Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:20][C:19]3=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:18]3[C:17]2=[O:26])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[C].[Pd].CO>[CH3:24][C:23]1[N:18]2[C:17](=[O:26])[N:16]([CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:20][C:19]2=[C:21]([CH3:25])[N:22]=1
Reactant: Cc1nc(C)n2c1CN(CCC1CCN(Cc3ccccc3)CC1)C2=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1nc(C)n2c1CN(CCC1CCNCC1)C2=O
Yield: 97.7 %

Procedure:
2-(2-(1-Benzyl-4-piperidinyl)ethyl)-5,7-dimethyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one (1.1 g) obtained in Example 94a), 10% palladium carbon (0.22 g) and ammonium formate (2.0 g) were added to methanol (30 ml), and mixed at room temperature for 2 days. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound as colorless powder (0.8 g, quantitative).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:31]4[CH:30]=[N:29][N:28]([CH2:27][C:26]([OH:43])([CH3:42])[CH3:25])[CH:32]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(-c3cnn(CC(C)(C)O)c3)cc1-2
Yield: 7.8 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (225 mg, 0.547 mmol) and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazol-1-yl)propan-2-ol (174.7 mg, 0.656 mmol) were reacted to give 331 (20.0 mg, 8% yield, M+1 471.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:6]([OH:8])=O.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])=[O:31])[CH:24]=[CH:23]2>>[ClH:19].[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30]([N:33]1[CH2:34][CH2:35][N:36]([C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:37][CH2:38]1)(=[O:31])=[O:32])[CH:24]=[CH:23]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: COc1cc(C(=O)O)ccc1-c1ccncc1
Agent: Cl
Product: COc1cc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)ccc1-c1ccncc1

Procedure:
In the same manner as in Example A-4, a reaction was conducted using 3-methoxy-4-(4-pyridyl)benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][NH:54]C(=O)OC(C)(C)C)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(Cl)Cl>FC(F)(F)C(O)=O>[NH2:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([CH2:23][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([NH:15][CH2:16][C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[O:14])=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])(=[O:25])=[O:26])=[CH:28][CH:29]=1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(CCCOCCOCCOCCOCCOCCOCCNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(CCCOCCOCCOCCOCCOCCOCCN)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A solution of carbamate 60 (85 mg, 0.098 mmol) in a mixture of trifluoroacetic acid (2 mL) and anhydrous DCM (8 mL) was stirred at 20° C. for 1 h. The solvent was evaporated and the residue was purified by column chromatography, eluting with 10% MeOH/DCM containing 1% aqueous NH3, to give amine 61 (56 mg, 75%) as a white gum: 1H NMR δ 9.22 (t, J=5.8 Hz, 1H, CONH), 8.56 (d, J=1.7 Hz, 1H, H-2′), 8.46 (dd, J=4.8, 1.6 Hz, 1H, H-6′), 7.99 (br d, J=8.6 Hz, 2H, H-2, H-6), 7.89 (br d, J=8.6 Hz, 2H, H-3, H-5), 7.73 (dt, J=7.9, 1.9 Hz, 1H, H-4′), 7.68 (br d, J=8.3 Hz, 2H, H-2″, H-6″), 7.44 (br d, J=8.3 Hz, 2H, H-3″, H-5″), 7.36 (ddd, J=7.8, 4.8, 0.6 Hz, 1H, H-5′), 4.65 (s, 2H, CH2SO2), 4.51 (d, J=5.8 Hz, 2H, CH2NH), 3.49-3.50 (m, 20H, CH2O), 3.43-3.45 (m, 2H, CH2O), 3.33-3.36 (m, 2H, CH2O), 2.72 (t, J=7.3 Hz, 2H, H-r), 2.64 (t, J=5.6 Hz, 2H, H-21′″), 2.12 (s, 3H, CH3), 1.79 (br q, J=7.2 Hz, 2H, H-2′″), NH2 not observed; 13C NMR δ 165.4, 157.9, 149.8, 148.8, 148.5, 148.0, 135.7, 135.3, 135.1, 134.8, 129.1 (2), 128.7, 128.3 (2), 128.0 (2), 125.9, 125.3 (2), 123.4, 72.6, 69.7 (7), 69.6, 69.5, 69.4, 68.9, 52.8, 41.1, 40.4, 31.4, 30.4, 9.5; HRMS calcd for C39H53N4O10S (MH+): m/z 769.3477. found m/z 769.3492.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C@@H:30](O)[CH2:31][C@H:32]([OH:34])[CH3:33].C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[C:1]([O:9][C@@H:30]([CH3:29])[CH2:31][C@H:32]([OH:34])[CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)C[C@H](C)OC(=O)c1ccccc1

Procedure:
After benzoic acid (300.6 mg, 2.46 mmol), triphenylphosphine (776.2 mg, 2.95 mmol), (2R,4R)-2,4-pentanediol (309.1 mg, 2.95 mmol), and THF (12 mL) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.55 ml, 2.95 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for ix hours. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-benzoyloxypentane-2-ol containing 1,2-hydrazinedicarboxylic acid diisopropyl ester as 525.3 mg of a colorless oily substance. Measurement of 1H-NMR showed that 380 mg of (4S,2R)-4-benzoyloxypentane-2-ol (yield: 74%/benzoic acid), and 146 mg of 1,2-hydrazinedicarboxylic acid diisopropyl ester were contained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[NH2:15][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:7]=[C:6]([CH2:5][C:4]3[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=4)=[O:36])[CH:25]=[CH:24][CH:23]=3)[C:14]=12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Cc2nn(Cc3ccccc3)c3ncnc(N)c23)c1
Product: Nc1ncnc2c1c(Cc1cccc(NC(=O)Nc3cccc(C(F)(F)F)c3)c1)nn2Cc1ccccc1

Procedure:
To the intermediate 3-(3-aminobenzyl)-1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine, molar equivalents of 3-(trifluoromethyl)phenyl isocyanate (Sigma-Aldrich) were added dropwise in ice-cold CH2Cl2. The reaction proceeded until completion as judged by TLC, was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to yield final compound BB6 1-(3-((4-amino-1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (ESI-MS m/z [M+H]+ found 518.4, calculated 518.2).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH2:18]>N1CCOCC1>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:9]3[CH2:8][CH2:7][O:18][CH2:1][CH2:5]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Reactant: O
Solvent: C1COCCN1
Product: CC(C)(C)c1nc2cc(N3CCOCC3)c([N+](=O)[O-])cc2s1

Procedure:
A solution of 170 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole described in Example 5, in 200 ml of morpholine is refluxed for 6.5 hours, cooled and poured into water. The solid is filtered, washed with water and cold alcohol to give 2-tert-butyl-5-[morpholin-4-yl]-6-nitrobenzothiazole melting at 119°-121°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.C(O)CCCC.[OH-].[K+:40]>>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+:40]
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCO
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Reaction time: 3 h

Procedure:
A vial (20 ml) was charged with Raltegravir free hydroxy (0.25 g) and pentanol (2 mL) to form a solution. KOH 85% (38 mg) was added at room temperature, forming a solution. This solution was stirred for 3 hours. The product precipitated and was isolated by centrifuge filtration. The isolated product was dried in a vacuum oven at 40° C. for 5 h to obtain Raltegravir potassium crystalline Form XIII.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[NH:13]=[C:14]1[NH:18][C:17](=[O:19])[CH2:16][S:15]1>>[NH:13]=[C:14]1[NH:18][C:17](=[O:19])[C:16](=[CH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[N:4]3)[S:15]1
Reactant: O=Cc1ccc2nccnc2c1
Reactant: N=C1NC(=O)CS1
Product: N=C1NC(=O)C(=Cc2ccc3nccnc3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from quinoxaline-6-carbaldehyde (intermediate 55) and 2-imino-1,3-thiazolidin-4-one, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 81 %

Procedure:
After the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (90 mg, 0.21 mmol) obtained in Example 338, N-methylpiperazine (0.036 ml, 0.33 mmol), 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) and triethylamine (0.045 ml, 0.32 mmol) were dissolved in dichloromethane (5 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) was added to the resulting solution at room temperature. The resulting mixture was stirred at room temperature for 14 hours. To the reaction mixture, N-methylpiperazine (0.036 ml, 0.33 mmol), triethylamine (0.045 ml, 0.32 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) were added further. The resulting mixture was stirred at room temperature for 14 hours, followed by concentration under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography and a fraction obtained from the elution portion with dichloromethane:methanol=25:1 was concentrated under reduced pressure, whereby the title compound (86 mg, 0.17 mmol, 80%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:27]=[C:26]([F:28])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[OH:29])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:30]1(O)[CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:27]=[C:26]([F:28])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[O:29][CH:30]2[CH2:33][CH2:32][CH2:31]2)=[O:17])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: OC1CCC1
Reactant: CCOC(=O)C1(NC(=O)c2cc(F)c3ccccc3c2O)Cc2ccccc2C1
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cc(F)c3ccccc3c2OC2CCC2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A solution of 2-[(4-fluoro-1-hydroxynaphthalene-2-carbonyl)amino]indan-2-carboxylic acid ethyl ester (303) (197 mg, 0.5 mmol) and 3,3-dimethyl-1,2,5-thiadiazolidine-5 triphenylphosphine-1,1-dioxide (example 307, 245 mg, 0.6 mmol, 1.2 eq) in DCM (6 mL) is treated with cyclobutanol (44 mg, 0.6 mmol, 1.2 eq) and stirred at RT for 6 days. The crude reaction mixture is purified by flash chromatography (100 g silica gel, 100% DCM) to give colorless oil. (120 mg, 54%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>C(OCC)C.C(#N)C>[Cl:1][C:2]1[C:7]([O:8][CH3:21])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Solvent: CC#N
Product: COc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Yield: 58.8 %

Procedure:
An acetonitrile (15 mL) solution of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.78 g, 2.63 mmol), potassium carbonate (0.27 g, 1.97 mmol) and methyliodide (0.33 mL, 5.26 mmol) was stirred for 6.5 hours under reflux. A saturated ammonium chloride solution (15 mL) and diethyl ether (15 mL) were added to the resulting mixture, and the organic layer was separated and then the aqueous layer was extracted with diethyl ether (15 mL×2 times). The organic layer combined was washed with a saturated sodium chloride solution (20 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/1) to obtain a white solid of 2-(4-chloro-2-fluoro-5-methyloxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.36 g, yield:44.3%).
Reaction SMILES: [C:1]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17](=O)([O-:21])[O:18][CH2:19][CH3:20].[O-]CC.[Na+].[Na]>C(O)C>[C:1]1([CH:11]([C:17]([O:18][CH2:19][CH3:20])=[O:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1cccc2ccccc12
Reactant: CCOC(=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1cccc2ccccc12
Temperature: 105 °C

Procedure:
A mixture of 103.9 g (485 mmol) of ethyl naphthalene-1-acetate and 430 ml of ethyl carbonate is stirred at 105° C., and a solution of sodium ethoxide (11 g (478 mmol) of sodium in 255 ml of absolute ethanol) is then added in such a way that the ethanol distils in the course of the introduction. The mixture is heated for a further 15 min. to distil the maximum amount of ethanol, the flask is rapidly cooled and the mixture is poured onto 300 g of crushed ice and 20 ml of concentrated hydrochloric acid. It is extracted with diethyl ether, the organic phase is dried over magnesium sulphate and filtered, and the solvent is evaporated under reduced pressure. An oil is obtained which crystallises in pentane in the cold. The crystals are separated by filtration, treated with vegetable charcoal in diethyl ether and filtered, the filtrate is evaporated and the residue is recrystallised in a 25:75 mixture of diethyl ether/pentane. 97 g (339 mmol) of crystals are obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[C:5]([CH3:16])([CH3:15])[C:4]1=[O:17])[CH3:2]>CO.O1CCCC1.[Pd]>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([CH3:15])([CH3:16])[C:4](=[O:17])[N:3]2[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: CCN1C(=O)C(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCN1C(=O)C(C)(C)c2ccc(N)cc21
Reaction time: 4 h

Procedure:
To a solution of 1-ethyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (5.9 g, 25.19 mmol) in methanol/tetrahydrofuran (THF) (1:1, 80 ml) palladium on charcoal (10%, 1.2 g) was added and the mixture hydrogenated at room temperature for 4 h. After filtration and evaporation of the solvents 5.05 g (98%) 6-amino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one was isolated as white solid.
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C:3]2([CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]([OH:27])([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[O:2]1.[OH-].[K+]>>[CH2:29]1[CH2:1][O:2][C:3]2([CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]([OH:27])([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[O:28]1
Reactant: CCCCCC(C)(O)CC[C@H]1CCC2(OCCO2)[C@@H]1CCCCCCC(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCC(C)(O)CC[C@H]1CCC2(OCCO2)[C@@H]1CCCCCCC(=O)O

Procedure:
Treatment of 1-methyl 9,9-(ethylenedioxy)-15-hydroxy-15-methyl-prostanoate (Example 736) with potassium hydroxide in the manner of Example 58 is productive of the subject compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[OH-].[K+].C([O-])=O.[NH4+]>CO.[Pd].CO.C(Cl)Cl>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:8]=3)[NH:13][CH:14]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: c1cc2cc(N3CCOCC3)ncc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3cnc(N4CCOCC4)cc23)CC1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
A solution of 200 mg (1.0 mmol) of 5-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridine and 398 mg (2.0 mmol, 2 eq) of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester in 5 mL of MeOH was treated with 224 mg (4.0 mmol, 4 eq) of potassium hydroxide. The reaction mixture was stirred at 65° C. for 12 h and volatiles were removed. The crude product was partitioned between CH2Cl2 (100 mL) and 20 mL of H2O. The organic layer was washed with H2O (2×20 mL), dried over Na2SO4 and concentrated. The yellow powder was treated with 630 mg (10 mmol, 10 eq) of ammonium formate and 10% Pd—C (50 mg). The reaction mixture was stirred at 65° C. for 1 h. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a yellow solid. Column chromatography (silica, 5% MeOH/CH2Cl2) provided 180 mg (47% for 2 steps) of a yellow solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.40. MS (electrospray): exact mass calculated for C21H30N4O3, 386.23; m/z found, 387.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]([OH:19])[C:17]#[CH:18])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].I[C:21]1[CH:22]=[C:23]([OH:31])[C:24](=[CH:29][CH:30]=1)[C:25]([O:27][CH3:28])=[O:26]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]([OH:19])[C:17]#[C:18][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([OH:31])[CH:22]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CC(O)c1ccc(N(CC)CC)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CCN(CC)c1ccc(C(O)C#Cc2ccc(C(=O)OC)c(O)c2)cc1C(C)(C)C
Yield: 81.4 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 3.7 g (15 mmol) of 1-(3-tert-butyl-4-diethylaminophenyl)prop-2-yn-1-ol with 3.3 g (12 mmol) of methyl 4-iodosalicylate, 114 mg (0.6 mmol) of copper iodide and 210 mg (0.3 mmol) of bis(triphenylphosphine)palladium chloride. 4 g of methyl 4-[3-(3-tert-butyl-4-diethylaminophenyl)-3-hydroxyprop-1-ynyl]-2-hydroxybenzoate are obtained in the form of yellow oil (yield=66%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][C:22]=1[OH:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:34]([O:38][C:39](=[O:50])[NH:40][CH:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48]O)[CH2:43][CH2:42]1)([CH3:37])([CH3:36])[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CO.C(OCC)(=O)C>[C:34]([O:38][C:39](=[O:50])[NH:40][CH:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][O:33][C:22]2[CH:23]=[N:24][C:25]3[C:30]([C:21]=2[O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH2:43][CH2:42]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: COc1ccc2ncc(O)c(OCc3ccccc3)c2n1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)c(OCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 116.4 %

Procedure:
Diethyl azodicarboxylate (5.48 g, 31.46 mmol, 2.0 eq) is added at room temperature to a stirred solution of 4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-ol (4.44 g, 15.73 mmol, 1.0 eq), [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (5.76 g, 23.59 mmol, 1.5 eq) and triphenylphosphine (8.25 g, 31.46 mmol, 2.0 eq) in tetrahydrofuran (150 mL). After 15 hours stirring at room temperature, tetrahydrofuran is evaporated and the resulting crude product is purified by column chromatography (silica gel, eluent: ethyl acetate:methanol, 10:0 to 9:1, v/v) to afford {1-[2-(4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as a light brown viscous oil (9.31 g, 88% yield).