Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:24])[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=4)[N:13]=3)[CH:3]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-trifluoromethylphenyl)-6-methyl-pyrimidine (example E.47) (0.39 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.4 g, 76%). MS (ISP) 526.3 [(M+H)+]; mp 163° C.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[C:21]([OH:24])(=[O:23])[CH3:22]>CS(C)=O.O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:9]2[C:2]([CH3:1])=[C:3]([CH:4]=[CH:4][CH2:3][CH2:2][CH2:9][CH2:8][CH2:22][C:21]([OH:24])=[O:23])[CH:6]=[CH:7][CH:8]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: Cc1c(C=O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1c(C=CCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 2 °C
Reaction time: 16 h

Procedure:
A solution of 2.585 g of 2-methyl-3-(4-chlorobenzoyl)benzaldehyde and 5.49 g of ω-carbethoxyhexyl triphenyl phosphonium bromide in 25 ml of a 1:1 dimethylsulfoxidetetrahydrofuran mixture was added with stirring in 3 minutes to 520 mg of a 60% oil suspension of sodium hydride in 15 ml of a 1:1 dimethylsulfoxide-tetrahydrofuran mixture cooled to 2° C. and stirring was continued for 16 hours at 24° C. after the temperature had risen. The mixture was then cooled to 5° C. and 2 ml of acetic acid were added thereto. The solvents were removed and the residue was empasted with isopropyl ether and then filtered to remove insolubles. The filtrate was evaporated and the residue was saponified in a mixture of 50 ml of methanol and 15 ml of a 2 N sodium hydroxide solution at 80° C. for 1 hour. The methanol was removed and water was added. The mixture was extracted with ether and the aqueous phase was treated with activated carbon, filtered and acidified with concentrated hydrochloric acid. The oily residue was extracted with ether and the ether phase was washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to obtain 2.98 g of 8-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-oct-7-enoic acid with an Rf=0.35 (8:2 CH2Cl2 -acetone mixture).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C.FC(F)(F)S(O[CH2:44][CH:45]([F:47])[F:46])(=O)=O>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([CH2:44][CH:45]([F:47])[F:46])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1
Reactant: Cc1nc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(CC(F)F)C4)CC2)no1
Reaction time: 16 h

Procedure:
To a mixture of trans-8-chloro-1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.100 g, 0.237 mmol) and N-ethyldiisopropylamine (0.122 ml, 0.712 mmol) in dichloromethane (2.4 ml) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.061 g, 0.29 mmol). After stirring for 16 h the reaction mixture was partitioned between ethyl acetate (50 ml) and 0.5 M aqueous sodium hydroxide solution (50 ml). The layers were separated. The aqueous layer was extracted with one 50 ml-portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.031 g, 33%) as colorless solid. MS m/e: 449 ([M+H]+).
Reaction SMILES: C([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:24]4[C:18]5([CH2:27][CH:21]([C:22](=[O:26])[C:23]=4[Cl:25])[CH2:20][CH2:19]5)[CH2:17][C:14]=32)=[N:9]1)C1C=CC=CC=1.Cl.N1C=CC=CC=1>>[Cl:25][C:23]1[C:22](=[O:26])[CH:21]2[CH2:27][C:18]3([C:24]=1[C:13]1[CH:12]=[CH:11][C:10]4[NH:9][N:8]=[CH:16][C:15]=4[C:14]=1[CH2:17]3)[CH2:19][CH2:20]2
Reactant: O=C1C(Cl)=C2c3ccc4nn(Cc5ccccc5)cc4c3CC23CCC1C3
Agent: Cl
Solvent: c1ccncc1
Product: O=C1C(Cl)=C2c3ccc4[nH]ncc4c3CC23CCC1C3
Temperature: 195 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-benzyl-6-chloro-2,9,10,11-tetrahydro-8,10a -methanoazuleno[2,1-e]indazol-7(8H)-one (0.622 g, 1.66 mmol) and pyridine hydrochloride (10 g, 87 mmol) was heated to 195° C. After 2.5 hours the reaction mixture was allowed to cool to room temperature and was partitioned between EtOAc and water. The organic phase was washed successively with water (3×), 1N aqueous HCl, water and brine and dried over MgSO4. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel (elution with 15:85 to 80:20 EtOAc/hexanes) to yield 6-chloro-3,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:17]2[O:18][CH2:19][C:20]3[N:21]([CH:22]=[CH:23][CH:24]=3)[C:16]2=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[Sn](CCCC)(CCCC)CCCC)[CH3:31]>O1CCOCC1.CS(C)=O>[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:17]2[O:18][CH2:19][C:20]3[N:21]([CH:22]=[CH:23][CH:24]=3)[C:16]2=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH3:31]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1cccn1-2
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1cccn1-2
Temperature: 95 °C
Yield: 64.8 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino]-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (Intermediate 16, 0.107 g) and N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.179 g) in dioxane (3 mL) and DMSO (0.3 mL) was degassed and purged with nitrogen. Tris-(dibenzylideneacetone)dipalladium (0) (0.01 g) and tri-tert-butylphosphonium tetrafluoroborate (0.006 g) were added and the mixture was degassed and purged with nitrogen again, then the mixture was heated to 95° C. for 1 hour. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with more ethyl acetate and the combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-5% to give methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (0.074 g) as a sticky yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:12]>>[NH2:12][C:4]1[N:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[CH:2][N:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Product: Nc1ncc([N+](=O)[O-])cn1

Procedure:
Reaction of 4,6-dichloro-5-nitropyrimidine XX′ with nucleophile NH3 and R7LYH affords amino-5-nitropyrimidine XXI′. Suitable solvents for this reaction include ethanol, methylene chloride, acetonitrile, and tetrahydrofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[N:4]([CH3:16])[C:3]=1[CH2:17][C:18]([O:20]C)=[O:19].C(O)C>[OH-].[Na+]>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:8])[N:4]([CH3:16])[C:3]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cc1c(Cl)cc(C(=O)c2ccc(C)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C(=O)c2cc(Cl)c(CC(=O)O)n2C)cc1

Procedure:
A suspension of 3.3 g. of methyl 3-chloro-1-methyl-5-(p- toluoyl)pyrrole-2-acetate (0.0108 mole) from Example II in 12 ml. of IN sodium hydroxide and 5 ml. of ethanol is refluxed for 30 min. The ethanol is evaporated from the yellow solution, and the latter is poured into dilute HCl. The precipitate is collected, air dried, and recrystallized from 2-propanol to give 3-chloro-1-methyl-5-(p-toluoyl) pyrrole-2-acetic acid as a white solid; m.p. 163°-164° C (dec.)
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9](I)=[C:4]2[C:3]=1[Cl:13].[Si:14]([O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([N:28]2[CH:32]=[C:31](B(O)O)[CH:30]=[N:29]2)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl>[Si:14]([O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([N:28]2[CH:32]=[C:31]([C:9]3[CH:8]=[N:7][C:6]([NH2:11])=[C:5]4[O:12][C:2]([Cl:1])=[C:3]([Cl:13])[C:4]=34)[CH:30]=[N:29]2)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: Nc1ncc(I)c2c(Cl)c(Cl)oc12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(B(O)O)cn2)CC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(Cl)c(Cl)c34)cn2)CC1
Temperature: 75 °C

Procedure:
A mixture of 2,3-dichloro-4-iodo-furo[2,3-c]pyridin-7-ylamine (500 mg, 1.52 mmol), [1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]boronic acid (542 mg, 1.67 mmol) (1,1′-bis-(diphenylphosphine)-ferrocene) palladium dichloride (111 mg, 0.152 mmol) and potassium carbonate (525 mg, 3.80 mmol) in 1,4-dioxane (5.06 mL) and water (2.2 mL) was heated to 75° C. for 2 h. The reaction mixture was concentrated, suspended in ethyl acetate (10 mL), filtered through a pad of Celite, and concentrated onto silica gel. Purification by ISCO chromatography (5 to 50% acetone:heptane) afforded 437 mg (51%) of the title compound as a red-brown solid. 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1 H), 7.65 (d, J=0.5 Hz, 1 H), 7.57 (d, J=0.8 Hz, 1 H), 5.03 (br. s., 2 H), 3.99-4.41 (m, 1 H), 3.54-3.86 (m, 1 H), 2.14-2.42 (m, 2 H), 2.03 (dd, J=14.4, 3.5 Hz, 2 H), 1.81-1.96 (m, 2 H), 1.45-1.64 (m, 2 H), 0.91 (s, 9 H), 0.05-0.17 (m, 6 H); MS (APCl): 481.31, 483.37 [M+H]+; HPLC tR=3.99 min (ZQ3: nonpolar—4 min).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][C:13]1=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][C:13]1=[O:18]
Reactant: O=C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COCCN1c1ccc([N+](=O)[O-])cc1F
Temperature: 140 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A mixture of 1,2-difluoro-4-nitrobenzene (7.95 g, 50.0 mmol), morpholin-3-one (5.06 g, 50.0 mmol) and K2CO3 (13.82 g, 100 mmol) in DMF (80 mL) was stirred at 140° C. overnight. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a yellow solid (5.00 g, 42%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH2:27]([NH2:31])[CH:28]([CH3:30])[CH3:29]>>[CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](=[O:24])[NH:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: CC(C)CN
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCC(C)C)cn2)CC1
Yield: 77 %

Procedure:
By the same procedure as described example 24, the synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using isobutylamine. And then, the product was recrystallized with ethanol and hexane to give a desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:25](C(C)C)C(C)C)C.ClC(OCC(C)C)=O.N>O1CCCC1>[C:13]([C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:14])[NH2:25]
Reactant: O=C(N[C@@H](Cc1cccnc1)C(=O)O)OCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)[C@H](Cc1cccnc1)NC(=O)OCc1ccccc1
Temperature: -9 °C
Reaction time: 0.5 h

Procedure:
A suspension of (S)-2-benzyloxycarbonylamino-3-(pyridin-3-yl)propionic acid (2.60 kg, 8.65 mol) in tetrahydrofuran (60 l) was cooled to −9° C. At this temperature, N-ethyldiisopropylamine (1.33 kg, 10.29 mol) was added over a period of 5 min. At −9° C., isobutyl chloroformate (1.36 kg, 9.96 mol) was then added within 20 min, the internal temperature in the end increasing to −6° C. After 10 min of vigorous stirring, ammonia gas (2.1 kg, about 123 mol) was introduced at a constant temperature of (−5)–(−6)° C. into the resulting thin suspension in the course of 3 h. The reaction was initially strongly exothermic (requires initially slow introduction), later on less exothermic. Over a period of 30 min, the reaction mixture was warmed to 16° C., which gave a thick but still stirrable crystal slurry. At a jacket temperature of 30° C., the solvent was removed under reduced pressure. The white, greasy residue was suspended in ethyl acetate (125 l). A solution of sodium hydrogen carbonate (3.0 kg) in water (50 l) was added and the mixture was stirred vigorously for 30 min, after which all of the solid had dissolved. The organic phase was separated off and dried over sodium sulfate (1.0 kg), the drying agent was filtered off and the filtrate was concentrated under reduced pressure at a bath temperature of 30° C. to a volume of about 6 l. The resulting precipitate was filtered off with suction, washed with ethyl acetate (1.5 l) and dried at 30° C. under reduced pressure. Yield: 2.26 kg (7.55 mol, 87.3% of theory). The chemical purity was 99.9% (HPLC: 125×4.0 mm RP18 Purospher, 40° C., detection 210 nm); the enantiomeric purity was 100% ee (HPLC: 250×4.6 mm CSP Chiralpak AD Daicel, 40° C.; detection 248 nm; mobile phase: n-hexane/isopropanol/ethanol 84/12/4+0.1% diethylamine; tret [(S)-isomer] 14.93 min). M.p.: 152.8° C. (by DSC); MS (ESI+): m/z (%): 300 ([M+H+], 100); 1H-NMR (200 MHz, DMSO-d6): δ=2.77 (dd, J=9.5 and 7.0 Hz, 1H), 3.02 (dd, J=9.5 and 3.5 Hz, 1H), 4.19 (m, 1H), 4.96 (s, 3H), 7.00–7.40 (m, 7H), 7.40–7.60 (m, 2H), 7.60–7.76 (m, 1H), 8.36–8.53 (m, 2H); IR (KBr): ν=3306.8, 1674.9, 1537.7, 1424.0, 1271.6, 1251.3 cm−1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:33][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:38])[CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CC1
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: O=C(N[C@H]1CC[C@@H](NC(=O)C2CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:23]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1cccc(Cn2cnc(N)c2C(N)=O)c1
Product: COc1cccc(Cn2cnc(NC(=O)c3ccccc3F)c2C(N)=O)c1
Yield: 82 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 1, using 1.97 g (8.00 mmol) of 4-amino-1-(3-methoxybenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 81 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain 2.42 g of 4-(2-fluorobenzoylamino)-1-(3-methoxybenzyl)-5-imidazole carboxamide (yield 82%).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:3])=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)=O
Reactant: OCCCCCOCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCOCc1ccccc1
Temperature: 0 °C
Yield: 93 %

Procedure:
Jones reagent was added dropwise to an ice cooled solution of 5-benzyloxy-pentan-1-ol 28 (5 g, 25.74 mmol) in acetone (170 ml). Addition of the Jones reagent was stopped when the acetone solution acquired a persistent yellow color with the concurrent formation of green chlomium salts. The mixture was filtered and concentrated in vacuo to give an oily crude product that was purified by a flash chromatography (EtOAc/hexanes, 1:3) to give compound 29 (4.98 g, 93%) as a colorless oil: TLC Rf=0.68 (silica gel, 50% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.35-7.31 (m, 5H), 4.502 (s, 2H), 3.51-3.47 (t, 3J=6 Hz, 2H), 2.41-2.36 (t, 3J=6.8 Hz, 2H), 1.79-1.64 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 179.713, 138.651, 128.609, 127.870, 127.795, 73.158, 69.968, 33.915, 29.243, 21.749; HRMS calcd for C12H16O3+Na+ 231.0997; found 231.0992 [M+Na+].
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:26](O)[CH3:27]>>[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([C:13]([O:15][CH2:26][CH3:27])=[O:14])[CH2:11][CH2:12]2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C(O)C1CCC(N2CCCC2=O)CC1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C1CCC(N2CCCC2=O)CC1
Temperature: 10 °C
Yield: 102 %

Procedure:
To 4-(2-pyrrolidon-1-yl)cyclohexylcarboxylic acid are added ethanol (30 mL, 10V/W) and conc. sulfuric acid (0.4 g, 0.2 W/W), and the mixture is heated to reflux for 3.5 hours. After cooling the reaction solution to 10° C., sodium bicarbonate (powder) is thereto added. After foaming is stopped, ethanol is evaporated under reduced pressure. The residue is extracted with ethyl acetate and saturated brine. The resultant solution is dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure to give ethyl 4-(2-pyrrolidon-1-yl)cyclohexylcarboxylate (oil, 2.3 g, 102%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17]([C@H:25]2[C:34]3[C:33](=[O:35])[CH2:32][C@@H:31]([CH2:36][CH2:37][CH3:38])[CH2:30][C:29]=3[NH:28][C:27]([CH3:39])=[C:26]2[C:40]#[N:41])[CH:18]=[C:19]([O:22][CH2:23][CH3:24])[C:20]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:14][C:15]1[CH:16]=[C:17]([C@H:25]2[C:34]3[C:33](=[O:35])[CH2:32][C@@H:31]([CH2:36][CH2:37][CH3:38])[CH2:30][C:29]=3[NH:28][C:27]([CH3:39])=[C:26]2[C:40]#[N:41])[CH:18]=[C:19]([O:22][CH2:23][CH3:24])[C:20]=1[O:10][CH2:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: CCC[C@@H]1CC(=O)C2=C(C1)NC(C)=C(C#N)[C@H]2c1cc(Br)c(O)c(OCC)c1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC[C@@H]1CC(=O)C2=C(C1)NC(C)=C(C#N)[C@H]2c1cc(Br)c(OCc2cc(F)c(F)cc2[N+](=O)[O-])c(OCC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (4,5-difluoro-2-nitro-phenyl)-methanol (Example 72f, 5.1 g), (4R,7S)-4-(3-Bromo-5-ethoxy-4-hydroxy-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (Example 72e, 10.0 g) and polymer-supported triphenylphosphine (13.5 g, 3 mmol/g loading) in THF (500 ml), cooled to 0° C., was added diisopropyl azodicarboxylate (DIAD) (5.3 ml). After 1.5 h, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 4/1-2/3 (v/v) as eluent.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][C:25]=2[N:26]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:28]2[CH:29]=[CH:30][C:24]3[S:23][C:22]([CH3:21])=[N:26][C:25]=3[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: Cc1nc2cc(C=O)ccc2s1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2sc(C)nc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 2-methylbenzo[d]thiazole-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 396.76 g/mol.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH2:15][OH:16])=[C:10]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].[OH:26]O>CC(C)=O>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH2:15][OH:16])=[C:10]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:8]([C:9]=23)=[N+:7]1[O-:26])[CH3:25]
Reactant: OO
Reactant: CCN(CC)CCn1nc2c3c(c(CO)ccc31)Sc1ccccc1-2
Solvent: CC(C)=O
Product: CCN(CC)CCn1c2ccc(CO)c3c2c([n+]1[O-])-c1ccccc1S3
Reaction time: 8 h

Procedure:
To a solution of 2-(2-(diethylamino)ethyl)-2H(1)benzothiopyrano[4,3,2-cd]indazole-5-methanol (0.18 g.) in acetone (3 ml.) was added 30% aqueous hydrogen peroxide (0.21 ml.) and the mixture left overnight at room temperature. Evaporation under reduced pressure and crystallization from ethanol-ethyl acetate gave 2-(2-(diethylamino)ethyl)-2H(1)benzothiopyrano[4,3,2-cd]indazole-5-methanol N-oxide one-third hydrate which melted at 142°-143° (decomp.).
Reaction SMILES: C1(O[C:8](=[O:15])[NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)C=CC=CC=1.[N:16]1([CH2:22][C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[S:11]1[CH:12]=[CH:13][N:14]=[C:10]1[NH:9][C:8]([N:19]1[CH2:20][CH2:21][N:16]([CH2:22][C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:17][CH2:18]1)=[O:15]
Reactant: c1ccc2ncc(CN3CCNCC3)cc2c1
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Product: O=C(Nc1nccs1)N1CCN(Cc2cnc3ccccc3c2)CC1

Procedure:
The title compound was prepared from thiazol-2-yl-carbamic acid phenyl ester and 3-piperazin-1-ylmethyl-quinoline in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 9.03 (d, J=2.0 Hz, 1H), 8.24-8.20 (m, 2H), 7.94 (d, J=8.1 Hz, 1H), 7.86-7.81 (m, 1H), 7.70-7.66 (m, 1H), 7.43 (d, J=3.3 Hz, 1H), 6.98 (d, J=3.5 Hz, 1H), 3.87 (s, 2H), 3.73-3.69 (m, 4H), 2.68 (bs, 4H).