Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)#[CH:15].C(N(CC)CC)C.I.C(N(CC)CC)C>O1CCCC1.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.[Cu]I>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:15]#[C:14][C:16]2[CH:17]=[CH:18][C:19]([S:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(I)ccc1O
Reactant: C#Cc1ccc(S(=O)(=O)Oc2ccc(C)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Oc3ccc(C)cc3)cc2)ccc1O
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
Ethyl 2-hydroxy-5-iodobenzoate (58.5 g, 0.2 mol), 4-methylphenyl 4-ethynylbenzenesulfonate (54.4 g, 0.2 mol) and triethylamine (40 g, 0.4 mol) were dissolved in tetrahydrofuran (100 g). The solution was heated to 50° C. and dichlorobis(triphenylphosphine)palladium (0.5 g, 0.72 mmol) and copper(I)iodide (1 g, 5.2 mmol) were) added simultaneously with stirring. The reaction mixture turned dark and triethylamine hydroiodide started to precipitate after about 10 min. After keeping at 45° C. for 45 min, the suspension was poured into dilute hydrochloric acid and the mixture was extracted with toluene. The toluene solution was evaporated to dryness. The residue was triturated with acetonitrile, filtered off and dried. Yield 73 g, (84%). The pooled material from several batches (270 g) was recrystallized from acetonitrile (1.2 l). Yield 250 g.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9]([CH3:26])=[N:10][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:12]=1[CH:13]1[CH2:15][CH2:14]1)=[O:7])C>>[CH:13]1([C:12]2[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)[N:10]=[C:9]([CH3:26])[C:8]=2[C:6]([OH:7])=[O:5])[CH2:14][CH2:15]1
Reactant: CCOC(=O)c1c(C)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)O

Procedure:
The title compound was prepared by sodium hydroxide hydrolysis of the minor isomer-cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester from formation of intermediate 11. MS: 311.1 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([NH:34][C:35]1([CH2:51][O:52][N:53]([CH3:61])[C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([Br:50])[CH:48]=2)[O:43][C:37]2([CH2:42][CH2:41][CH2:40][O:39][CH2:38]2)[CH2:36]1)C=C.C(O)(=O)C1C(=CC=CC=1)S>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:34][C:35]1([CH2:51][O:52][N:53]([CH3:61])[C:54](=[O:60])[O:55][C:56]([CH3:57])([CH3:58])[CH3:59])[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([Br:50])[CH:48]=2)[O:43][C:37]2([CH2:42][CH2:41][CH2:40][O:39][CH2:38]2)[CH2:36]1
Reactant: C=CCNC1(CON(C)C(=O)OC(C)(C)C)CC2(CCCOC2)Oc2ccc(Br)cc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(O)c1ccccc1S
Solvent: C1CCOC1
Product: CN(OCC1(N)CC2(CCCOC2)Oc2ccc(Br)cc21)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
A solution of Pd2(dba)3 (7.6 mg, 0.038 mmol) and 1,4-bis(diphenylphosphino)butane (3.6 mg, 0.038 mmol) in THF (3 mL) under N2 atmosphere was stirred for 15 min. Then the solution was added to a solution of tert-butyl (4-(allylamino)-6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-yl)methoxy(methyl)carbamate produced in previous step in THF (3 mL), followed by thiosalicylic acid (14 mg, 0.91 mmol). The mixture was stirred for 16 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to recover 28 mg of starting material as TFA salt and 10 mg of the desired product as TFA salt. MS ESI+ve m/z 457 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1.C(=O)=O>O.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH3:2]
Reactant: CCOC(=O)C(CCCC1CCCCC1)C(=O)O
Agent: C=O
Agent: O=C=O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCCC1CCCCC1)C(=O)OCC
Temperature: 60 °C

Procedure:
51 g of (3-cyclohexylpropyl)-malonic acid ethyl ester, 6.4 g of paraformaldehyde, 50 ml of pyridine and 2.1 g of piperidine are warmed to 60° C. When the evolution of carbon dioxide is complete (approx. 1 hour), the mixture is stirred for a further hour at 60° C. and is poured into 800 ml of water and the mixture is extracted with 4 times 200 ml of petroleum ether. The combined organic phases are washed with 200 ml of water, 200 ml of 2 N hydrochloric acid, 200 ml of water and 200 ml of saturated sodium bicarbonate solution and are dried over sodium sulphate and concentrated. The residue is purified by chromatography on a silica gel column. (Migrating agent 80:20 petroleum ether/ethyl acetate). This gives 36.7 g of 5-cyclohexyl-2-methylenevaleric acid ethyl ester in the form of a nearly colourless oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4]C(OC1C2C(=CC=CC=2)C=CC=1)C(O)=O)#[N:2].[OH-].[K+].[CH2:22]([O:24][C:25](=[O:43])[CH:26]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:23].C(#N)C=C>C(OCC)(=O)C>[CH2:30]([O:29][C:27](=[O:28])[C:26]([CH2:4][CH2:3][C:1]#[N:2])([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)[C:25]([O:24][CH2:22][CH3:23])=[O:43])[CH3:31]
Reactant: CCOC(=O)C(Oc1cccc2ccccc12)C(=O)OCC
Reactant: N#CCCC(Oc1cccc2ccccc12)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C=CC#N
Product: CCOC(=O)C(CCC#N)(Oc1cccc2ccccc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 120 h

Procedure:
4-Cyano-2(R,S)-α-naphthoxybutyric acid: 0.11 ml of a 50% aqueous KOH solution is added at 0°, while stirring, to a mixture of 5.0 g of α-naphthoxymalonic acid diethyl ester and 1.09 ml of acrylonitrile. The reaction mixture is stirred for 5 days at room temperature and then dissolved in ethyl acetate. The ethyl acetate solution is washed with 2N sodium bicarbonate solution, 2N hydrochloric acid and brine, dried over sodium sulphate and concentrated by evaporation, leaving (2-cyanoethyl)-α-naphthoxymalonic acid diethyl ester.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:14][CH3:15])(=[O:13])/[CH:8]=[CH:9]/[C:10]([O-:12])=O.[C:16]([O:24][NH:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CN(C=O)C>[C:16]([O:24][N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])[C:10](=[O:12])/[CH:9]=[CH:8]/[C:7]([O:14][CH3:15])=[O:13])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCCCCNOC(=O)c1ccccc1
Reactant: COC(=O)/C=C/C(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)/C=C/C(=O)N(CCCCNC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
Oxalyl chloride (0.39 mL, 4.5 mmol) was added dropwise to a solution of mono-methyl fumarate (0.64 g, 4.9 mmol) in distilled CH2Cl2 (7 mL) at 0° C., then a drop of anhydrous DMF was added. The resulting mixture was stirred at this temperature for 20 minutes before it was warmed to room temperature and stirred for another 30 minutes. A solution of 3 (1.16 g, 3.75 mmol) in distilled CH2Cl2 (3 mL) was added at 0° C., followed by the addition of freshly distilled triethylamine (1.05 mL, 7.5 mmol) and DMAP (0.049 g, 0.40 mmol). The reaction was stirred at room temperature for 2 h. A saturated aqueous solution of NH4Cl was added and the aqueous layer was extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude oil, which was purified by column chromatography on silica gel (hexanes/ethyl acetate=10:1) to afford 4 (1.14 g, 2.7 mmol) as a colorless oil in 72% yield: IR (thin film): 3368, 2976, 1768, 1713, 1520, 1240, 1170, 1006 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.15-8.03 (m, 2H), 7.68 (t, J=7.5 Hz, 1H), 7.52 (t, J=7.7 Hz, 2H), 7.13 (d, J=15.7 Hz, 1H), 6.92 (d, J=15.4 Hz, 1H), 4.65-4.56 (br, 1H), 3.89 (t, J=6.9 Hz, 2H), 3.73 (s, 3H), 3.18-3.13 (m, 2H), 1.75-1.70 (m, 2H), 1.61-1.52 (m, 2H), 1.39 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3): δ 165.80, 164.62, 156.15, 135.03, 133.03, 131.28, 130.37, 129.20, 126.24, 79.31, 52.43, 52.39, 48.38, 40.20, 28.54, 27.48, 24.50 ppm. HRMS (m/z): [M+Na]+ calcd. for C21H28N2NaO7, 443.1788; found, 443.1792.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][C:27]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: CC1(C)OB(c2cc(F)ccc2OCC2CC2)OC1(C)C
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-5-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c4) the title compound is obtained as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]([CH3:30])[C:15](=[O:29])[CH:16]=[C:17]([O:18][S:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:12]=3[C:11](=[O:31])[N:10]([CH:32]3[CH2:34][CH2:33]3)[C:9]2=[O:35])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)(Cl)Cl>[CH:32]1([N:10]2[C:11](=[O:31])[C:12]3[C:17]([O:18][S:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)(=[O:21])=[O:20])=[CH:16][C:15](=[O:29])[N:14]([CH3:30])[C:13]=3[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])[CH:3]=3)[C:9]2=[O:35])[CH2:33][CH2:34]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2cccc(N)c2)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2cccc(NS(C)(=O)=O)c2)cc1
Yield: 95 %

Procedure:
To toluene-4-sulfonic acid 1-(3-aminophenyl)-3-cyclopropyl-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 13 (5 g) obtained in Step 7 was added pyridine (40 ml), a solution of methanesulfonyl chloride 14 (0.9 ml) in chloroform (10 ml) was added dropwise with stirring under ice-cooling, and the mixture was stirred for 3 hrs in an ice bath. The reaction mixture was concentrated under reduced pressure, 2N hydrochloric acid was added and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant solid was suspended in diethyl ether:hexane=1:1, and filtered by suction to give toluene-4-sulfonic acid 3-cyclopropyl-1-(3-methanesulfonylaminophenyl)-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 15 (5.5 g, 95%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+].[CH3:21][CH2:22]O>>[CH2:21]([O:9][C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([NH2:1])[CH2:3][CH2:4]1)=[O:10])[CH3:22]
Reactant: CCO
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-4-amino-cyclohexanecarboxylic acid (15 g, 83.8 mmol), sulfuric acid (9 mL) and EtOH (400 mL) was stirred at RT overnight. A saturated aqueous solution of NaHCO3 and NaHCO3 (solid) were added until the pH of the mixture reached 7. The solvent was then removed under reduced pressure. Aqueous K2CO3 (50%) was added and the resulting mixture was extracted with EtOAc, the organic extracts dried over Na2SO4, filtered and evaporated under reduced pressure to provide trans-4-amino-cyclohexanecarboxylic acid ethyl ester (12.81 g) as a light yellow oil.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.[OH-].[Na+].[CH:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17](Cl)=[O:18])=[CH:11][CH:10]=1>O.O1CCCC1>[OH:6][CH:4]1[CH2:5][N:2]([C:17]([O:16][CH2:15][C:12]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)=[O:18])[CH2:3]1
Reactant: OC1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
To a solution of azetidin-3-ol hydrochloride (2 g, 18.26 mmol, 1.00 equiv) and sodium hydroxide (1.53 g, 38.25 mmol, 2.10 equiv) in water (10 mL) and tetrahydrofuran (25 mL) was added Cbz-Cl (3.27 g, 19.17 mmol, 1.05 equiv) dropwise with stirring at 0° C. over 30 min. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of 20 mL of water. The mixture was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×40 mL of sodium chloride (sat.). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). Purification afforded 2.0 g (53%) of benzyl 3-hydroxyazetidine-1-carboxylate (50.2) as a light yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:43]=1[C:49]1[C:53]([CH2:54]O)=[C:52]([C@H:56]([CH3:59])[CH2:57][CH3:58])[O:51][N:50]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([Cl:41])[C:43]=1[C:49]1[C:53]([CH2:54][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:52]([C@H:56]([CH3:59])[CH2:57][CH3:58])[O:51][N:50]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: CC[C@@H](C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC[C@@H](C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)OC)ccc3c2)cc1
Temperature: 90 °C
Yield: 51.2 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (154 mg, 0.550 mmol), triphenylphosphine (144 mg, 0.550 mmol) and {3-(2,6-dichlorophenyl)-5-[(1R)-1-methylpropyl]-4-isoxazolyl}methanol (150 mg, 0.500 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.099 mL, 0.550 mmol) dropwise. The solution was heated in a microwave reactor at 90° C. for 10 minutes. The solution was adsorbed onto silica gel and purified by chromatography (silica gel, 0-60% ethyl acetate in hexanes gradient elution). A second purification was done by chromatography (silica gel, 1% methanol in dichloromethane) to afford methyl 6-{4-[({3-(2,6-dichlorophenyl)-5-[(1R)-1-methylpropyl]-4-isoxazolyl}methyl)oxy]phenyl}-2-quinolinecarboxylate (144 mg 0.256 mmol, 51%). 1H-NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.18-8.10 (m, 3H), 7.73 (d, J=8 Hz, 2H), 7.63-7.51 (m, 3H), 6.92 (d, J=8 Hz, 2H), 4.88 (app q, J=12 Hz, 2H), 3.94 (s, 3H), 3.27-3.22 (m, 1H), 1.73-1.66 (m, 2H), 1.32 (d, J=7 Hz, 3H), 0.83 (t, J=7 Hz, 3H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.O=[C:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1>O1CCCC1>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][C:18](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask was charged with NaH (50 g, 1.25 mol, 60% in mineral oil) and tetrahydrofuran (2,500 ml) and cooled to 0° C. A solution of ethyl 2-(diethoxyphosphoryl)acetate (260 g, 1.16 mol) in tetrahydrofuran F (200 ml) was added dropwise. The resulting solution was allowed stir for 1 h at 0° C. Then a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (215 g, 1.16 mol) in tetrahydrofuran (300 ml) was added dropwise. The resulting solution was allowed to stir for 0.5 hours at 0° C. The reaction mixture was quenched by the addition of 1,000 ml of saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (3×2,000 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether gradient) to afford tert-butyl-3-(2-ethoxy-2-oxoethylidene)pyrrolidine-1-carboxylate as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@@H:11]([C@@H:13]([OH:26])[CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([O:26][C@H:13]([CH2:14][O:15][Si:16]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:19])[CH3:18])[C@@H:11]([CH3:12])[NH:10][C:9](=[O:27])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:38][CH:39]=1)([O-:30])=[O:29]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)[Si](OC[C@H](O)[C@@H](C)NC(=O)OCc1ccccc1)(C(C)C)C(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)[Si](OC[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H](C)NC(=O)OCc1ccccc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
Benzyl{(2R,3R)-3-hydroxy-4-[(tripropan-2-ylsilyl)oxy]butan-2-yl}carbamate (7.00 g, 17.7 mmol) synthesized in Example (89b) was dissolved in toluene (80 mL), and 4-nitro benzoic acid (6.10 g, 36.5 mmol) and triphenylphosphine (11.85 g, 45.2 mmol) were added, followed by cooling to 0° C. Under nitrogen atmosphere, diethyl azodicarboxylate (40% toluene solution, 20.3 mL, 44.7 mmol) was added dropwise over 10 minutes, and stirring was carried out at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-15%) to afford the desired compound (7.90 g, yield 82%) as a yellow liquid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1>[S:20]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a solution of 1H-indole-4-carbaldehyde (2.9 g, 20 mmol) in THF (50 mL) cooled in an ice bath was added NaH (0.96 g, 60% in oil, 24 mmol) with vigorous stirring. After stirring for 30 min, 4-toluenesulfonyl chloride (5.73 g, 30 mmol) was added. The mixture was stirred at RT overnight and the solvent was removed in vacuo. The residue was diluted with DCM (500 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with a petroleum ether/EtOAc gradient (5 to 10% EtOAc) to afford 900 mg (15%) of 1-tosyl-1H-indole-4-carbaldehyde (42) as white solid: MS (ESI) m/z=300.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].[Na].CO>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:22][OH:23])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
178.7 g (628 mmol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carbonitrile and 65.5 g (941 mmol) of hydroxylamine hydrochloride were added to a solution prepared from 17.3 g (753 mmol) of sodium and 1.5 l of methanol. The reaction mixture was stirred at room temperature overnight and subsequently diluted with 1 l of water. The suspension obtained was suction filtered and the crystals were dried. There were obtained 169.7 g (85%) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxamidoxime of decomposition point 269°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(=O)([O-])O.[Na+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1O
Reactant: ClCCN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCCN1CCOCC1
Temperature: 70 °C
Reaction time: 17 h
Yield: 34.8 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2,4-difluorophenyl)urea (174 mg) was dissolved in N,N-dimethylformamide (9 ml), and potassium carbonate (64 mg), tetra-n-butylammonium iodide (14 mg), and N-(2-chloroethyl)morpholine hydrochloride (86 mg) were then added to the solution. The mixture was stirred at 70° C. for 17 hr, and a saturated aqueous sodium hydrogencarbonate solution was then added to the reaction solution, followed by extraction with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (20/1) to give 75 mg (yield 35%) of the title compound.