Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[N:2]([C@@H:5]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C@H:11]([O:23]C(C2C(C3C=CC=CC=3)=CC=CC=2)=O)[C@@H:10]([CH2:38][O:39][Si:40]([C:53]([CH3:56])([CH3:55])[CH3:54])([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:9][C@H:6]1[S:7][CH3:8])=[N+:3]=[N-:4]>CO.C1COCC1>[N:2]([C@@H:5]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C@H:11]([OH:23])[C@@H:10]([CH2:38][O:39][Si:40]([C:53]([CH3:56])([CH3:55])[CH3:54])([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[O:9][C@H:6]1[S:7][CH3:8])=[N+:3]=[N-:4]
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OC(=O)c2ccccc2-c2ccccc2)cc1
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CO[C@H]2[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Sodium (89 mg) was reacted in dry MeOH (50 mL) then a solution of methyl 2-azido-4-O-biphenylcarbonyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (11) (3 g, 3.88 mmol) in THF (25 mL) was added. The reaction mixture was stirred at 40° C. for 30 minutes, then cooled to room temperature. The solution was neutralized by Amberlite IR 120 (H+) ion exchange resin. The suspension was filtered, the filtrate was evaporated. The residue was purified by chromatography using EtOAc—hexane 1:4 as the mobile phase to give methyl 2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (10) (2.1 g, 91%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[C:25](OCC)=[O:26])=[CH:20][CH:19]=1.C(O)(=O)C>C(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2]([N:1]=[C:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:25](=[O:26])[N:9]2[CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(=O)c1ccc(OC)cc1
Reactant: CC(=O)NCCNc1cc(Br)ccc1N
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(-c2nc3ccc(Br)cc3n(CCNC(C)=O)c2=O)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of crude N-(2-(2-amino-5-bromophenylamino)ethyl)acetamide from Example 14 in ethanol (0.74 mL) 870 mg of ethyl 2-(4-methoxyphenyl)-2-oxoacetate was added. To that mixture acetic acid was added resulting in of 1% v/v AcOH in EtOH solution. The reaction mixture was stirred at 80° C. for 18 h and allowed to cool to room temperature. The yellow precipitate was collected by filtration and washed with two 5 mL portions of EtOH. The yellow solid was dried under vacuum to provide N-(2-(7-bromo-3-(4-methoxyphenyl)-2-oxoquinoxalin-1(2H)-yl)ethyl)acetamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14](Br)=[N:13][C:12]=2[CH3:17])=[O:10])[CH:2]=1.[NH:18]1[C:22](B(O)O)=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:22]3[NH:18][N:19]=[CH:20][CH:21]=3)=[N:13][C:12]=2[CH3:17])=[O:10])[CH:2]=1
Reactant: OB(O)c1ccn[nH]1
Reactant: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Temperature: 100 °C
Yield: 87.7 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (pyridine-3-ylmethyl)-amide (5.0 g, 16.0 mmol) in toluene (30 mL), water (10 mL) and ethanol (10 mL) was added 1H-pyrazole-5-boronic acid (2.15 g, 19.2 mmol), Pd(PPh3)4 (1.85 g, 1.60 mmol), and potassium carbonate (6.64 g, 48.1 mmol). The resulting mixture was degassed three times and heated to 100° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was recrystallized from ethyl acetate to provide 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridine-3-ylmethyl)amide as a white solid (4.20 g, 85% yield).
Reaction SMILES: [Cl-].[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH2+:16][CH:17]=2)=[CH:5][CH:4]=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([Cl:22])=[O:21]>C(O)(C(F)(F)F)=O>[Cl-:22].[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH2+:16][CH:17]=2)=[CH:5][CH:4]=1)=[O:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Oc1ccc2c(c1)C(CC1=C[NH2+]C=N1)CC2
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)C(CC1=C[NH2+]C=N1)CC2

Procedure:
4-(6-hydroxy-indan-1-ylmethyl)-1H-imidazol-1-ium chloride (100 mg, 0.399 mmol) and 2,2-dimethylpropionic acid chloride (510 mmol) were reacted in TFA (1 ml) and purified as described in example 1. Yield 74 mg (56%) of a white solid. M.p. 176-177° C. 1H NMR (CDCl3, TMS): δ 1.33 (s, 9H), 1.69-1.78 (m, 1H), 2.16-2.25 (m, 1H), 2.74-2.88 (m, 3H), 3.23 (dd, 1H), 3.57 (qui, 1H), 6.83 (dd, 1H), 6.89 (s, 1H), 6.93 (s, 1H), 7.16 (d, 1H), 8.85 (s, 1H), 14.38 (s, 1H), 14.47 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>ClCCl>[C:16]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: Nc1cccnc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccnc1)OCc1ccccc1
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of 3-aminopyridine (10 g, 0.106 mol) and triethyl amine (16.3 mL, 0.117 mol) in dichloromethane (100 mL) at 0° C., was added benzyl chloroformate (15.2 mL, 0.106 mol) slowly. The reaction mixture was stirred overnight and was washed with water, saturated NaHCO3, dried over MgSO4, and evaporated. The residue was purified on a silica gel column to give the product (9.51 g)
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[CH2:29][C:30]2[C:31]([CH3:38])=[C:32]([CH:36]=O)[NH:33][C:34]=2[CH3:35])[CH2:24][CH2:23]1.N1CCCCC1>C(O)C>[OH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[CH2:29][C:30]2[C:31]([CH3:38])=[C:32](/[CH:36]=[C:14]3\[C:15](=[O:20])[NH:16][C:17]4[C:13]\3=[CH:12][C:11]([S:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])=[CH:19][CH:18]=4)[NH:33][C:34]=2[CH3:35])[CH2:24][CH2:23]1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1CCC(O)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (180 mg, 0.68 mmol) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated and triturated with methanol to give the titled compound as an orangish-red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Cl)c1cc(F)c(F)cc1Cl

Procedure:
In accordance with the above reaction scheme, a solution of 2-chloro-4,5-difluorobenzoic acid (V) in acetonitrile containing a catalytic amount of dimethylformamide is reacted under an inert atmosphere with the dropwise addition of oxalyl chloride, giving 2-chloro-4,5-difluorobenzoic acid chloride (VI) which is dissolved in diethyl ether and slowly added to a cold solution of magnesium diethylmalonate, followed by the addition to ice water and acidification to pH 2.5, giving (2-chloro-4,5-difluorobenzoyl)propanedioic acid diethyl ester (VII). A solution of compound (VII) in p-dioxane and water is heated at reflux, then evaporated and distilled, giving 2-chloro-4,5-difluoro-β-oxobenzenepropanoic acid ethyl ester (VIII). A solution of compound (VIII) and triethyl orthoformate in acetic anhydride is heated at 150° C. for 2 hours, giving 2-chloro-α-(ethoxymethylene)-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (IX). Cyclopropylamine is added to a solution of compound (IX) in ethanol, giving 2-chloro-α-[(cyclopropylamino)methylene]-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (X). Compound (X) is reacted with sodium hydride in dry dimethylformamide under an inert atmosphere with heat, giving 1-cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester (XI). Ester (XI) is then refluxed with acid, giving the desired 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (XII).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40][OH:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:51][C:52]([O:54]CC)=[O:53]>CC(C)=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=3)[C:22]([CH2:40][O:41][CH2:51][C:52]([OH:54])=[O:53])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(COCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 144 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-hydroxymethyl-pyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (130 mg) is dissolved in acetone (2.5 ml), and thereto are added potassium carbonate (108 mg) and ethyl bromoacetate (0.129 ml). The mixture is stirred at room temperature for 6 days. The reaction solution is concentrated under reduced pressure, and thereto is added water. The mixture is stirred for 40 hours, and partitioned by adding chloroform to the reaction solution. The organic layer is dried over magnesium sulfate, then concentrated under reduced pressure to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxymethoxymethylpyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (33.8 mg). MS (m/z): 672 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH3:2].[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[NH:41][CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[N:41]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:13])=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C=C(Cl)c1ccccc1C
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1ccccc1C)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21

Procedure:
The title compound was synthesized from 3-chloro-3-o-tolyl-acrylic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure outlined in Example 18, step (d), in a 35% yield of an E/Z isomeric mixture. 1H NMR (CDCl3) δ 7.46 (m, 0.6H), 7.30 (m, 4.8H), 7.10 (in, 1.6H), 7.03 (d, 0.6H, J=3.6 Hz), 6.94 (m, 1H), 6.85 (m, 0.4H), 6.70 (m, 1H), 6.53 (d, 0.8H, J=2.8 Hz), 6.47 (d, 0.2H, J=2.8 Hz), 6.30 (s, 0.2H), 5.82 (s, 0.8H), 4.39 (m, 2H), 4.10 (m, 2H), 3.78 (m, 2H), 3.22 (t, 2H, J=6.8), 2.75 (t, 2H, J=68), 2.07 (s, 2.4H), 2.02 (s, 0.6H), 1.94 (m, 2H), 1.53 (s, 9H), 1.05 (m, 3H).
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([C:24]([OH:26])=[O:25])[C:11](=[CH:15][C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[NH:17]([C:16]1[CH:15]=[C:11]2[C:12](=[O:14])[O:26][C:24](=[O:25])[C:10]2=[CH:9][C:8]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=C1OC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21

Procedure:
A steady stream of argon is passed through a suspension of 23.4 g (67.18 mmol) of 4,5-bis(anilino)phthalic acid in 250 ml of toluene, and 19.0 m1(201.5 mmol, 3 eq) of acetic anhydride is added. The reaction mixture is heated to 60°-65° for 90 minutes with vigorous stirring. The reaction mixture is cooled to 10° for 30 minutes, and the yellow to orange crystals are filtered off and washed with toluene/hexane to yield the title compound in the form of yellow crystals, FAB-MS: 331 [M+ +H].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[CH2:10]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])[CH3:11].[OH-].[K+]>CO>[CH2:10]([O:12][C:13]([N:15]1[CH2:16][CH:17]=[C:18]([C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:19][CH2:20]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: c1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N1CC=C(c2c[nH]c3ncccc23)CC1
Yield: 57.5 %

Procedure:
A suspension 5.51 g (0.05 mol) of 7-azaindol, 9.6 g (0.056 mol) of 4-oxo-piperidine-1-carboxylic acid ethyl ester and 5 g (0.075 mol) of potassium hydroxide in 120 ml of methanol was heated at 75° C. for 16 hours. The crude mixture was cooled at room temperature and the precipitate formed was filtered off. 7.8 g (57% of yield) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][O:13][CH3:14])=[C:5]2[C:15]([O:17][CH3:18])=[O:16].[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:21][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][O:13][CH3:14])=[C:5]2[C:15]([O:17][CH3:18])=[O:16]
Reactant: CI
Reactant: COCc1c(C(=O)OC)c2cc(O)ccc2n1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1c(C(=O)OC)c2cc(OC)ccc2n1C
Temperature: 50 °C
Yield: 89.6 %

Procedure:
14.9 g of 5-hydroxy-3-methoxycarbonyl-2-methoxymethyl-1-methylindole (59.8 mmol) obtained in Example 1 was dissolved in 150 ml of anhydrous dimethylformamide, and the solution was stirred in a stream of nitrogen under ice cooling. To this were added 2.63 g (65.8 mmol) of sodium hydride (60% oil dispersion) and 4.1 ml (65.9 mmol) of methyl iodide in that order. After 2 hours of heating at 50° C., the resulting reaction mixture was cooled down, mixed with water and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off and the solvent was distilled off under reduced pressure, the resulting residue was purified by a silica gel column chromatography (eluent: hexane-ethyl acetate, 3:1) to obtain 14.1 g of the title compound with a yield of 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([OH:16])(=O)[CH3:14]>>[CH3:7][O:6][C:4]([C:3]1[CH:8]=[C:9]([N:12]2[C:13](=[O:16])[C:14]3[CH2:9][CH2:10][CH2:11][CH2:2][C:3]=3[C:4]2=[O:5])[CH:10]=[CH:11][C:2]=1[Cl:1])=[O:5]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(N)ccc1Cl
Product: COC(=O)c1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Temperature: 25 °C

Procedure:
A solution of 9.1 g (0.06 mole) of 3,4,5,6-tetrahydrophilic anhydride and 11.1 g (0.06 mole) of methyl 2-chloro-5-aminobenzoate dissolved in glacial acetic acid (30 ml.) is vigorously refluxed for one hour. The reaction mixture is cooled to room temperature and the crude product is collected by filtration, washed with water and then dried to afford 14.9 g of N-[3-methoxycarbonyl-4-chlorophenyl]-3,4,5,6-tetrahydrophthalimide m.p. 113°-115° C.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[N:6]=[CH:7][N:8]=[N:9][C:10]=1[CH2:11][NH:12][C:13]([CH:15]1[CH2:18][C:17](=[O:19])[CH2:16]1)=O.CC#N.O=P(Cl)(Cl)Cl>CN(C=O)C>[CH3:3][O:4][C:5]1[C:10]2=[CH:11][N:12]=[C:13]([CH:15]3[CH2:18][C:17](=[O:19])[CH2:16]3)[N:9]2[N:8]=[CH:7][N:6]=1
Reactant: COc1ncnnc1CNC(=O)C1CC(=O)C1
Agent: N#N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ncnn2c(C3CC(=O)C3)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In an oven-dried flask filled with N2 was added N-[(5-methoxy-1,2,4-triazin-6-yl)methyl]-3-oxocyclobutanecarboxamide (2.40 g, 0.00833 mol) followed by MeCN (200 mL) and DMF (40 mL). The reaction mixture was treated with POCl3 (3.1 mL, 0.033 mol) dropwise at 0° C. under N2 over 10 min. The reaction was stirred at rt overnight. The reaction mixture was concentrated and poured into ice, saturated aqueous NaHCO3 solution was added to adjust the pH to 7. The mixture was extracted with DCM (150×3). The organic extracts were combined, dried (Na2SO4) and concentrated under reduced pressure to give a crude residue, which was then purified by flash chromatography on silica gel using hexanes:EtOAc (1:1) as the eluent.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[CH3:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[C:16]([C:28]#[C:29][Si](C)(C)C)[CH:15]=[N:14]1>CO>[C:28]([C:16]1[CH:15]=[N:14][N:13]([CH3:12])[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=1)#[CH:29]
Reactant: Cn1ncc(C#C[Si](C)(C)C)c1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cnn(C)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 4.5 h
Yield: 86.3 %

Procedure:
Under cooling in an ice bath, potassium carbonate (148 mg) was added to a tetrahydrofuran (16 mL) and methanol (36 mL) solution of 1-methyl-5-[4-(trifluoromethyl)phenyl]-4-[(trimethylsilyl)ethynyl]-1H-pyrazole (3.45 g), and the obtained solution was then stirred for 4.5 hours. Thereafter, the reaction solution was filtrated with Celite, and the filtrate was then concentrated under a reduced pressure. The residue was diluted with ethyl acetate, and was then washed with a saturated ammonium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel 60N, hexane:ethyl acetate=85:15 to 60:40), so as to obtain the title compound (2.31 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[CH2:18][O:19][C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:26]2=[O:50])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[CH2:18][O:19][C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:50])=[CH:22][CH:21]=1
Reactant: CN1c2ccccc2CC1COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1c2ccccc2CC1COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
3.1 ml of trifluoroacetic acid were added to a solution of 2.50 g of 5-[4-(1-methylindolin-2-yl-methoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 7) in 25 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was worked up following the procedure described in Example 1, to give 1.20 g of the title compound, melting at 46.1°-48.9° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[OH:14][C:15]([C@H:18]1[CH2:22][CH2:21][NH:20][C@H:19]1[CH3:23])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:14][C:15]([C@H:18]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[C@H:19]1[CH3:23])([CH3:17])[CH3:16]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using 4-fluoro-2-(trifluoromethyl)benzonitrile (946 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.04 g) and lithium carbonate (784 mg), the title compound was obtained as a colorless solid (yield: 1.28 g) by an operation similar to that in Example 3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:16]1[CH2:24][O:23][CH2:22][C@H:21]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C@@H:20]([O:36][Si](C(C)C)(C(C)C)C(C)C)[C@H:19]([CH3:47])[O:18][C:17]1=[O:48])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Na+].[Cl-]>[C:11]([O:10][C:9]([N:8]([C@H:16]1[CH2:24][O:23][CH2:22][C@H:21]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C@@H:20]([OH:36])[C@H:19]([CH3:47])[O:18][C:17]1=[O:48])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)[Si](O[C@@H]1[C@@H](Cc2cccc3ccccc23)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](Cc2cccc3ccccc23)[C@H]1O
Reaction time: 3.5 h
Yield: 72 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-9-methyl-7-(1-naphthylmethyl)-2-oxo-8-triisopropylsilyloxy-1,5-dioxonan-3-yl]carbamate (2.54 g, 3.70 mmol) in THF (18.5 ml) was added TBAF (1.94 g, 7.41 mmol, 1M in THF) at room temperature. The reaction was stirred for 3.5 h, diluted with a 1/2 sat. aqueous NaCl solution (10 mL), and extracted with EtOAc (3×10 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The resulting clear oil was purified by flash chromatography (SiO2, 0→50% acetone/hexanes) to afford tert-butyl N-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-8-hydroxy-9-methyl-7-(1-naphthylmethyl)-2-oxo-1,5-dioxonan-3-yl]carbamate (1.41 g, 72%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.11 (dd, J=8.5, 1.4 Hz, 1H), 7.87-7.79 (m, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.54-7.41 (m, 2H), 7.42-7.27 (m, 2H), 5.19 (dd, J=8.8, 5.7 Hz, 1H), 5.00-4.88 (m, 1H), 4.10 (dd, J=11.9, 5.8 Hz, 1H), 3.89 (dd, J=12.0, 8.7 Hz, 1H), 3.68-3.51 (m, 4H), 2.79 (t, J=12.2 Hz, 1H), 2.58-2.51 (m, 1H), 2.15 (q, J=8.7, 7.4 Hz, 1H), 1.51 (d, J=6.4 Hz, 3H), 1.46 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 169.95, 152.69, 135.84, 134.02, 132.04, 128.77, 127.46, 127.16, 126.03, 125.56, 125.25, 124.04, 83.17, 77.69, 76.26, 73.23, 70.87, 57.38, 46.90, 33.38, 27.92, 18.67; ESIMS m/z 553 ([M+Na]+).