Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH2:16].O1CCOC[CH2:24]1>>[CH3:24][C:20]1[C:14]2[C:13](=[O:22])[O:21][C:6](=[O:7])[NH:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: C1COCCO1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: Cc1cccc2[nH]c(=O)oc(=O)c12
Temperature: 25 °C
Yield: 87 %

Procedure:
To a suspension of CDI (49.35 g, 305 mmol) in 100 mL of dioxane was added at room temperature a solution of the anthranilic acid (20 g, 132 mmol) in 100 mL of dioxane over 30 minutes. The reaction was stirred at ambient temperature until the mild exotherm subsided. The reaction mixture was filtered through a bed of silica gel (dioxane), concentrated then diluted with about 200 mL of water. The resulting precipitate was filtered, washed with water and dried affording 20.3 g (87%) of 5-methyl-2H-3,1-benzoxazin-2,4 (1H)-dione.
Reaction SMILES: [CH:1]1([CH2:7][PH:8](=[O:10])[O-:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11](N(CC)CC)[CH3:12]>O1CCCC1>[CH:1]1([CH2:7][PH:8](=[O:9])[O:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=[PH]([O-])CC1CCCCC1
Solvent: C1CCOC1
Product: CCO[PH](=O)CC1CCCCC1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
19.3 g of cyclohexylmethylphosphinate are dissolved in 60 ml of absolute tetrahydrofuran under an inert atmosphere. The solution is cooled to 0° C. and a suspension forms which is treated with 12.14 g of triethylamine. An exothermic reaction occurs. The suspension is re-cooled to 0° C. before dropwise addition of 13.02 g of ethylcycloformate. A further exothermic reaction with gas-evolution is observed together with the formation of a white precipitate. The resulting suspension is warmed to 20° and stirred for 20 hours. The solid is removed by filtration and the filtrate is evaporated to dryness. The residue is dissolved in dichloromethane and washed with water. Drying and removal of the solvent affords a pale yellow oil. Distillation under high vacuum affords ethyl cyclohexylmethylphosphinate, b.p. 120°-130° C./2×10-1 mbar. 'H-NMR (CDCl3): δ (ppm)=7.17 (1 H, d, t, 5=527 MZ, P-H), 4.13 (2 H, m, CH2OP), 1.95-1.58 (7 H, m, 3×CH2 +CH), 1.38-0.95 (6 H, m, 3×CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][NH:7]1.Br[CH2:27][C:28](Br)=[O:29].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][NH2:38]>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][N:7]1[CH2:27][C:28]([NH:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=1)=[O:29]
Reactant: NCc1ccccn1
Reactant: COc1ccc(OC)c(CC2NCCc3c(OC)ccc(OC)c32)c1
Reactant: O=C(Br)CBr
Product: COc1ccc(OC)c(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)c1

Procedure:
prepared by reaction of 1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Li])CCC.C([Cu])#N.C(OC([N:24]1[C:28]2=[N:29][CH:30]=[C:31]([Cl:33])[CH:32]=[C:27]2[C:26]([CH2:34]Cl)=[CH:25]1)=O)(C)(C)C.N>O1CCCC1.CCCCCC.O>[Cl:33][C:31]1[CH:32]=[C:27]2[C:26]([CH2:34][C:7]3[C:2]([F:1])=[N:3][C:4]([F:8])=[CH:5][CH:6]=3)=[CH:25][NH:24][C:28]2=[N:29][CH:30]=1
Reactant: Fc1cccc(F)n1
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cc(Cl)cnc21
Agent: N#C[Cu]
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Fc1ccc(Cc2c[nH]c3ncc(Cl)cc23)c(F)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 2,6-Difluoropyridine (58, 3.40 g, 0.0295 mol) in tetrahydrofuran (200.0 mL), under an atmosphere of nitrogen at −78° C., 2.50M of n-butyllithium in hexane (12.0 mL) was added slowly. After 60 minutes, CuCN.2LiCl (0.75M in tetrahydrofuran, 40.0 mL) was added to the reaction mixture. After 5 minutes, 5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (535, 4.20 g, 0.0139 mol, prepared as described in Example 49, Scheme 164) in tetrahydrofuran (20 mL) was added to the reaction. The reaction was stirred at −78° C. overnight, then poured into water and ammonia (10 mL), and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 15% ethyl acetate in hexane to give a white solid (P-0155, 300 mg, 7.7%). MS (ESI) [M−H+]−=278.1.
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@@H:3]([OH:7])[CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=1[C:19]([O:21][CH3:22])=[O:20].O>ClC1C=CC=CC=1.CN1CCCN(C)C1=O>[OH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:1]([O:8][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:2]1
Reactant: O[C@@H]1CCC[C@H](O)C1
Reactant: COC(=O)c1c(C)cccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: Clc1ccccc1
Product: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](O)C1
Yield: 13.7 %

Procedure:
5 g (42.8 mmol) of cis-1,3-cyclohexanediol were dissolved in 40 ml of chlorobenzene and 10 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, dimethylpropyleneurea), admixed at 20–23° C. with 3.36 g (30 mmol) of potassium tert-butoxide (KOtBu) and stirred. After 10–15 minutes, the mixture was cooled to 15–20° C. and 3.7 g (approx. 50%) of methyl 2-bromomethyl-6-methylbenzoate were added dropwise. The mixture was stirred at 20° C. for 1.5 h and then added to water. The organic phase was removed and concentrated under reduced pressure. The residue was taken up in NMP/water and, to remove impurities, washed twice with n-heptane. Subsequently, the product was isolated by extracting twice with MTBE. The combined MTBE phases were washed with water, dried (Na2SO4) and concentrated under reduced pressure. The residue (1.2 g) was chromatographed on silica gel (1:1 ethyl acetate/n-heptane). 580 mg of the desired compound were obtained as a slightly yellow oil; 1H-NMR (CDCl3), δ =1.27 (m, 1H), 1.45 (m, 1H), 1.55 (m, 1H), 1.74 (m, 1H), 1.83 (m, 1H), 2.05 (m, 1H), 2.34 (s, 3H), 3.47 (m, 1H), 3.72 (m, 1H), 3.91 (s, 3H), 4.58 (dd, 2H), 7.15 (d, 1H), 7.20 (d, 2H), 7.27 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([Cl:12])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[C:4]([CH:13]=O)=[C:3]1Cl.C([O-])([O-])=O.[K+].[K+].[SH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[C:10]2[C:5]=1[C:4]1[CH:13]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[S:22][C:3]=1[N:2]2[CH3:1]
Reactant: COC(=O)CS
Reactant: Cn1c(Cl)c(C=O)c2c(Cl)cc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3c(Cl)cc(Cl)cc3n(C)c2s1
Yield: 32.5 %

Procedure:
Prepared from (48) (6.5 g), K2CO3 (9.59 g) and methyl 2-mercaptoacetate (3.82 ml) yielding (53) 2.5 g (32.5%). M.p. 231°-232° C. The product was purified by cromatography on silicagel using toluene as eluent. The compound was crystallized by trituration with methanol.
Reaction SMILES: C(OC([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[C:28]([NH:38][C:39](=[O:47])[C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[N:27]=1)=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:48]>CO.C(Cl)(Cl)Cl.C(OCC)(=O)C>[ClH:46].[ClH:48].[C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[C:28]([NH:38][C:39](=[O:47])[C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[N:27]=1)(=[NH:8])[NH2:10]
Reactant: COc1ccc2nc(NC(=O)c3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc2nc(NC(=O)c3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=N)N)c2c1

Procedure:
A solution of 120 mg of cis-N-[N,N′-bis(tert-butoxycarbonyl)]amidino-2-[2-(4-chlorobenzoylamino)-6-methoxyquinazolin-4-yl]aminocyclohexylamine in 5 mL of methanol and 5 mL of chloroform was combined with 3 mL of a 4N solution of hydrogen chloride in ethyl acetate, and reacted at 50° C. for 72 hours. After concentrating, treatment was performed with methanol-ethyl ether to obtain 22 mg of the desirable compound as pale yellow powder.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:54]([O:61][C:62]1[CH:70]=[CH:69][C:65]([C:66](O)=[O:67])=[CH:64][N:63]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C=O)C.O>[CH2:54]([O:61][C:62]1[CH:70]=[CH:69][C:65]([C:66]([NH:11][CH2:12][C:13](=[O:14])[N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]2)=[O:67])=[CH:64][N:63]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)nc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 45.1 %

Procedure:
DIPEA (253 mg, 0.34 mL, 1.9 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (184 mg, 0.52 mmol) in DMF (4 mL). HOBT (64.8 mg, 0.479 mmol) and EDCI (167 mg, 0.87 mmol) were then added at room temperature. After 2 minutes, 6-benzyloxy-nicotinic acid (100 mg, 0.43 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 102 mg (45.33% yield) 6-benzyloxy-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-nicotinamide. LCMS Purity: 98.91%. 1H NMR (DMSO-d6): δ 8.7 (d, 2H), 8.2-8.1 (d, 1H), 7.9-7.64 (m, 5H), 7.62-7.5 (m, 1H), 7.5-7.3 (m, 3H), 7.0-6.9 (d, 1H), 5.4 (s, 2H), 4.24-4.06 (d, 2H), 3.8-3.56 (m, 4H), 3.54-3.4 (m, 2H), 3.2-3.02 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH:19]=[C:20]([C:2]2[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1cc(F)cnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ncc(F)cc2N)CC1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A degassed solution of 2-chloro-5-fluoro-3-amino-pyridine (3.5 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8.89 g) (prepared as described in WO 2006/003494) and bis(triphenylphosphine)palladium(II) chloride (0.84 g) in dioxane (157 ml) was treated with a degassed solution of sodium carbonate (7.6 g) in water (72 ml). The reaction mixture was stirred at reflux for 1 hour, cooled to ambient temperature and the solvent evaporated in vacuo. The residue was diluted with ethyl acetate, washed with water then brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane/ethyl acetate 8:2) afforded 3-amino-5-fluoro-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (4.6 g) as a solid. MS (ES+) 294 (MH+), 238 (M-isoprene); 1H NMR (400 MHz, CDCl3) 1.48 (s, 9H), 2.53 (m, 2H), 3.64 (t, 2H), 3.99 (m, 2H), 4.08 (m, 2H), 5.99 (m, 1H), 6.70 (dd, 1H), 7.85 (d, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[C:13]([CH2:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:40]([NH:41]C(=O)CC3SC=CC=3)[C:39](=[O:50])[N:21]2[C:22]=1[C:23]([O:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])#[N:14].CO>C(Cl)Cl>[NH2:41][C@@H:40]1[C:39](=[O:50])[N:21]2[C:22]([C:23]([O:25][CH:26]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[C:17]([CH2:16][CH2:15][C:13]#[N:14])[CH2:18][S:19][C@H:20]12
Reactant: N#CCCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: N#CCCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A suspension of phosphorus pentachloride (606 mg., ca 2.9 mmole) in methylene dichloride (5 ml) was warmed until most of the phosphorus pentachloride had dissolved. A solution of pyridine in methylene dichloride (4.6 ml., as a 10% v/v solution, ca 5.7 mmole) was added, and the mixture cooled to 0°. A solution of diphenylmethyl 3-(2-cyanoethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (700 mg ca 1.3 mmole) in methylene dichloride (9 ml) was added and the mixture was stirred at 0° for 30 minutes. After a further 30 minutes at 25° the solution was run into a vigorously stirred mixture of methanol (2 ml.) and methylene dichloride (10 ml). the resulting solution was washed with dilute aqueous sodium bicarbonate solution and water, and dried and evaporated in vacuo the residue was triturated with petroleum to remove traces of pyridine and the resulting solid (500 mg) dissolved in ethyl acetate. The solvent was removed in vacuo and the residue washed with ether to give the title compound (450 mg) as small needles m.p. 118° to 122° (decomp) [α]D25 49.1° (c 1.3, CHCl3) λmax. (CHCl3) 258.5 nm (ε 5,950) νmax. (CHBr3) 3450 and 3380 (NH2), 1780 (β-lactam) 1728 CO2R) and 758 and 740 (CHPh2) cm.-1 τ (CDCl3) 2.62 (Ph), 3.05 (CHPh2) 5.06 and 5.23 (C6 and C7 --H, two doublets J 5 Hz.) 6.48 and 6.65 (C2 --CH2AB-quartet, J 18 Hz.) 7.1 to 7.6 (CH2CH2CN complex) 7.5 (NH2). The compound ran to the cathode on electrophoresis at pH 1.9
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:17]1[O:19][CH2:18]1.O>O1CCCC1.CCCCCC>[C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[CH2:17][CH2:18][OH:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2ccnc2)cc1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OCCc1nccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1-Phenylimidazole (3.00 g) was dissolved in tetrahydrofuran. To the solution was added dropwise a solution of n-butyllithium (1.6 M) in hexane (16.9 ml) at −70° C. The mixture was stirred for 30 minutes at the same temperature, to which 50% solution (4.76 g) of ethyleneoxide in tetrahydrofuran. The mixture was warmed up to room temperature over 1 hour, and stirred 19 hours at the same temperature. To the reaction mixture was added water. The mixture was subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to column chromatography on silica gel (developing solvent: ethyl acetate-methanol 100:0→93:7) to give the title compound.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:7]([O:6][C:4](=[O:5])[C@@H:3]1[CH2:9][CH2:10][CH2:11][N:1]([CH2:13][CH2:14][OH:15])[CH2:2]1)[CH3:8]
Reactant: OCCBr
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCO)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The (R)-enantiomer of ethyl nipecotate (100 g, 0.64 mole) (Akkerman, A. M. et al., Gazz.Chim.Ital., 102 (1972) 189) was mixed in dry acetone (300 ml) with 2-bromoethanol (85 g, 0.68 mole), dried, powdered potassium carbonate (188 g, 1.28 mole) and potassium iodide (21.6 g, 0.13 mole). The reaction mixture was stirred at room temperature for 18 h and at reflux for 24 h. Filtration of the reaction mixture and evaporation of the resultant filtrate gave (R)-1-(2-hydroxyethyl)nipecotic acid ethyl ester as an oil, which was purified by distillation in vacuo (110-115C, 0.1 mmHg), yield (72.2 g, 56%). TLC: rf=0.20 (SiO2; dichloromethane/methanol=19:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[O:17])[CH:25]=1)[CH3:19]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (131)(50 mg, 0.19 mmol) was coupled to aniline (64)(40 mg, 0.21 mmol) using Method D. The residue was triturated with TBME (3 ml) to give the title compound.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:10][C:11]([C@:13]1([NH:35]C(OC(C)(C)C)=O)[C@H:18]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:17][C@@H:16]2[C@H:14]1[C@@:15]2([F:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:12])[CH3:9].C(=O)([O-])O.[Na+]>>[CH2:8]([O:10][C:11]([C@:13]1([NH2:35])[C@H:18]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:17][C@@H:16]2[C@H:14]1[C@@:15]2([F:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](NCc3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1NCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Reaction time: 6 h
Yield: 92.3 %

Procedure:
2.8 mL of a solution of 4N hydrogen chloride/ethyl acetate was added to 28 mg of (1R,2R,3R,5R,6R)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzylamino)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester, and the mixture was stirred for 6 hours at ice-cooling and further stirred for 18 hours at room temperature. The reaction solution was ice-cooled and then neutralized with a saturated aqueous solution of sodium hydrogen carbonate, followed by separation. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure, thereby yielding 21 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylamino)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.[CH2:19]([N:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:27][CH2:28]O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C(/N=N/C(N(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:28][CH2:27][N:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1
Reactant: OCCN(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(Cl)c2ccc(O)cc21
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(Cl)c2ccc(OCCN(Cc3ccccc3)Cc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
Tert-butyl 3-chloro-6-hydroxyindazole-1-carboxylate (4.3611 g) which can be prepared according to the method described in Reference example 39, etc. and 2-(dibenzylamino)ethanol (4.1529 g; manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved in dehydrated THF (100 mL), added with triphenylphosphine (7.9370 g; manufactured by Kanto Chemical Co., Inc.) and TMAD (5.2270 g; manufactured by Masuda Chemical Industries Co., Ltd.), and then stirred overnight at room temperature. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in toluene, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (“COLUMN-D”; n-hexane:ethyl acetate=90:10→75:25) to obtain the title compound (7.1028 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH3:2].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC(=O)c1cccc(C)c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)c1cccc(C)c1
Yield: 70 %

Procedure:
3-Oxo-3-m-tolylpropionic acid-ethyl ester (1 g, 4.84 mmol) obtained in Step 1 was dissolved in benzene, and benzaldehyde, acetic acid (0.15 g, 2.49 mmol) and piperidine (0.06 g, 0.8 mmol) were added thereto, followed by refluxing for 4 hrs. Upon the completion of the reaction, the mixture washed successively with saturated saline and saturated sodium bicarbonate, and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 1 g of the titled compound (yield: 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1[NH2:5].C1N=CN([C:19](N2C=NC=C2)=[O:20])C=1.[CH3:26][NH:27][C:28]([C:30]1[CH:35]=[C:34]([O:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:29].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:4]=1[NH:5][C:19]([NH:41][C:40]1[CH:42]=[CH:43][C:37]([O:36][C:34]2[CH:33]=[CH:32][N:31]=[C:30]([C:28](=[O:29])[NH:27][CH3:26])[CH:35]=2)=[CH:38][CH:39]=1)=[O:20]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3OC)cc2)ccn1
Reaction time: 16 h
Yield: 28.8 %

Procedure:
To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH2Cl2 (15 mL) at 0° C. was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over 1 h, was stirred at room temp. for 16 h, then was treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow solution was stirred at room temp. for 72 h, then was treated with H2O (125 mL). The resulting aqueous mixture was extracted with EtOAc (2×150 mL). The combined organics were washed with a saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, 30%): TLC (100% EtOAc) Rf 0.62; 1H NMR (DMSO-d6) δ2.76 (d, J=4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, J=4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m/z 461 ((M+H)+).