Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:34])=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O.C([O-])(O)=O.[Na+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:34])=[C:21]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH:20]=1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 90 °C
Yield: 118.9 %

Procedure:
To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (1.053 g, 3.617 mmol), 5-amino-2-methylphenylboronic acid pinacol ester (1.2607 g, 5.4081 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.1311 g, 0.1852 mmol), and potassium carbonate (1.385 g, 10.02 mmol) was added 1,4-dioxane (20 mL, 200 mmol) and water (2 mL, 100 mmol). The reaction mixture was then heated at 90° C. for 2 hours and then cooled to room temperature. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted twice with dichloromethane. The combined organics were dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-80% ethyl acetate in dichloromethane) to yield 1.3653 g (119%) of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): M+H=318.2; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.16 (s, 1H), 8.47 (s, 1H), 7.92 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.63 (dd, J=8.5, 1.5 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.60-6.49 (m, 2H), 4.93 (s, 2H), 2.14-2.02 (m, 4H), 0.85 (dd, J=12.4, 6.1 Hz, 4H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][Si:14]([CH3:31])([C:27]([CH3:30])([CH3:29])[CH3:28])[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1.CI>CCCCCC.O1CCCC1>[CH3:31][Si:14]([CH3:13])([C:27]([CH3:30])([CH3:29])[CH3:28])[O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:1])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:20][CH:21]=1
Reactant: CC(C)NC(C)C
Reactant: CC(C(=O)O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CC(C)(C(=O)O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Distilled diisopropylamine (1.98 g, 19.6 mmol) was added to dry tetrahydrofuran (10 ml) under anhydrous conditions. To the stirred solution at 0° C. was added 1.55M n-butyllithium (12.6 ml, 19.6 mmol) in hexane dropwise. After 15 minutes a solution of the compound (1a) (2.2 g, 7.8 mmole) in tetrahydrofuran (10 ml) was added dropwise at 0° C. The reaction mixture was stirred for 1 hour at ambient temperature 30 minutes at 50° C. and then cooled to 0° C. Methyl iodide (2.78 g, 19.6 mmol) was added dropwise, and the reaction mixture stirred at ambient temperature for about 16 hours. The reaction was quenched with saturated ammonium chloride (20 ml) and acidified with 3N hydrochloric acid. The reaction mixture was extracted with diethyl ether (3×100 ml), the extracts combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give a tan solid. This compound was chromatographed on a 5×15 cm column of silica gel eluted with 5 percent isopropanol/hexane to yield the desired product as a solid, m.p. 78-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26](=[O:27])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: Cc1ccc(CC(=O)O)cc1
Product: Cc1ccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1

Procedure:
Example 9 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0055 g) and (4-methylphenyl)acetic acid (0.03 g) to give thetitle compound (0.024 g).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:21])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12]([Cl:20])=[C:13]([CH3:19])[NH:14]2)([CH3:4])([CH3:3])[CH3:2].[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N.C(O)(=O)CC(O)=O>CCOCC.O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[C:22]([O:21][CH:7]([CH2:6][NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12]([Cl:20])=[C:13]([CH3:19])[NH:14]2)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1[nH]c2cccc(OCC(O)CNC(C)(C)C)c2c1Cl
Agent: N
Agent: O=C(O)CC(=O)O
Agent: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1[nH]c2cccc(OCC(CNC(C)(C)C)OC(=O)c3ccccc3)c2c1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3.1 g of 1-tert.butylamino-3-(3-chloro-2-methyl-indol-4-yloxy)-2-propanol, 6.1 g of benzoic acid and 12 ml of hexamethyl phosphoric acid triamide are heated on a steam bath until all of the benzoic acid is dissolved. After cooling to room temperature, 2.9 g of benzoic acid anhydride are added and stirring is effected for 15 hours. The resulting clear yellow solution is poured onto ice, 250 ml of ether are added and stirring effected for 1 hour. After making the liquid alkaline with concentrated ammonia, the ether phase is separated, shaken out with tartaric acid, made alkaline while cooling with ice, with concentrated ammonia and extracted with methylene chloride. After evaporating the methylene chloride, the residual title compound is crystallised with 1 mol of malonic acid from tetrahydrofuran and ether. M.p. of hydrogen malonate form: 176°-177°.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:27][C@@:28]12[C@@H:36]([OH:37])[CH2:35][CH2:34][C@H:33]1[C@@H:32]1[CH2:38][CH2:39][C:40]3[C@@:46]([CH3:47])([C@H:31]1[CH2:30][CH2:29]2)[CH2:45][CH2:44][C:42](=[O:43])[CH:41]=3.O>ClCCl.C(O)C>[CH3:27][C@@:28]12[C@@H:36]([OH:37])[CH2:35][CH2:34][C@H:33]1[C@@H:32]1[CH2:38][CH2:39][C:40]3[C@@:46]([CH3:47])([C@H:31]1[CH2:30][CH2:29]2)[CH2:45][CH2:44][C:42](=[O:43])[CH:41]=3.[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O-:13])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CCCC[C@H]1CC[C@H](C(=O)[O-])CC1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Trans-4-n-butylcyclohexanecarboxylic acid (11, 50.0 g, 0.27 mol) was added to a solution of trifluoroacetic anhydride (57.0 g, 0.27 mol) in dry dichloromethane (600 ml) and the resulting solution was stirred for 30 min. at 20° C. Testosterone (7, 78.3 g, 0.27 mol) was then added and the mixture was stirred for a further 2 hr at 20° C. After this period, water (500 ml) was added and the two layers were briskly stirred together for 15 min. The dichloromethane layer was separated and washed successively with saturated NaHCO3 (2×250 ml) and then H2O (250 ml). Evaporation of the solvent gave the crude testosterone ester (139.6 g), as an oil which solidified slowly on standing. The solid was dissolved in anhydrous ethanol (140 ml) by warming and the solution was then cooled to 5° C. and held at this temperature for 2 hr. The precipitated solid was filtered and recrystallised twice more from ethanol (70 ml and 80 ml) to give testosterone trans-4-n-butylcyclohexanecarboxylate (65 g, 99.1%) as a white crystalline solid, m.p. 132-134° C. It was identical with the sample prepared by means of Method A.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24]([NH2:27])[CH2:25][CH3:26]>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:27][CH2:24][CH2:25][CH3:26])[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: CCCN
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Product: CCCNc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and propylamine in DME. ES-MS m/e (%): 264 (M+H+, 100).
Reaction SMILES: [N:1]([C@H:4]([C:23](=[O:36])N1[C@H](C2C=CC=CC=2)COC1=O)[C@H:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:8]=1)[CH3:6])=[N+:2]=[N-:3].OO.[OH-:39].[Li+]>O.C1COCC1>[N:1]([C@@H:4]([C@H:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH:8]=1)[CH3:6])[C:23]([OH:36])=[O:39])=[N+:2]=[N-:3]
Reactant: [OH-]
Reactant: C[C@@H](c1cn(C(=O)OC(C)(C)C)c2ccccc12)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@H]1c1ccccc1
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](c1cn(C(=O)OC(C)(C)C)c2ccccc12)[C@H](N=[N+]=[N-])C(=O)O
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 3-((2S,3S)-3-azido-4-oxo-4-((R)-2-oxo-4-phenyloxazolidin-3-yl)butan-2-yl)-1H-indole-1-carboxylate (3.38 g, 6.90 mmol) in Water (29 mL) and THF (86 mL) at 0° C. was added hydrogen peroxide (4.67 ml, 45.7 mmol), then lithium hydroxide (0.331 g, 13.81 mmol). The reaction was stirred for 2 h. The reaction was quenched with Na2SO3 (7 g) in 40 mL water. The reaction was stirred for 30 min at rt. The solvent was removed under vacuum and then the reaction was diluted with EtOAc and water. The pH was adjusted to 2. The organic phase was collected, washed with brine, dried over sodium sulfate and concentrated under vacuum to give a residue which was triturated in Et2O to give a solid which was collected by filtration and dried to give (2S,3S)-2-azido-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid, 2.38 g (100%). ESI-MS(−) m/z 343.3 (M−H). 1H NMR (500 MHz, chloroform-d) d 8.15 (d, J=5.5 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.58-7.55 (m, 1H), 7.33 (td, J=7.7, 1.1 Hz, 1H), 7.27-7.23 (m, 1H), 4.29 (d, J=6.5 Hz, 1H), 3.68 (quin, J=6.9 Hz, 1H), 1.70 (s, 9H), 1.51 (d, J=7.1 Hz, 3H).
Reaction SMILES: C([CH:5]1[CH2:10][N+:9]([O-:19])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:8][CH2:7][N:6]1C([O-])=O)(C)(C)C>FC(F)(F)C(O)=O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N+:9]1([O-:19])[CH2:8][CH2:7][NH:6][CH2:5][CH2:10]1
Reactant: COc1ccccc1[N+]1([O-])CCN(C(=O)[O-])C(C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1[N+]1([O-])CCNCC1
Temperature: 0 °C
Yield: 74.4 %

Procedure:
To a stirred ice cold solution of 260 ml trifluoroacetic acid there was added under nitrogen, 26 g of tert-butyl-4-(2-methoxyphenyl)-1-piperazinecarboxylate 4-oxide and stirred for another 6 hours at ambient temperature. The solvent was removed in vacuo. The slurry was taken up in 200 ml ether and extracted twice with each 150 ml of water. The aqueous solution was applied to a column packed with 500 g Dowex 2 (×4, 20-50 mesh, OH- form) and the N-oxide-base eluted with water. After evaporation of the solvent in vacuo, the white foam (18.6 g) was dissolved in a minumum of methylene chloride and the base precipitated by addition of diisopropylether to give 13.1 g colorless hygroscopic crystals of 1-(2-methoxyphenyl)piperazine 1-oxide, mp 157°-160°. The dihydrochloride was crystallized from ethanol/ether, mp 192°-194°.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][CH3:3].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.[C:25]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1C(O)=O)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>ClCCl.C(OCC)(=O)C>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:25]2[N:33]3[C:34]([CH2:35][CH2:36][CH2:37][CH2:38]3)=[C:2]([C:1]([O:5][CH3:6])=[O:4])[CH:3]=2)[CH:27]=1
Reactant: CCC(=O)OC
Reactant: O=C(O)C1CCCCN1C(=O)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2cccnc2)n2c1CCCC2

Procedure:
1.33 g of methyl propionate are added to a solution of 3.01 g of para-toluenesulphonyl chloride in 17 cm3 of dichloromethane. A solution of the triethylamine salt of N-nicotinoylpiperidine-2-carboxylic acid in 17 cm3 of dichloromethane, prepared from 3.38 g of N-nicotinoylpiperidine-2-carboxylic acid and 2 cm3 of triethylamine, is added slowly with stirring. 2.3 cm3 of triethylamine are then added slowly. The mixture is kept at 25° C. with stirring overnight at ambient temperature. The reaction mixture is concentrated at reduced pressure (2.7 kPa) at a temperature close to 40° C. A residue is thus obtained, which is taken up in 25 cm3 of ethyl acetate and filtered. The filtrate is concentrated at reduced pressure (2.7 kPa) at a temperature close to 40° C. This residue is taken up again in 25 cm3 of ethyl acetate and filtered and then the filtrate is concentrated to dryness. The residue is crystallized from 15 cm3 of ethyl ether. The solid is filtered off and dried in air. 1.1 g of methyl 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate are thus obtained in the form of a cream solid melting at 122° C., containing approximately 5% of methyl 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-2-carboxylate.
Reaction SMILES: C(OC[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C@H:15]1[O:19][C:18](=[O:20])[N:17]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2[C:32]2[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[C:35]([F:41])=[CH:34][C:33]=2[O:42][CH3:43])[C@H:16]1[CH3:44])C1C=CC=CC=1.Cl>CO.[OH-].[OH-].[Pd+2]>[F:41][C:35]1[C:36]([CH:38]([CH3:40])[CH3:39])=[CH:37][C:32]([C:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:29])[F:30])=[CH:27][C:22]=2[CH2:21][N:17]2[C@@H:16]([CH3:44])[C@H:15]([C:11]3[NH:12][CH:13]=[CH:14][N:10]=3)[O:19][C:18]2=[O:20])=[C:33]([O:42][CH3:43])[CH:34]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2nccn2COCc2ccccc2)[C@@H]1C
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@@H](c2ncc[nH]2)[C@@H]1C
Reaction time: 8 h

Procedure:
A mixture of (4S,5S)-5-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 244) (16.9 mg, 0.028 mmol), 20% palladium hydroxide on carbon (8.3 mg) and 1N HCl (28 uL) in MeOH (1 mL) was stirred under hydrogen (balloon) overnight, after which time it was filtered through Celite and concentrated in vacuo. The crude material was purified by flash chromatography to afford (4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-(1H-imidazol-2-yl)-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=492.18; found=492.2 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.71 (s, 0.5 H); 7.67 (s, 0.5 H); 7.65 (s, 0.5 H); 7.64 (s, 0.5 H); 7.37 (d, J=3.2 Hz, 0.5 H); 7.35 (d, J=3.3 Hz, 0.5 H); 7.09 (d, 2 H); 7.02 (d, J=8.4 Hz, 0.5 H); 6.99 (d, J=8.5 Hz, 0.5 H); 6.72 (d, J=4.3 Hz, 0.5 H); 6.69 (d, J=4.2 Hz, 0.5H); 5.76 (d, J=8.3 Hz, 0.5 H); 5.64 (d, J=8.7 Hz, 0.5 H); 4.72 (d, J=15.8 Hz, 0.5 H); 4.68 (d, J=15.8 Hz, 0.5 H); 4.20 (d, J=15.7 Hz, 0.5 H); 4.01 (d, J=15.7 Hz, 0.5 H); 3.90 (br, s, 1H); 3.79-3.72 (m, 4H); 3.25-3.18 (m, 1 H); 1.28-1.22 (m, 6 H); 0.67 (d, J=6.5 Hz, 1.5 H); 0.59 (d, J=6.5 Hz, 1.5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8](O)=[O:9].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([Cl:16])=[O:9]
Reactant: COc1cccc(C=CC(=O)O)c1
Reactant: O=S(Cl)Cl
Product: COc1cccc(C=CC(=O)Cl)c1

Procedure:
A solution of 3-methoxycinnamic acid (75.0 g, 0.42 mol) in thionyl chloride (250 mL) was heated at reflux for 1 h. The majority of the the thionyl chloride was then distilled off and the resulting residue was treated with dichloromethane and residual thionyl chloride was removed by codistillation to give 3-methoxycinnamic acid chloride of sufficient purity to be used without further purification. Pyridine (186 mL, 2.3 mol) and N,O-dimethylhydroxylamine hydrochloride (45.17 g, 0.46 mol) were added to a 0° C. solution of 3-methoxycinnamic acid chloride(0.42 mol) in dry dichloromethane (500 mL). The solution was stirred for 18 h at room temperature, diluted with dichloromethane (200 mL), and washed sequentially with 1N HCl, saturated sodium bicarbonate, and brine. It was then dried over MgSO4 and concentrated in vacuo to give the title compound as a dark oil (88.43 g, 95%): 1H NMR (300 MHz, CDCl3) δ 3.25 (s, 3H), 3.68 (s, 3H), 3.84 (s, 3H), 6.82-6.86 (m, 1H), 7.00 (d, J=16.1 Hz, 1H), 7.10 (br s, 1H), 7.15-7.20 (m, 1H), 7.32 (t, J=6.6 Hz, 1H), 7.72 (d, J=16.0 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.C(Cl)(Cl)=O.ClC([O-])=O.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2(C3C=CC(O)=CC=3)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>C(Cl)Cl>[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)CCCCCCCCCCC2)cc1
Agent: O=C(Cl)Cl
Agent: O=C([O-])Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Oc1ccc(C2CCCCCCCCCCC2)cc1
Temperature: 18.75 °C
Reaction time: 2 h

Procedure:
43.6 g (0.124 mol) of 1,1-bis(4-hydroxyphenyl)-cyclododecane was suspended in 410 mL of methylene chloride, to which 25.0 g (0.248 mol) of triethylamine was added for dissolution. The obtained solution was dropped into a solution, which was prepared by dissolving 24.8 g (0.250 mol) of phosgene in 225 mL of methylene chloride, at 14 to 18.5 degrees C. for 2 hours and 50 minutes. After stirring at 18.5 to 19 degrees C. for one hour, 250 mL of methylene chloride was distilled away at 10 to 22 degrees C. 73 mL of deionized water, 4.5 mL of concentrated hydrochloric acid and 0.47 g of hydrosulphite were added to the residual solution for cleaning. Subsequently, cleaning with 330 mL of deionized water was repeated four times. A methylene chloride solution of a 1,1-bis(4-hydroxyphenyl)-cyclododecane oligomer having a chloroformate group at its molecular terminal was obtained. The obtained solution had a chloroformate concentration of 0.92 mol/L, a solid concentration of 0.23 kg/L and an average number of repeating units of 1.06. A content of an amide compound in the obtained 1,1-bis(4-hydroxyphenyl)-cyclododecane oligomer was found to be 210 mass ppm. A mass of nitrogen derived from triethylamine was 0.3 mass ppm. This obtained ingredient will be referred to as “CDE-CF” hereinafter.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][C@:11]2([CH2:17]OS(C)(=O)=O)[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[I-].CO[CH2:27][CH2:28]OC>[Zn]>[CH2:27]([O:16][C:14]([C@@H:13]1[CH2:12][C@:11]2([CH3:17])[C@@H:9]([CH2:10]2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:15])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)O)C[C@@]2(COS(C)(=O)=O)C[C@@H]12
Reactant: COCCOC
Agent: [I-]
Agent: [Na+]
Agent: [Zn]
Product: CCOC(=O)[C@@H]1C[C@@]2(C)C[C@H]2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R,3S,5S)-5-methanesulfonyloxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (100 mg, 0.24 mmol) in DME (2.6 mL) were successively added NaI (355 mg, 2.37 mmol) and zinc powder (155 mg, 2.37 mmol). The reaction mixture was refluxed 30 min under argon atmosphere, cooled to RT and quenched by addition of a saturated aqueous solution of NH4Cl (1.6 mL). CH2Cl2 (1.6 mL) and few Na2S crystals were added and the biphasic mixture was stirred at RT for 1 h. The layers were separated, the organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane to c-hexane/EtOAc). TLC, Rf (c-hexane/EtOAc 2:1)=0.60; MS (UPLC/MS): 270.3 [M+H]+, 214.2 [MH−tBu]+, 170.2 [MH−Boc]+; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 4.11 (m, 2H), 3.95 (m, 1H), 3.10 (m, 1H), 2.42 (m, 1H), 1.84 (m, 1H), 1.38 (m, 9H), 1.20 (t, 3H), 1.18 (s, 3H) 0.69 (dd, 1H), 0.64 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCC[CH2:22]1>C[Mg]Br>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16]([C:15]([CH3:22])=[CH:14][CH2:13][CH2:12]2)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C1CCCc2cc(OCc3ccccc3)ccc21
Agent: C[Mg]Br
Agent: Cl
Product: CC1=CCCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the obtained 6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-one (34.5 g) in tetrahydrofuran (300 mL), methyl magnesium bromide (3M diethyl ether solution, 55 mL) was added at 0° C., followed by stirring at room temperature for 1 hour. The reaction mixture was cooled to 0° C. and poured into ice-saturated aqueous ammonium chloride solution. After adding 2N hydrochloric acid, the mixture was stirred at room temperature for 3 hours. Then, the resultant was extracted with ethyl acetate and the organic layer was successively washed with water and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to thereby give the title compound (24.8 g) having the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:31]=1[CH2:32]Br>CC#N>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:32][C:31]3[C:30]([Cl:29])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:38])=[CH:19][CH:20]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OCc3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (5.00 g; 16.3 mmol) and K2CO3 (6.74 g; 48.8 mmol) in CH3CN (100 mL) was stirred for one hour at RT. Subsequently 2,6-dichlorobenzyl bromide (4.29 g; 17.9 mmol) was added and the resulting mixture was stirred overnight at RT. The reaction mixture was partitioned between EtOAc (250 mL) and 5% aqueous NaHCO3 solution (100 mL). The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1) to afford 3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester (7.40 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:15][CH2:14][CH2:13][Br:12])[CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: Fc1ccc2c(c1)OCCN2
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)OCCN2CCCBr
Temperature: 70 °C
Yield: 47.3 %

Procedure:
A mixture of 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.3 g, 1 eq, 8.49 mmol) obtained in step (iii) above, 1,3-dibromo propane (8.6 ml, 10 eq, 84.9 mmol) and anhydrous sodium carbonate (2.7 g, 3 eq, 25.4 mmol) in dry DMF (85 ml) was heated at 70° C. for 16 h. The reaction was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to afford the title compound (1.1 g, yield 47%) as viscous oil.