Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2CCOCC2)[CH2:14][CH2:13]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[N:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1
Reactant: CN(C)C(=O)N1CCCCC1
Reactant: c1ccc(N2CCOCC2)c(N2CCOCC2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN(C)C(=Nc1ccccc1N1CCOCC1)N1CCCCC1

Procedure:
Reaction of 1-dimethylcarbamoylpiperidine (3.7 g) in benzene (25 ml) with 4-(2-morpholinophenyl)morpholine (3.5 g) in the presence of phosphorus oxychloride for 35 hours at 80°-85° C. gave N,N-dimethyl-N'-(2-morpholinophenyl)piperidine-1-carboxamidine (m.p. 88°-90° C.) which was recrystallised from petroleum ether (b.p. 40°-60° C.)
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[O:5])C.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[OH:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3)=[O:5])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: COc1cc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1OC
Temperature: 190 °C

Procedure:
A mixture of 6,7-dimethoxy-4-hydroxy-3-quinoline carboxylate ethyl ester (J. Am. Chem. Soc., 68, 1264 (1946)) (139 mg) and 4-chlorobenzylamine (0.61 mL) are heated at 190° C. for 1 h. The resulting mixture is diluted with toluene (1.5 mL) and allowed to cool to rt. The crude product is purified by column chromatography (dichloromethane/methanol; 100/1, 100/5) and recrystallization (acetic acid, water) to afford 26 mg of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1N=C2C(=CC=1OCC)C=C1N2C(C)CNC1.[C:19]([O:23][C:24]([N:26]1[CH2:38][C@@H:37]([CH3:39])[N:36]2[C@H:28]([CH2:29][C:30]3[C:35]2=[N:34][C:33]([C@@H:40]([O:42][CH3:43])[CH3:41])=[C:32]([CH2:44][OH:45])[CH:31]=3)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[H-].[Na+].CI>>[C:19]([O:23][C:24]([N:26]1[CH2:38][C@@H:37]([CH3:39])[N:36]2[C@H:28]([CH2:29][C:30]3[C:35]2=[N:34][C:33]([C@@H:40]([O:42][CH3:43])[CH3:41])=[C:32]([CH2:44][O:45][CH3:2])[CH:31]=3)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CO[C@@H](C)c1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CCOc1cc2cc3n(c2nc1Cl)C(C)CNC3
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCc1cc2c(nc1[C@H](C)OC)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-7-hydroxymethyl-6-(1-(S)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and methyl iodide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]([CH3:35])([CH3:34])[NH:5][C:6](=[O:33])[C@H:7]([CH2:28][O:29][C:30]#[C:31][CH3:32])[NH:8][C:9](=[O:27])[C:10]([CH3:26])([CH3:25])[NH:11][C:12](=[O:24])[C:13]([CH3:23])([CH3:22])[NH:14]C(OC(C)(C)C)=O.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH3:1][O:2][C:3](=[O:36])[C:4]([CH3:35])([CH3:34])[NH:5][C:6](=[O:33])[C@H:7]([CH2:28][O:29][C:30]#[C:31][CH3:32])[NH:8][C:9](=[O:27])[C:10]([CH3:26])([CH3:25])[NH:11][C:12](=[O:24])[C:13]([CH3:22])([CH3:23])[NH2:14]
Reactant: CC#COC[C@H](NC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#COC[C@H](NC(=O)C(C)(C)NC(=O)C(C)(C)N)C(=O)NC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
N-tert-butoxycarbonyl α,α-dimethylglycyl α,α-dimethylglycyl O-propynyl-L-seryl α,α-dimethylglycine methyl ester 16 (4.79 g, 9.35 mmol) was dissolved in 50% (v/v) TFA in CH2Cl2 (70 mL) and the reaction mixture stirred for 1 h 30 min at room temperature. The solvent and bulk of excess TFA were evaporated and CH2Cl2 (2×70 mL) added and evaporated. The residue was washed with Et2O (3×35 mL), redissolved in CH2Cl2 (100 mL), the solvent evaporated and the residue washed with Et2O (70 mL). Finally, CH2Cl2 (3×120 mL) was added and evaporated and the residue dried under high vacuum affording a white solid (4.93 g, 100%); 1H NMR (200 MHz, DMSO-d6) δ 8.38-8.00 (m, 5H, NH3+/NH(Aib2)/NH(Aib4)), 7.25 (d, J=7.8 Hz, 1H, NH(propSer)), 4.33 (q, J=5.4 Hz, 1H, CαH), 4.11 (d, J=2.4 Hz, 2H, CH2CCH), 3.62 (d, J=5.4 Hz, 2H, CH2), 3.54 (s, 3H, OCH3), 3.43 (t, J=2.3 Hz, 1H, CCH), 1.49 (s, 6H, CH3), 1.40 (s, 6H, CH3), 1.35 (s, 6H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 174.2, 173.2, 171.3, 168.6, 158.4 (q, JCF=32 Hz), 117.1 (q, J=297 Hz), 80.1, 77.3, 69.0, 57.7, 56.7, 56.6, 55.1, 52.4, 51.9, 25.0, 24.8, 24.7, 24.6, 23.3, 23.3; HRMS (m/z): M+ calcd. for C19H33N4O6, 413.2400. found, 413.2391; Anal. Calcd. for C21H33F3N4O8: C, 47.91; H, 6.32; N, 10.64. Found: C, 47.2; H, 6.2; N, 10.5.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[C:5]([CH:15]=[CH2:16])=[CH:4][N:3]=1.[OH-].[Na+]>C(OCC)(=O)C>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5]([CH:15]=[CH2:16])=[CH:4][N:3]=[C:2]2[Cl:1]
Reactant: C=Cc1cnc(Cl)c2cccc([N+](=O)[O-])c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C=Cc1cnc(Cl)c2cccc(N)c12
Reaction time: 2 h
Yield: 76.4 %

Procedure:
The 1-chloro-5-nitro-4-vinylisoquinoline (15 g) obtained in Step C mentioned above was dissolved in ethyl acetate (700 ml), added with stannous chloride dihydrate (72 g), and stirred for two hours. The reaction mixture was poured on ice, and then added with 5 N aqueous sodium hydroxide. The organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (10 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](I)=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CC(C)([O-])C.[Na+].COC(C)(C)C>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: Cc1nc(Cl)cc2c1c(N1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
6-Chloro-3-iodo-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 1C; 2 g, 3.73 mmol), morpholine (0.488 mL, 5.60 mmol), sodium tert-butoxide (0.538 g, 5.60 mmol), and chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (0.152 g, 0.187 mmol) was dissolved in dioxane (10 mL) and degassed under argon for five minutes. The reaction mixture was heated to 60° C. for 30 min under microwave irradation. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo while loading onto silica gel. Purification by flash chromatography (5-30% EtOAc/Hexanes) gave 4-(6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine. MS ESI calc'd. For C30H28ClN4O [M+H]+ 495. found 495.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=2)=[CH:6][C:5]=1[N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([O-])=O>[Pd].C1(C)C=CC=CC=1.CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=2)=[CH:6][C:5]=1[N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1N
Yield: 75 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[2-nitro-5-(3-phenylphenoxy)phenyl]-N-methylcarbamate (8.7 g), palladium on carbon (10%, 0.69 g) and toluene/methanol=7/3 (100 ml) and the reaction mixture was purified to give the title compound (6.06 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[NH:11]1.O>C(O)(=O)C>[Br:1][C:13]1[CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:9])[NH:11][C:12]=1[C:20]([F:21])([F:23])[F:22]
Reactant: COC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(Br)c(C(F)(F)F)[nH]c1=O

Procedure:
At room temperature, 0.36 g (2.04 mmol) of N-bromosuccinimide was added to a suspension of 0.3 g (1.36 mmol) of methyl 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate in 10 ml of glacial acetic acid, and the mixture was then heated under reflux for 2 days. The reaction mixture was then added to water and extracted with dichloromethane. The extract was concentrated, and the residue was purified further by preparative HPLC. This gave 227 mg (56% of theory) of a colorless powder.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][O:26][C:27](=[O:37])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1>ClCCl>[CH3:25][O:26][C:27](=[O:37])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:2]2[C:3]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=4)=[C:9]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:31]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: COC(=O)COc1cccc(N)c1
Solvent: ClCCl
Product: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1

Procedure:
Heat 4.7 g (14 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 3.03 g (16.7 mmol) of 3-aminophenoxyacetic acid methyl ester to 150° C. in an oil bath for 1.5 h. After cooling, add dichloromethane to the residue and purify by means of silica gel (eluent: cyclohexane/ethyl acetate 2:1). 2.29 g (34.1% of theory) of the target compound are obtained as a pale yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:31](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][CH2:24][C:25]5[N:26]([CH3:30])[CH:27]=[N:28][CH:29]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:42][CH3:43].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:31][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][CH2:24][C:25]5[N:26]([CH3:30])[CH:27]=[N:28][CH:29]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:42][CH3:43]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNCCc4cncn4C)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCCc4cncn4C)ccnc3[nH]1)cn2C
Yield: 92.3 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (k), starting with 0.070 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-[2-(3-methyl-3H-imidazol-4-yl)ethyl]amine instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34 stage (k) and 0.5 cm3 of 5N potassium hydroxide. 0.048 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-[2-(3-methyl-3H-imidazol-4-yl)ethyl]amine is obtained with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]2)=[N:3][C:2]([C:33]2[CH:34]=[C:29]([Cl:28])[C:30]([OH:45])=[C:31]([Cl:44])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Cl)nc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, (6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexyl amino}-1,5-naphthyridin-3-yl)(cyclopropyl)methanone (60 mg, 0.16 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (66 mg, 73%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.41 (s, 1H), 8.46 (d, J=8.9 Hz, 1H), 8.34 (d, J=8.9 Hz, 1H), 8.12 (s, 2H), 5.74-5.64 (m, 1H), 3.09 (d, J=6.6 Hz, 2H), 2.93 (s, 6H), 2.92-2.85 (s, 1H), 2.47-2.40 (m, 2H), 2.08-1.96 (m, 3H), 1.72-1.60 (m, 2H), 1.47-1.34 (m, 2H), 1.32-1.18 (m, 4H). ESI MS m/z 513 [M+H]+; HPLC>99% (AUC), tR=9.67 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:30][C@H:31]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:32][C:33](O)=[O:34])(=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(Cl)CCl.CI>>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:33](=[O:34])[CH2:32][C@H:31]([O:30][C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Solvent: ClCCCl
Solvent: CI
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Yield: 94.1 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (0.212 g, 1.08 mmol) was acylated with (R)-3-tetradecanoyloxytetradecanoic acid (0.541 g, 1.19 mmol) in the presence of EDC·MeI (0.353 g, 1.19 mmol) to give 0.642 g (94%) of N-[(R)-3-tetradecanoyloxytetradecanoyl]-L-serine benzyl ester as a waxy solid: mp 56-61° C.; 1H NMR (CDCl3) δ 0.88 (t, 6H, J=˜7 Hz), 1.1-1.7 (m, 42H), 2.29 (t, 2H, J=7.5 Hz), 2.50 (m, 2H), 3.87 (br t, 1H), 3.95 (m, 2H), 4.65 (m, 1H), 5.1-5.25 (m, 3H), 6.69 (d, 1H, J=7 Hz), 7.34 (br s, 5H).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:23]([O:25]CC)=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH2:13][C@H:12]2[O:28][CH3:29])=[O:9])[NH:5][C:6]=1[I:7].[OH-].[Li+]>>[I:1][C:2]1[N:3]=[C:4]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:23]([OH:25])=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH2:13][C@H:12]2[O:28][CH3:29])=[O:9])[NH:5][C:6]=1[I:7]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(I)c(I)[nH]3)[C@H](OC)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Product: CO[C@@H]1CN(c2nc(C)c(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(I)c(I)[nH]1
Yield: 83.4 %

Procedure:
The same operation as in Example (1i) was performed using ethyl cis(±)-2-(4-{[(4,5-diiodo-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (71d) (83 mg, 0.13 mmol) and 2 N lithium hydroxide (2 mL), to obtain 66.9 mg of the title compound as a white solid (84%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][NH:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(C(C)C)CC)(C)C.[C:27](Cl)([O:29][CH2:30][CH:31]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28].OS([O-])(=O)=O.[K+]>ClCCl>[CH3:17][O:16][CH:3]([O:2][CH3:1])[CH2:4][N:5]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:27]([O:29][CH2:30][CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[C:43]1=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:28]
Reactant: CCCCC/C=C/CCCNCC(OC)OC
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC/C=C/CCCN(CC(OC)OC)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
2-(trans-Dec-4-en-1-ylamino)acetaldehyde dimethyl acetal (10.5 g, 43.2 mmol) was mixed with dichloromethane (300 mL) and 7.5 mL (43.2 mmol) diisopropylethyl amine and 11.2 g (43.2 mmol) of FMOC-Cl was added portionwise. The reaction was stirred at room temperature for 3 hours and then poured into a solution of 10% KHSO4 (200 mL). The organic layer was washed with water (200 mL), dried over MgSO4, and concentrated under reduced pressure. The resulting oil was chromatographed on silica gel in 10% EtOAc/Hexanes to give 16.1 g (34.6 mmol) of N-Fmoc-2-(trans-dec-4-en-1-ylamino)acetaldehyde dimethyl acetal as a clear oil that was used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH3:37])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:37][NH:36][S:33]([C:30]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:32][CH:31]=1)(=[O:34])=[O:35]
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-methyl-benzenesulfonamide (example B.27) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (390 mg, 74%). MS (ISP) 525.2 [(M+H)+]; mp 231-233° C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Br[CH2:11][CH:12]([CH3:42])[C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([O:37][C:38]([O:40][CH3:41])=[O:39])[CH2:23][C@@H:24]2[O:32][C:33]([O:35][CH3:36])=[O:34])=[CH:19][CH:18]=3)[CH2:15][CH2:14]1.O>CS(C)=O>[CH3:42][CH:12]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([O:37][C:38]([O:40][CH3:41])=[O:39])[CH2:23][C@@H:24]2[O:32][C:33]([O:35][CH3:36])=[O:34])=[CH:19][CH:18]=3)[CH2:15][CH2:14]1)[CH2:11][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CBr)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CSc5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
In 2 ml of dimethyl sulfoxide under ice-cooling, 55 mg of thiophenol and 20 mg of sodium hydroxide were stirred. Then, 54 mg of 21-bromo-20-methyl-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene was added and the mixture was further stirred at ambient temperature for 3 hours. The reaction mixture was then poured into water and extracted with diethyl ether. The extract was washed with water and aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 39 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylthiopregna-5, 7-diene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](SC)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=C([C:37](OO)=[O:38])C=1.S(=O)(O)[O-].[Na+].C[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11]([O:38][CH3:37])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CSc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2ccc(Cl)c(Cl)c2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
131 mg (0.293 mmol) of 4-(3,4-dichlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of dichloromethane. 101 mg (0.586 mmol) of mCPBA (m-chloroperbenzoic acid) was added thereto at 0° C. and stirred at the same temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite solution was added thereto at the same temperature and stirred for 30 minutes heating to room temperature. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of methanol and excessive amounts of 565 mg (2.93 mmol) of sodium methoxide (28% methanol solution) was added at room temperature and stirred at 60° C. for 6 hours. After concentration under reduced pressure, the obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:33][CH3:34])[N:6]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:33][CH3:34])[N:6]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=2)[CH2:20][CH2:19]1
Reactant: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(Cc4ccc(CO)cc4)CC3)c2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(Cc4ccc(C=O)cc4)CC3)c2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
The compound (0.52 g, 1.10 mmol) obtained in Step (i) and manganese dioxide (0.95 g, 11.0 mmol) were added to chloroform (20 ml), and the mixture was stirred at room temperature for 15 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column (chloroform/methanol=100/1 to 50/1) to give the subtitle compound (0.47 g, 1.00 mmol) as a white solid. Yield: 92%.