g, 0.2 mmol) in methylene chloride (1 mL) is treated with trifluoroacetic acid (0.1 mL) at room temperature for 2 hours. The reaction is evaporated in vacuo to a white solid. The solid is treated with N,N-dimethylacetamide (0.3 mL), and triethylamine (27 □L, 0.2 mmol). A mixture of 3,4-(methylenedioxy)phenylacetic acid (39 mg, 0.22 mmol), 4-dimethylaminopyridine (27 mg, 0.22 mmol), and N,N-dimethylacetamide (0.1 mL) is added to the reaction, followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (42 mg, 0.22 mmol). The reaction is stirred at room temperature overnight. After work-up with ethyl acetate-hexane-water, the dried, evaporated residue is purified on silica gel in ethyl acetate-methylene chloride mixtures. The product, 2-((1R,2S)-2-{[2-(1,3-benzodioxol-5-yl)acetyl]amino}cyclopropyl)phenyl 4-(trifluoromethyl)-benzenesulfonate, is recrystallized from methanol-water. A yield of 80% is obtained. 1H NMR (400 MHz, CDCl3) d 1.15 (m, 1H); 1.25 (m, 1H); 2.07 (m, 1H); 2.80 (m, 1H); 3.50 (s, 2H); 5.97 (m, 3H); 6.78 (m, 4H); 7.05 (m, 1H); 7.13 (m, 1H); 7.21 (m, 1H); 7.85 (m, 2H); 8.02 (m, 2H). ESI+ for C25H20F3NO6S m/z=520 (M+H)+.
Reaction SMILES: [OH-].[K+].C(OC([N:13]1[CH2:18][CH2:17][C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=O)C1C=CC=CC=1.CO.C(Cl)(Cl)Cl>C(O)C>[C:24]1([C:16]2([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH2:15][CH2:14][NH:13][CH2:18][CH2:17]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccccc2)(N2CCCC2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1ccc(C2(N3CCCC3)CCNCC2)cc1
Yield: 151.7 %

Procedure:
11 g KOH were added to a solution of 7.3 g (1 eq) benzyloxycarbonyl-4-phenyl-4-(pyrrolidin-1-yl)piperidine in 100 ml ethanol and the reaction mixture was refluxed for 24 h. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). Once the conversion was complete, the solvent was distilled off completely and the residue mixed with 100 ml water and extracted 3 times with 100 ml CHCl3. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, 7 g of crude product were obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>ClCCl>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1)([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]
Reactant: Nc1ccc(CCCO)cc1
Reactant: C=CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)Nc1ccc(CCCO)cc1
Temperature: 0 °C
Yield: 87.5 %

Procedure:
To a round bottomed flask was added the 3-(4-aminophenyl)propanol (1.3 g, 8.6 mmol), pyridine (1.0 mL, 12 mmol) and dichloromethane (25 mL). The solution was cooled to 0° C. and treated with allyl chloroformate (1.0 mL, 9.4 mmol). After allowing to warm to 22° C. over 1 hour, the reaction mixture was diluted with dichloromethane and washed twice with 1N HCl, followed by sat. NaHCO3, water and sat. aq. NaCl. The organic extract was dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (50% EtOAc in hexane), provided 1.77 g (88%) of 3-(4-(N-carboallyloxy)aminophenyl)propanol as a clear oil which solidified on standing.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])([O-:4])=[O:3].[C:13](OCC)(=[O:19])[C:14]([O:16]CC)=[O:15].O>C(O)C>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[CH2:12][C:13](=[O:19])[C:14]([OH:16])=[O:15]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
Sodium metal (3.80 g, 165 mmol) was dissolved in absolute ethanol (66 mL) at 0° C. The 3-nitro-o-xylene (10 g, 66.2 mmol) and diethyl oxalate (18 mL, 132 mmol) were then added and the reaction was warmed to room temperature and stirred for 18 hours. The reaction was refluxed for 30 minutes, then cooled and water (22 mL) was added and the reaction was stirred at room temperature for one hour. The reaction was concentrated to remove the ethanol, then extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated to provide the desired product (13.92 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[N:16]=[C:12]3[NH:11][C:10]([CH3:25])=[C:9]2[C:26]([NH2:28])=O)=[CH:4][C:3]=1[F:29].CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[N:16]=[C:12]3[NH:11][C:10]([CH3:25])=[C:9]2[C:26]#[N:28])=[CH:4][C:3]=1[F:29]
Reactant: COc1ccccc1-c1cn2c(n1)NC(C)=C(C(N)=O)C2c1ccc(Cl)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccccc1-c1cn2c(n1)NC(C)=C(C#N)C2c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 35.8 %

Procedure:
To a suspension of 5-(4-chloro-3-fluorophenyl)-2-(2-methoxyphenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-6-carboxamide (351 mg, 0.85 mmol) in CH2Cl2 (10 mL) at 0° C. was added Et3N (0.73 mL, 5.27 mmol) followed by trifluoroacetic anhydride (0.38 mL, 2.72 mmol) over a period of 10 min. The reaction mixture was stirred at 0° C. for an additional 40 min and quenched with 10% Na2CO3 (5 mL) and H2O (10 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was triturated with ether and purified by column chromatography on silica gel eluting from 30% to 50% EtOAc in hexanes to give 5-(4-chloro-3-fluorophenyl)-2-(2-methoxyphenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-6-carbonitrile (120 mg, 36%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[N:17][N:16]([CH3:19])[C:15]=3[CH:20]=2)=[C:6]([CH:9]=1)[CH2:7]O.N1C=CC=CC=1.S(Cl)([Cl:29])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[N:17][N:16]([CH3:19])[C:15]=3[CH:20]=2)=[C:6]([CH2:7][Cl:29])[CH:9]=1
Reactant: Cn1nnc2ccc(Cc3ccc(Cl)cc3CO)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1nnc2ccc(Cc3ccc(Cl)cc3CCl)cc21
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To the solution of 5-chloro-2-[(1-methyl-1H-benzotriazole-6-yl)methyl]benzyl alcohol (0.16 g) from Example 77 and pyridine (0.05 ml) in methylene chloride (2 ml) was added thionyl chloride (0.04 ml) at 0° C., the mixture was stirred for 30 minutes. After removal of the solvent, the resulting residue was purified by chromatography on a silica gel column (methylene chloride:methanol=199:1), to give the title compound (0.12 g; 70%).
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CC(O)C.O>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([O:21][CH2:20][C@@H:18]([OH:17])[CH2:19][N:7]2[CH2:6][CH:5]3[O:9][CH:1]([CH2:2][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]3)[CH2:8]2)=[CH:23][CH:24]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: N#Cc1ccc(OC[C@@H]2CO2)cc1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)O2
Yield: 100 %

Procedure:
A mixture of tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (prepared in an analogous fashion to the compound of Preparation A(vi) above; 0.72 g, 3.2 mmol) and 4-[(2S)-oxiranylmethoxy]benzonitrile (from step (i) above; 0.56 g, 3.2 mmol) in IPA/water (11 mL of 10:1) was stirred at 60° C. for 18 h. The solvent was then evaporated to give 1.3 g (100%) of the sub-title compound, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([CH:43]=[CH:44][C:45]=1[CH3:46])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:32]=1)=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:24][C:25]2[CH:26]=[C:27]([CH:43]=[CH:44][C:45]=2[CH3:46])[C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[CH:32]=2)=[O:29])=[O:19])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 18, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with 3-amino-4-methyl-N-(3-morpholinophenyl)benzamide to give 3-[3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamido]-4-methyl-N-(3-morpholinophenyl)benzamide in 42% yield; NMR Spectrum: (DMSOd6) 1.38 (s, 9H), 1.54 (m, 2H), 1.91 (m, 2H), 2.27 (s, 3H), 3.06 (t, 4H), 3.2 (m, 2H), 3.64 (m, 2H), 3.72 (t, 4H), 5.01 (m, 1H), 6.66 (m, 1H), 7.18 (m, 2H), 7.28 (d, 1H), 7.4 (m, 3H), 7.56 (m, 2H), 7.77 (m, 1H), 7.92 (s, 1H), 9.98 (s, 1H), 10.01 (s, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1.[NH2:21][OH:22].[OH-].[K+].CO>C1COCC1>[OH:22][NH:21][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: COC(=O)C=CC=CCSc1ccc2ccccc2c1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(C=CC=CCSc1ccc2ccccc2c1)NO
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 6-(naphthalen-2-ylsulfanyl)-hexa-2,4-dienoic acid methyl ester (0.505 g, 1.78 mmol) in distilled THF (10 mL) containing 50% aqueous hydroxylamine (1.08 mL, 16.4 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 2.5 ml, 2.5 mmol) over a period of 30 minutes. After stirring the mixture at 0° C. for an additional hour, distilled water (10 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The solution was extracted with ethyl acetate (2×50 mL), and the combined extracts were dried over anhydrous MgSO4, and evaporated to dryness. The solid residue was recrystallised from ethyl acetate to give the title compound (0.315 g, 62%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:37][CH2:38][OH:39].C(=O)([O-])[O-].[K+].[K+].C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[N:6]([CH2:37][CH2:38][OH:39])[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1
Reactant: OCCBr
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)c(-c2ccc(F)cc2)s1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3n2CCO)c(-c2ccc(F)cc2)s1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E35 (250 mg, 0.53 mmol) was added slowly to an ice-cooled slurry of sodium hydride (43 mg, 1.1 mmol, 60% dispersion in mineral oil) in DMF (10 ml), under argon. After stirring for a further 0.5 h, 2-bromoethanol (0.045 ml, 0.64 mmol) was added. The mixture was heated at 110° C. for 48 h, but only a minor amount of product had formed (MS). Potassium carbonate (1.00 g), N,N-diisopropylethylamine (1.0 ml) and a further portion of 2-bromoethanol (0.5 ml) were added and heating was continued for 16 h. The volatiles were removed in vacuo from the cooled reaction mixture. The residue was partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-5% methanol-ethyl acetate) afforded the title compound as a white solid (78 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.C(N(CC)CC)C.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C1COCC1.C(OCC)C>[CH2:24]([NH:26][C:27]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=1)=[O:28])[CH3:25]
Reactant: CCN=C=O
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 60 °C
Yield: 85.5 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (30 g, 137 mmol, 1.0 equiv) in THF (300 ml) was added triethylamine (58 ml, 410 mmol, 3.0 equiv) and ethyl isocyanate (16.3 ml, 205 mmol, 1.5 equiv). The reaction was warmed to 60° C. for 2 hours. The reaction was cooled to room temperature and diluted with diethyl ether (600 ml). The precipitate was filtered and solid was washed with diethylether to afford desired product 34 g.
Reaction SMILES: C(N(C(C)C)C(C)C)C.CS(C)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24].O>C(Cl)Cl>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24]
Reactant: OCCCCCCCCCBr
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCCCCCCCBr
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
N-Ethyldiisopropylamine (23 mL) and DMSO (9.7 mL) were added to a solution of 9-bromo-1-nonanol (10.0 g) in dry DCM (230 mL) at RT under argon. The mixture was cooled to −15° C. and sulfur trioxide-pyridine complex (21.4 g) was added in 4 portions at 5 min intervals. The mixture was stirred for 15 min after completion of the addition then water (200 mL) was added and the layers were separated. The organic layer was washed with 1M aqueous sodium bisulfate solution (4×250 mL), saturated aqueous potassium carbonate (250 mL) and brine (2×200 mL), dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as an orange oil. Yield 9.02 g.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22]1([CH2:28][CH:29]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.CO.CC(O)=O>[CH2:29]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CCc1ccccc1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CCNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium triacetoxyborohydride (5.46 g, 26 mmol) is added in small portions to a stirred solution of aniline (2.0 g, 21.5 mmol) and phenylacetaldehyde (2.83 g, 24 mmol) in dry DMF/MeOH/AcOH (87:10:3, 120 ml). After stirring at rt for 90 min, the volatiles are removed under reduced pressure. The residue is dissolved in dichloromethane (200 ml) and extracted twice with 1 N HCl. The combined aqueous layers are washed with EtOAc, then ammonium hydroxide solution is added to pH 9, and the mixture is extracted with dichloromethane. The solvent is evaporated, and the crude product is purified by silica gel chromatography (hexane/EtOAc, 5:1) affording pure title compound as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[F:24][C:25]([F:38])([F:37])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32]CC(O)=O)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:37])[F:38])=[CH:31][CH:30]=2)[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccc(C(F)(F)F)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.086 g, 0.27 mmol) and 3-(4-(trifluoromethyl)phenyl)propanoic acid (60 mg, 0.27 mmol) taken in dry DCM (20 mL), DIPEA (72 mg, 1.37 mmol) followed by HATU (208 mg, 0.55 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.118 g, 90.07%) as solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].[CH2:6]([O:13][C:14](=[O:20])[NH:15][C@H:16]([CH3:19])[CH2:17]I)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.CSC.[Cu]Br>[CH2:6]([O:13][C:14](=[O:20])[NH:15][C@H:16]([CH3:19])[CH2:17][CH2:3][CH:2]=[CH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@H](CI)NC(=O)OCc1ccccc1
Reactant: C=CC[Mg]Cl
Agent: [Cu]Br
Solvent: CSC
Solvent: C1CCOC1
Product: C=CCC[C@@H](C)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Copper (I) bromide-dimethyl sulfide (1.93 g, 9.4 mmol) was dissolved in distilled THF (24 ml), then was cooled to −78 degrees C. A solution of allyl magnesium chloride (9.4 ml, 2M in THF, Aldrich) was added dropwise, then the solution was stirred for 30 minutes. ((R)-2-Iodo-1-methyl-ethyl)-carbamic acid benzyl ester (1.5 g, 4.7 mmol) in distilled TBF (3 ml) was added dropwise, then the reaction was warmed to −40 degrees C. and was stirred for 2.5 h. The reaction mixture was quenched with aq. sat. NH4Cl (4 ml) at −40 degrees C., warmed to RT and the gray reaction mixture turned sky blue. THF was removed in vacuo. Then, Et2O was added and the reaction mixture was filtered to remove precipitated solids. The solids were washed with additional Et2O. The combined organics were extracted with 10% NH4OH (3×), then brine. The combined organics were dried with MgSO4, filtered, concentrated in vacuo, then filtered through a plug of silica gel washing with 20% EtOAc/hexanes (100 ml). The solution was concentrated in vacuo, then the resultant colorless oil was used in the next reaction without further purification (0.8 g, 73%).
Reaction SMILES: B.CSC.[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:31]([O:33][CH3:34])=[O:32])=[CH:16][C:17]=3[N:18]3[C:25]=2[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[O:22][CH2:21][C:20](=[CH2:30])[CH2:19]3)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-:35].[Na+].OO>C1COCC1.CCOC(C)=O>[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:31]([O:33][CH3:34])=[O:32])=[CH:16][C:17]=3[N:18]3[C:25]=2[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[O:22][CH2:21][CH:20]([CH2:30][OH:35])[CH2:19]3)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C=C1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
Borane-dimethylsulfide complex (2M solution in THF, 1.6 eq) was added to a solution of methyl 14-cyclohexyl-7-methylene-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (from Step 1) in dry THF (0.12 M) at 0° C. The solution was stirred for 16 h at RT. The reaction mixture was cooled to 0° C. and treated dropwise with 3N NaOH (3 eq.) followed by 35% (v/v) H2O2 solution and the resulting mixture was stirred for 2 h at RT. The mixture was diluted with EtOAc, washed with aqueous saturated NaHCO3-solution and with brine, dried (Na2SO4). Evaporation afforded a crude residue which was purified by flash chromatography (4:1 PE/EtOAc). Methyl 14-cyclohexyl-7-(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (50%) was obtained as colorless solid; MS (ES+) m/z 402 (M+H)+.