Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:11]=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[C:54](C)[CH:53]=[CH:52][N:51]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([CH3:11])=[CH:52][N:51]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1ccnc(N)c1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: Cc1ccc(NC(=O)[C@H](CC2CCCCC2)N2Cc3ccccc3C2=O)nc1
Yield: 30 %

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 287 mg; 1.00 mmol) and 2-amino-4-methylpyridine (143 mg; 1.32 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 1, Step B) provided after flash chromatography (Biotage 40S; eluent: 30% ethyl acetate/hexanes) 344 mg of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-4-methyl-pyridin-2-yl-propionamide as a white foam: EI-HRMS m/e calcd for C23H27N3O2 (M+) 377.2103, found 377.2106.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 90 °C
Yield: 106.4 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 111.10 mmol) in AcN (200 mL) were added K2CO3(145.9 g, 333.30 mmol) and 2-(chloromethyl) quinoline (28.50 g, 133.32 mmol) at RT. The reaction mixture was heated at 90° C. for 12 h and then cooled to RT and filtered. The filtrate was concentrated in vacuo. The residue was then diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water, a saturated NH4Cl solution, and then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (38.0 g, 89%) as a solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[N+:8]([O-:11])([OH:10])=[O:9]>>[N+:8]([O-:11])([O-:10])=[O:9].[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])O
Product: CC[NH+](CC)CC
Product: O=[N+]([O-])[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
Ceric hydroxide (10.4 gm, 50 mmole) was dissolved in 35 ml of nitric acid with heating. The solution was allowed to cool slightly and triethylamine (20.9 ml, 150 mmole) was added dropwise over a period of about 5 minutes. The resulting reaction mixture was stirred at room temperature for 3 hours and then cooled in an ice bath. The resulting orange precipitate was filtered, washed quickly with deionized water, and recrystallized from hot water to give 4 gm of orange solid, mp 135° C. (yield 11%)
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([CH3:17])[C:10]=1[CH3:18]>C(OCC)(=O)C>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[C:10]([CH3:18])[C:11]=1[CH3:17])#[N:14]
Reactant: Cc1c(N)ccc(C#N)c1C
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C#N)c(C)c1C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
Acetic anhydride (1.36 ml, 14.4 mmol) was added to a solution of 4-amino-2,3-dimethylbenzonitrile (1.32 g, 9.03 mmol) in ethyl acetate (10 ml) at room temperature, and then the reaction was carried out for 4 hours under reflux conditions. After the reaction mixture was cooled, the precipitate obtained was collected by filtration and dried to obtain N-(4-cyano-2,3-dimethylphenyl)acetamide (1.39 g, 81.8%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C(OC([CH2:35][NH:36][C@@H:37]([CH2:41][OH:42])[C:38](O)=[O:39])=O)(C)(C)C>>[OH:42][CH2:41][C@H:37]([NH:36][CH3:35])[C:38]([NH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:27])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)=[O:39]
Reactant: CC(C)(C)OC(=O)CN[C@@H](CO)C(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Cl
Product: CN[C@@H](CO)C(=O)NC1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1

Procedure:
The preparation was carried out analogously starting from 50 mg (0.12 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 33 mg (0.13 mmol) of (S)-2-(tert-butoxycarbonylmethylamino)-3-hydroxypropionic acid. The product was purified by means of flash chromatography on silica gel. The protecting group was cleaved off analogously using HCl in methanol.
Reaction SMILES: COC1C=C(OC)C(OC)=CC=1C(N[C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1)=O.C(N(C(C)C)CCNC)(C)C.S([O-])(O)(=O)=O.[K+].C(OC(C)C)(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:16]([O:15][C:13]([C:11]1[N:12]=[CH:8][S:9][CH:10]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2OC)n1
Agent: CNCCN(C(C)C)C(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cscn1
Yield: 86 %

Procedure:
A suspension (1.5 ml) of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-(ethoxycarbonyl)-1,3-thiazole (732 mg) and N,N-diisopropyl-N′-methylethylenediamine (1.60 g) in dimethylacetamide was stirred at 140° C. for 5 hours. To the reaction mixture, an aqueous solution of potassium hydrogensulfate, a small quantity of ethyl acetate, and a small quantity of isopropyl ether were added for precipitation of crystals. Crystals so precipitated were collected by filtration and dried to thereby obtain 601 mg of 2-[N-4,5-dimethoxy-2-hydroxybenzoyl)amino]-4-(ethoxycarbonyl)-1,3-thiazole (yield: 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OCC[Si](C)(C)C)=O)[CH2:10][CH:9]2[O:23][CH2:24][C:25]2[CH:34]=[C:33]([OH:35])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:4][CH:3]=1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:23][CH2:24][C:25]2[CH:34]=[C:33]([OH:35])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(c2ccc(F)cc2)C(OCc2cc(O)c3ccccc3c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Oc1cc(COC2CNCCC2c2ccc(F)cc2)cc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
70 mg (0.141 mmol) of β-trimethylsilylethyl (3RS,4RS)-4-(4-fluorophenyl)-3-(4-hydroxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate were dissolved in 1.0 ml of tetrabutylammonium fluoride solution (1 M in tetrahydrofuran) and stirred at room temperature for one hour. Subsequently, the mixture was partitioned between methylene chloride and aqueous 5% sodium hydrogen carbonate solution, then the organic phase was dried over magnesium sulphate and finally the solvent was distilled off under reduced pressure. The crude product (72 mg) was purified by chromatography on silica gel with a 10:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained 41 mg (83% of theory) of (3RS,4RS)-4-(4-fluorophenyl)-3-(4-hydroxy-naphthalen-2-ylmethoxy)-piperidine as a colourless solid. MS: 352 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH2:12][N:13]3C(OC(C)(C)C)=O)[CH2:10]2)=[N:6][CH:7]=1.Cl>CCOC(C)=O.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH2:12][NH:13]3)[CH2:10]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H](Oc3ccc(Br)cn3)[C@@H]1C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Brc1ccc(O[C@@H]2C[C@@H]3CN[C@H]2C3)nc1
Reaction time: 3.25 h
Yield: 1177.2 %

Procedure:
xHCl. To the title compound of step A (149 mg, 0.0404 mmol) in EtOAc (1.5 mL) was added 4M HCl in dioxane (5 mL). After 3.25 h, the reaction was concentrated to give the title compound of step B (128 mg) which was used without further purification. MS (ESI) mass calcd. for C11H13BrN2O, 268.0. m/z found 269.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([Cl:63])[C:58]=2[F:64])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([Cl:63])[C:58]=2[F:64])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(Cl)c2F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(Cl)c2F)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.7 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 96 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-chloro-2-fluoro-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 4.5 h at rt, the reaction mixture was diluted with 50 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 107 mg white solid (68%). MS (ISP) 498.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8]
Reactant: Nc1ccccc1
Reactant: COc1cc(C(=O)O)ccn1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)Nc2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 6 h
Yield: 83.9 %

Procedure:
To a solution of 2-methoxyisonicotinic acid (2.00 g, 13.06 mmol) in anhydrous tetrahydrofuran (80 mL) was added 4-methyl morpholine (1.84 g, 18.28 mmol). After cooling to 0° C., isobutyl chloroformate (2.31 g, 16.98 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 6 hours, followed by the addition of aniline (1.70 g, 18.28 mmol). The resulting mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 mL) and washed with saturated aqueous sodium bicarbonate (2×50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford 2-methoxy-N-phenylisonicotinamide (2.50 g, 86%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 11.85 (s, 1H), 10.31 (s, 1H), 7.75-7.60 (m, 2H), 7.47 (d, J=4.6 Hz, 1H), 7.35-7.20 (m, 2H), 7.12-7.04 (m, 1H), 6.83-6.80 (m, 1H), 6.54-6.42 (m, 1H); MS (ES+) m/z 229.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH3:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(Br)cc2)c1
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a stirred mixture of the product of Step A (0.5 g 1.46 mmol) and K2CO3 (0.5 g) in anhydrous DMF (7 ml) was added CH3I (1 ml) and the stirring continued for 0.5 h at 50° C. The mixture was diluted to 50 ml with H2O and extracted with EtOAc (50 ml). The organic layer was washed with H2O and dried over MgSO4, passed through silica gel bead and the filtrate was evaporated to dryness to give the title compound (0.5 g, 96%) as pale solid. 1H-NMR (CDCl3) 7.58 (d, 2H, J=8.64 Hz); 7.40 (d, 2H, J=8.67 Hz); 7.18 (t, 1H, J=8.15 Hz); 6.80 (dd, 1H, J=8.34, 2.5 Hz); 6.69 (t, 1H, J=2.20 Hz); 6.58 (bd, 1H); 3.75 (s, 3H, OMe); 3.14 (s, 3H, N-Me).
Reaction SMILES: [PH3:1]=[O:2].[C:3]1([Li])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)(=O)C.CC(O)C.[CH3:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[PH3:1]=[O:2].[C:3]1([PH:1](=[O:2])[C:22]2[CH:21]=[CH:20][CH:25]=[CH:24][CH:23]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCC
Reactant: [Li]c1ccccc1
Agent: O=[PH3]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=[PH](c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To a stirred solution of phosphine oxide 10 (45 mg, 77 μmol) in anhydrous THF (600 μl) a 1.5 M solution of phenyl lithium in THF (75 μl, 105 μmol) was added at −20° C. under argon. The mixture was stirred for 20 min. and then cooled to −78° C. A precooled solution of 9 (6 mg, 33 μmol) in anhydrous THF (200 μl) was added via cannula and the reaction mixture was stirred for 3 h at −78° C. After that the reaction mixture was stirred at 4° C. overnight. Then ethyl acetate was added and organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on Waters silica gel Sep-Pack cartridge (hexane to 3% ethyl acetate/hexane) and then on HPLC (0.03% 2-propanol/hexane, 4 mL/min., Zorbax-silica 10×250 mm) to give 11.4 mg (21 mmol, 64% yield) of 11 at Rt=7.08 min. UV (hexane) λmax=242, 250, 261 nm; 1H NMR (400 MHz, CDCl3) δ 0.03 (3H, s), 0.04 (3H, s), 0.07 (3H, s), 0.08 (3H, s), 0.80 (3H, d, J=6.8 Hz), 0.86 (9H, s), 0.89 (9H, s), 2.18 (1H, dd, J=12.4 Hz, J=7.7 Hz), 2.86 (1H, br d, J=13.8 Hz), 4.42 (1H, m), 4.93 (1H, s), 4.96 (1H, s), 5.93 (1H, d, J=11.2 Hz), 6.20 (1H, d, J=11.2 Hz); 13C NMR (100 MHz, CDCl3) δ −5.1, −4.9, −4.8, 18.2, 18,2, 18.3, 21.6, 24.6, 25.8, 25.8, 27.8, 28.9, 29.8, 31.9, 38.7, 47.5, 50.7, 50.8, 52.7, 71:9, 72.3, 106.3, 113.7, 122.4, 132.9, 143.7, 153.0; MS (EI) m/z 544 (3, M+), 448 (9), 412 (36), 366 (14), 313 (11), 290 (100); exact mass calculated for C33H60O2Si2 544.4132, found 544.4131.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:26][CH:27]1[O:32][CH:31]([CH3:33])[CH2:30][NH:29][CH2:28]1.O>CN(C)C=O>[CH3:33][CH:31]1[O:32][CH:27]([CH3:26])[CH2:28][N:29]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:30]1
Reactant: CS(=O)(=O)OC1CCN(c2ccc(C#N)cc2)CC1
Reactant: CC1CNCC(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(C2CCN(c3ccc(C#N)cc3)CC2)CC(C)O1
Temperature: 92.5 °C
Reaction time: 6 h
Yield: 43.8 %

Procedure:
To a solution of 4-(4-methanesulfonyloxypiperidin-1-yl)benzonitrile (4.90 g) in N,N-dimethylformamide (DMF) (50 ml) were added potassium carbonate (4.83 g) and 2,6-dimethylmorpholine (3.02 g), and the mixture was stirred at 90-95° C. for 6 hours. After cooling, the reaction mixture was poured into water (300 ml) and extracted twice with a mixture of ethyl acetate and n-hexane (100 ml:30 ml). The extracts were combined and washed in turn with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting precipitates were washed with IPE (100 ml), collected by filtration and dried in vacuo to give 4-[4-(2,6-dimethylmorpholin-4-yl)piperidin-1-yl]benzonitrile (2.29 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].BrC1C=CC(Cl)=CC=1[CH2:20][O:21][CH2:22]OC>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH2:4][O:5][CH2:20][O:21][CH3:22]
Reactant: COCOCc1cc(Cl)ccc1Br
Reactant: O=C(O)c1c(F)cccc1Br
Product: COCOCc1c(F)cccc1Br

Procedure:
This compound was made from 2-bromo-6-fluorobenzoic acid in the same manner as compound 18d: 1H NMR (300 MHz, CDCl3) δ (ppm) 3.43 (s, 3H), 4.74 (s, 2H), 4.76 (d, J=2.1 Hz, 2H), 7.05 (t, J=9.1 Hz, 1H), 7.18 (td, J=8.2, 5.9 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H).
Reaction SMILES: [Cl:1]C(OC=C)=O.[F:7][C:8]1[CH:25]=[CH:24][C:11]2[C:12]([CH:15]3[CH2:21][CH:20]4[N:22](C)[CH:17]([CH2:18][CH2:19]4)[CH2:16]3)=[N:13][O:14][C:10]=2[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[ClH:1].[F:7][C:8]1[CH:25]=[CH:24][C:11]2[C:12]([CH:15]3[CH2:16][CH:17]4[NH:22][CH:20]([CH2:19][CH2:18]4)[CH2:21]3)=[N:13][O:14][C:10]=2[CH:9]=1
Reactant: CN1C2CCC1CC(c1noc3cc(F)ccc13)C2
Reactant: C=COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: Cl
Product: Fc1ccc2c(C3CC4CCC(C3)N4)noc2c1

Procedure:
Vinyl chloroformate (2.9 g) was added dropwise to a solution of 3-(6-fluoro-1,2-benzisoxazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane (5.6 g) and potassium carbonate (3.6 g) in 125 ml of 1,2-dichloroethane at 0° C. The resulting suspension was heated at reflux for 3 hours, the solution was cooled, and the solvent was removed in vacuo. The residue was suspended in 125 mL of ethanol and acidified with HCl in ethanol (to about a pH of 1), and the mixture was heated at reflux for 2 hours. The mixture was cooled, and 3.6 g of 3-(6-fluoro-1,2-benzisoxazol-3-yl)-8-azabicyclo[3.2.1]octane hydrochloride, m.p. 248°-250° C., crystallized out of solution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]=[C:11]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:12]([NH2:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:33])=[CH:4][C:3]=1[N:10]=[C:11]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:12]([NH2:14])=[O:13]
Reactant: NC(=O)C(=Nc1cc(O)c(Cl)cc1Cl)N1CCCC1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1cc(N=C(C(N)=O)N2CCCC2)c(Cl)cc1Cl
Yield: 55.6 %

Procedure:
0.5 g of the obtained 2-(2,4-dichloro-5-hydroxyphenylimino)-2-(pyrrolidine-1-yl)acetamide was dissolved in 50 ml of acetonitrile and 0.25 g of potassium carbonate was then added and the entire mixture was heated to reflux for 1 hour. 0.37 g of ethyl 2-bromopropionate was added to the resulting reaction solution and further heated to reflux for 1 hour. Insolubles were removed from the resultant reaction solution by filtration and the concentrate obtained by evaporating solvents from the filtrate by evaporation under reduced pressure was purified by silica gel column chromatography to obtain 0.37 g of 2-[2,4-dichloro-5-(1-ethoxycarbonylethoxy)phenylimino]-2-(pyrrolidine-1-yl)acetamide (1-3) (yield 55%). m.p. 160-163° C.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=2)[O:10][C:11]=1[CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:13]([C:9]2[O:10][C:11]([CH3:12])=[C:7]([CH:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[CH:26][CH:27]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2cc(C(Cl)CC(C)C)c(C)o2)cn1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (382 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (400 mg), sodium carbonate (170 mg) and sodium iodide (240 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 65% ethyl acetate/hexane) to give ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. The obtained ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.7 mL) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (153 mg, 25%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15](=[O:28])[C:16]([OH:27])([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH2:10]1.C[Br:30].[CH3:31]COCC>C(#N)C.C(Cl)(Cl)Cl>[Br-:30].[OH:27][C:16]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:15]([O:14][C@@H:11]1[CH2:12][CH2:13][N+:9]([CH3:31])([CH2:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:10]1)=[O:28]
Reactant: CCOCC
Reactant: CBr
Reactant: O=C(O[C@@H]1CCN(CCCc2cccs2)C1)C(O)(c1cccs1)c1cccs1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C[N+]1(CCCc2cccs2)CC[C@@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.3 g (0.00069 mol) of 2-Hydroxy-2,2-dithien-2-ylacetic acid (3R)-1-(3-thien-2-ylpropyl)pyrrolidin-3-yl ester (Intermediate 1-3) were dissolved in 4 ml of acetonitrile and 6 ml of CHCl3. To this solution 3.45 ml (0.00345 mol) of a 1 M solution of methyl bromide in acetonitrile were added. After stirring the mixture at room temperature under N2 atmosphere during 24 h, the solvents were evaporated. Ether was added to the residue and the mixture stirred to obtain a solid. This solid was treated with ether several times, filtered and washed with ether. The yield was 0.34 g (93.2%) of the title compound as a mixture of two stereoisomers.