Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:39])[C:20]4[C:25]([O:26][C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]3[N:34]([CH3:38])[N:35]=[C:36](I)[C:23]3=[CH:22][CH:21]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][CH2:42]OC(C)=O>C1(C)C=CC=CC=1.C1CCCCC1.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>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:39])[C:20]4[C:25]([O:26][C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]3[N:34]([CH3:38])[N:35]=[C:36]([CH:41]=[CH2:42])[C:23]3=[CH:22][CH:21]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(I)c2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Product: C=Cc1nn(C)c2c1ccc1c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of {1-[4-(3-iodo-1-methyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (27 mg, 0.0417 mmol), tetrakis(triphenylphosphine)palladium(0) (4.8 mg, 0.004 mmol) and vinyltributylin (0.0183 mL, 0.063 mmol) in toluene (2 mL) was stirred at 90° C. under nitrogen. After 3 hours, reaction mixture cooled to RT and was subjected to flash chromatography (SiO2, gradient 20 to 40% EtOAc in cyclohexane) to afford the title compound (23.4 mg) as a yellow gum. LCMS (Method H): RT=4.67 min, [M+H]+=548.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH:27]2[CH:34]3[CH2:35][CH:30]4[CH2:31][CH:32]([CH2:36][CH:28]2[CH2:29]4)[CH2:33]3)=[O:25])[CH2:19]1)=[O:17])[CH3:14].[CH3:37][O:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Br>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1([CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[O:38][CH3:37])[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH:27]2[CH:28]3[CH2:29][CH:30]4[CH2:31][CH:32]([CH2:33][CH:34]2[CH2:35]4)[CH2:36]3)=[O:25])[CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1CCCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Reactant: COc1ccccc1CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2OC)CCCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a stirred solution of diisopropylamine (6.3 g, 62.7 mmol) in dry THF (120 mL) at −20° C. under N2 was added 2.5 M n-BuLi (25.1 mL, 62.7 mmol). The resulting solution was added dropwise to a stirred solution of 1-(2-adamantyl) 3-ethoxycarbonylpiperidine-1-carboxylate (14.0 g, 41.8 mmol) in dry THF (170 mL) at −70° C. The mixture was stirred for 1 h at −70° C. and 2-methoxybenzyl bromide (10.9 g, 54.3 mmol) was added. The mixture was stirred for 4 h at rt, quenched with brine and extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography to afford the title compound (14.3 g, 75%). LC-MS Method 3 tR=2.04 min, m/z=456.
Reaction SMILES: [IH:1].CS[C:4](=[NH:8])[NH:5][CH2:6][CH3:7].[OH:9][C:10]1([CH2:21][NH2:22])[CH2:16][O:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[O:12][CH2:11]1>C(O)C>[IH:1].[OH:9][C:10]1([CH2:21][NH:22][C:4]([NH:5][CH2:6][CH3:7])=[NH:8])[CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[O:15][CH2:16]1
Reactant: CCNC(=N)SC
Reactant: NCC1(O)COc2ccccc2OC1
Agent: I
Solvent: CCO
Product: CCNC(=N)NCC1(O)COc2ccccc2OC1

Procedure:
A mixture of S-methyl-N-ethylisothiourea hydriodide (2.46 g., 10 millimoles), 3-hydroxy-3-aminomethyl-3,4-dihydro-2H-1,5-benzodioxepin 1.95 g. (10 millimoles) from Example 1, Step E, and 20 ml. of ethanol is refluxed for four hours. The solution then is evaporated to a small volume and diluted with ether to afford 3-hydroxy-3-(3-ethylguanidinyl)methyl-3,4-dihydro-2H-1,5-benzodioxepin hydriodide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([F:30])[CH:28]=4)[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:41]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([F:30])[CH:28]=4)[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[CH:7][CH:8]=1)(=[O:41])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.1 g, 0.17 mmol) prepared in Example 48 in DMSO (5 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.39 g, 3.4 mmol), then aqueous solution (1N) of NaOH (1.7 mL, 1.7 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichloromethane and hexanes to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid (Yield 0.1 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4](O)[CH:5]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)=[O:11])[CH2:6][CH2:7][CH2:8][CH3:9].CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH:4]([F:30])[CH:5]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)=[O:11])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(C(=O)N1CCC[C@H]1c1ncco1)[C@H](O)C(=O)OC
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCCCC(C(=O)N1CCC[C@H]1c1ncco1)C(F)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2(S)-hydroxy-3-(2(S)-oxazol-2-yl-pyrrolidin-1-carbonyl)-heptanoic acid methyl ester C-1 (5 mmol) in DCM (5 mL) is added DAST (15 mmol) at −20° C. The solution is stirred for 16 hours at rt. The reaction mixture is washed with aqueous NaHCO3 and brine, dried (Na2SO4) and concentrated then purified on silica gel (EtOAc/hexanes) to afford 2-(R/S)-fluoro-3-(2(S)-oxazol-2-yl-pyrrolidin-1-carbonyl)-heptanoic acid methyl ester C-2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]([CH3:26])([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH3:17])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[CH3:26]
Reactant: Cc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Reactant: CC(C)(N)c1ncco1
Product: Cc1ccc(C(=O)NC(C)(C)c2ncco2)nc1-c1cccc(Cl)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): 356.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:26]=3[OH:27])[N:23]=[CH:22][CH:21]=[N:20]4)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:36]1C=C(O)C(C2C3C(=CC=CC=3)N(CC3C=CC(OC)=CC=3)C2=O)=CC=1C#N>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:18]=[C:19]5[C:24]([N:23]=[CH:22][CH:21]=[N:20]5)=[CH:25][C:26]=4[O:27][CH2:36]3)[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1C(c2cc3nccnc3cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3nccnc3cc12

Procedure:
Following the procedure as described in EXAMPLE 2.40 and making non-critical variations using 1-(diphenylmethyl)-3-(7-hydroxyquinoxalin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile, 1′-(diphenylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one was obtained (34%): 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J=1.5 Hz, 1H), 8.46 (d, J=1.5 Hz, 1H), 8.07-8.04 (m, 1H), 7.63-6.86 (m, 15H), 6.55-6.52 (m, 1H), 5.10 (ABq, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18](C(O)=O)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:23])[CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].O.C(=O)([O-])[O-].[Na+].[Na+]>N1C2C(=CC=CC=2)C=CC=1>[CH3:23][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1)[CH:19]=[CH:18]2
Reactant: Cc1ccc2nc(-c3ccc(C(=O)O)cc3)cc(C(=O)O)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: Cc1ccc2nc(-c3ccc(C(=O)O)cc3)ccc2c1
Temperature: 170 °C
Yield: 70 %

Procedure:
In 5 ml of quinoline was dissolved 0.1 g of the 2-(4-carboxyphenyl)-6-methyl-4-quinolinecarboxylic acid obtained in Example 16 and solution was heated at 170° C. for 0.5 hour. Then the reaction mixture was poured into water, made alkaline by adding sodium carbonate and washed with toluene. The aqueous layer was neutralized with 3M hydrochloric acid until a precipitate was formed. After extracting with dichloromethane, 0.06 g of 4-(6-methylquinolin-2-yl)benzoic acid were obtained. NMR (270 MHz, CD3OD): δ 7.5-8.3 (m,9H); 2.56 (s,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](OC)=[O:25])=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]([F:38])([F:37])[C:30]1[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:36][C:33]3[CH:34]=[N:35][C:30]([C:29]([F:38])([F:28])[F:37])=[CH:31][CH:32]=3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)nc3)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Yield: 37.8 %

Procedure:
The title compound was prepared by following the procedure as described for Example-137 using methyl 2-[(2,6-dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-6, 0.200 g, 0.493 mmol) and 6-(trifluoromethyl)pyridin-3-amine (0.119 g, 0.740 mmol), trimethyl aluminium (2M solution in toluene) (0.071 g, 0.986 mmol) and dry toluene (5.0 mL) to afford 0.100 g of the desired product. 1HNMR (DMSO-d6): δ 1.58 (s, 6H), 3.09 (s, 2H), 7.39 (m, 3H), 7.53 (m, 1H), 7.89 (d, J=8.4 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.99 (s, 1H), 10.07 (s, 1H), 10.94 (s, 2H); MS [M]+: 536.17.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH3:26][O:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][CH2:32][CH:33]2[NH2:38]>>[CH2:24]([O:23][C:21]([C:3]1[C:4]([CH3:20])=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[C:10]([O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:38][CH:33]1[C:34]3[C:29](=[C:28]([O:27][CH3:26])[CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:31][CH2:32]1)=[O:17])[CH:9]=[CH:8][CH:7]=2)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: COc1cccc2c1CCCC2N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCCc4c(OC)cccc43)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine as a brown solid (40%). MS 506 (MH+).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH3:20])=[C:13]([S:29][CH2:30][CH3:31])[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>CO.C1COCC1>[CH2:30]([S:29][C:13]1[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)[CH:16]=[C:15]([CH3:17])[C:14]=1[C:18](=[O:28])[N:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH3:20])[CH3:31]
Reactant: CCSc1nc(N2CCC(C(=O)OC)CC2)cc(C)c1C(=O)N(C)c1cccc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCSc1nc(N2CCC(C(=O)O)CC2)cc(C)c1C(=O)N(C)c1cccc(F)c1
Temperature: 70 °C
Yield: 81.2 %

Procedure:
A solution of 146 mg (0.32 mmol) 1-[6-Ethylsulfanyl-5-[(3-fluorophenyl)-methyl-carbamoyl]-4-methyl-pyridin-2-yl]-piperidine-4-carboxylic acid methyl ester (example 13) in a MeOH/THF mixture (1:1 v/v, 2 ml) was treated with 1 ml (2.0 mmol) 2M aq. LiOH sol. and heated to 70° C. for 16 h. Subsequently pH 3-4 was adjusted with a 2M aq. HCl sol., followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. As residue 112 mg (0.26 mmol, 79%) 1-[6-Ethylsulfanyl-5-[(3-fluorophenyl)-methyl-carbamoyl]-4-methyl-pyridin-2-yl]-piperidine-4-carboxylic acid (example 14) were obtained. [M+H]+432.2.
Reaction SMILES: [CH2:1]([O:10][CH2:11][C:12]([CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:15][CH3:16])[CH2:13][OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].CN(C)C1C=CC=CC=1.O1CCCC1.[C:42](Cl)(=[O:52])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>O>[CH2:19]([O:18][CH2:17][C:12]([CH2:11][O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])([CH2:15][CH3:16])[CH2:13][O:14][C:42](=[O:52])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCOCC(CC)(CO)COCCCCCCCCC
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCOCC(CC)(COCCCCCCCCC)COC(=O)CCCCCCCCC
Temperature: 25 °C
Yield: 60 %

Procedure:
To a 1-L three-neck flask provided with a stirrer, thermometer, condenser and dropping funnel with a gas inlet tube, 73.4 g (0.19 mol) of 2,2-bis(nonyloxymethyl)butane-1-ol, 26.7 g (0.22 mol) of N,N-dimethylaniline and 150 mL of tetrahydrofuran were put, to which 38.1 g (0.2 mol) of decanoyl chloride was dropped and stirred at the room temperature under nitrogen stream. After the dropping, the mixture was heated to 45 degrees C. and stirred for five hours. After the reaction, a small amount of distilled water was added to the mixture to dissolve the generated white solid. The mixture was transferred to a separating funnel. After an aqueous layer was separated while an organic layer was added with 50 mL of tetrahydrofuran, washed with 200 mL of saturated saline and with 20 mL of dilute sulfuric acid and then washed with distilled water until the organic layer became neutral. The obtained organic layer was dried with magnesium sulfate. After the solvent was removed by an evaporator, 100 g of the mixture was subjected to vacuum distillation to be fractioned. The obtained fraction was subjected to mass analysis, NMR analysis and IR analysis, whereby the fraction was confirmed to be an ester (target compound) (mass analysis result: m/z=540). The obtained amount was 61.8 g (0.114 mol) (a yield of 60%).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[O:4]=[V+3:5].[CH2:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8].Cl>C1(C)C=CC=CC=1>[Cl-:1].[CH2:6]([O:11][V+:5]([O:11][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: O=[V+3]
Reactant: CC(C)(C)CO
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)(C)CO[V+](=O)OCC(C)(C)C

Procedure:
Added to a glass bottle with a capacity of 200 ml sealed with a rubber stopper after drying and nitrogen substitution were 0.05 mol of VOCl3 (oxovanadium trichloride), 0.10 mol of neopentyl alcohol, and toluene. Then, hydrochloric acid generated while bubbling with nitrogen was removed through a needle to obtain a toluene solution of dineopentoxy oxovanadium chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: N#Cc1ccc(Br)nc1
Product: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 2-bromo-5-cyanopyridine in Step 4. LC-MS Method 2 tR=1.301, m/z=416; 1H NMR (CDCl3) 1.09 (d, 6H), 1.49 (d, 3H), 2.09-2.22 (m, 4H), 2.37 (m, 1H), 2.87 (m, 1H), 5.68 (m, 1H), 6.92-7.01 (t, 2H), 7.06 (m, 2H), 7.23 (m, 2H), 7.71 (d, 1H), 7.78 (d, 2H), 7.91 (d, 1H), 8.88 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=O)[C:6](=[O:15])[CH2:5]2.[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl.CN(C=O)C>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:12](=[O:14])[CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[CH2:5][C:6]2=[O:15])=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(O)CN1C(=O)Cc2cc(Cl)ccc21
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: *CC(*)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)CN2C(=O)Cc3cc(Cl)ccc32)cc1
Reaction time: 40 h

Procedure:
In a 1 ml polypropylene vial, 300 μl of a 0.15 M stock solution of (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetic acid 59 in a 1/1 CH2Cl2/DMF mixture were added onto N-dicyclohexyl-N-methyl polystyrene (from Novabiochem, loading: 1.9 mmol/g, 35 mg) and N,N-diisopropyl-methyl-polystyrene (from Argonaut, loading: 3.49 mmol/g, 25.4 mg) followed by 4tertbutyl-aniline (0.044 mmol, 6.6 mg). The reaction mixture was stirred 40 h under vortex and quenched with DMF (400 μl). The suspension was allowed to sediment and the liquid was concentrated under vacuo to afford N-(4-tert-butyl-phenyl)-2-(5-chloro-2-oxo-2,3-dihydro-indol-1-yl)-acetamide 85 (10 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([Cl:13])[CH:3]=1.O[CH2:15][CH:16]([CH2:18]O)O.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].C(O)C>S(=O)(=O)(O)O>[Cl:13][C:4]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=[C:2]2[C:3]=1[CH:15]=[CH:16][CH:18]=[N:1]2
Reactant: CCOC(=O)c1ccc(N)cc1Cl
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc2ncccc2c1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of ethyl 4-amino-2-chlorobenzoate (20 g), glycerol (32.17 g) and sodium 3-nitrobenzenesulfonate (46.73 g) in sulfuric acid (75%) (160 ml) was stirred for 3 hours at 100° C. and for 1 hour at 140° C. After the mixture was cooled to 60° C. and ethanol (200 ml) was added, the mixture was stirred for 16 hours at 60° C. Ethanol was evaporated and the residue was poured into ice water, neutralized with NH4OH and extracted with ethylacetate. The separated organic layer was dried over MgSO4, filtered and the filtrate evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /ethylacetate 97.5/2.5). The desired pure fractions were collected and evaporated, yielding 7.56 g (28%) ethyl 5-chloro-6-quinolinecarboxylate (intermediate 1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7])C.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([OH:23])[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([O:23][C:4](=[O:3])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CO
Reactant: CCOC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)COC(=O)c1ccccc1N
Reaction time: 8 h
Yield: 96 %

Procedure:
467 parts of anthranilic acid ethyl ester are heated with 1000 parts of isobutanol and 10 parts of potassium carbonate. The separated ethanol is distilled off over a column, this operation requiring about eight hours. After collecting an intermediate fraction being the mixture of both alcohols, the excess quantity of isobutanol is distilled off, the remaining residual quantity being removed in vacuo. The catalyst is filtered off. There are obtained 556 parts of anthranilic acid isobutyl ester (nD25 1.540; anthranilic acid ethyl ester content according to gas chromatography below 2%). The filtrate maintains its limpid character even at prolonged storage. The yield is 96% of the theory.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]1C(OCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd].[Ni]>[CH2:1]([C@@H:8]1[CH2:13][C@H:12]([OH:14])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CN(C(=O)OCc2ccccc2)C(Cc2ccccc2)C1
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Product: O[C@@H]1CCN[C@H](Cc2ccccc2)C1

Procedure:
150 g (0.467 mol) of 2-benzyl-N-benzyloxycarbonyl-2,3-dihydro-4-(1H)-pyridone in 1.5 l of methanol are hydrogenated with 7.5 g of Pd/C (10%) as catalyst, then 50 g of Raney nickel and a further 200 ml of methanol are added, and hydrogenation is left to go to completion. Filtration is followed by evaporation in a rotary evaporator, and the brownish oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (60:10:1). The title compound is obtained as a semi-crystalline mass which is used further without additional purification. Crystallisation of a sample from ether/hexane yielded white crystals of melting point 111°-112°. TLC: methylene chloride/methanol/conc. ammonia (40:10:1) Rf =0.55, FD-MS: M+ =191.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.O>CN(C1C=CC=CN=1)C.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([S:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.7 %

Procedure:
To a mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.67 g, 8.88 mmol), p-toluenesulfonyl chloride (1.72 g, 9.02 mmol) and triethylamine (2.50 mL, 18.0 mmol) in CH2C2 (15 mL), dimethylaminopyridine (30 mg, 0.24 mmol) was added. It was stirred at room temperature for 20 h. Water and CH2Cl2 were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine as a solid (3.03 g).