Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1(O)C=CC=CN1.[OH-].[Na+].Br[C:12]1[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=1[O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24]C=1)C1OCCNC1>>[C:15]1([O:14][C:13]2[CH:12]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccccc1OC(c1ccccc1)C1CNCCO1
Agent: OC1(Br)C=CC=CN1
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 75 °C
Yield: 133.5 %

Procedure:
A solution of 2-bromopyridinol 1 (7.6 g, 44 mmol) in 1N aqueous sodium hydroxide (44 mL, 44 mmol) was stirred at room temperature for 30 minutes. Phenylglycidol 2 (5.0 g, 33 mmol) was added in one portion and the reaction mixture was heated at 75° C. for 5 h. The reaction mixture was brought to room temperature and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and solvent was removed under reduced pressure. The reaction product was purified on silica gel (eluent 1:1 hexanes/ethyl acetate) to give the diol 3 (7.5 g, 69%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 1H), 7.36 (m, 5H), 7.00 (m, 1H), 6.92 (m, 1H), 5.32 (d, 1H), 4.00 (m, 2H), 3.84 (m, 1H), 2.94 (m, 1H), 2.60 (m, 1H).
Reaction SMILES: [OH-].[Na+].Cl.[N:4]1([CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=4)[CH:18]=3)[CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>CO>[N:4]1([CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=4)[CH:18]=3)[CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Yield: 99 %

Procedure:
3N Aqueous sodium hydroxide solution (1.8 ml) was added to methanol solution (20 ml) of methyl 4-[[2-(2-piperidinoethyl)-6-tetralinyl]oxymethyl]benzoate hydrochloride (1.06 g), which was refluxed with heating for 6 hours. After the reaction mixture was concentrated, water was added to the reaction mixture. Further, 1N hydrochloric acid was added to make the pH of the mixture about 7. The resulting crystals were filtered to give the titled compound (0.93 g). Recrystallization from ethanol gave crystals of the following melting points.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])N.[C:31]([N:50]=[C:51]=[O:52])(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>>[C:31]([NH:50][C:51](=[O:52])[O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)N=C=O
Agent: NC(=O)[O-]
Product: CCCCCCCCCCCCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 42 %

Procedure:
The compound 89 (245 mg, 0.6 mmol) was converted to the carbamate with stearoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 96 (179 mg, 42%). Mp. 73-77° C. Rf 0.46 (EtOAc).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:30])[CH:27]([NH2:29])[CH3:28]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:26][CH:27]([NH2:29])[CH3:28])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC(N)CN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(C)N)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and propane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.91 (dd, J=7.83, 1.01 Hz, 1 H), 7.83 (d, J=7.33 Hz, 1 H), 7.69 (s, 1 H), 7.58 (d, J=1.26 Hz, 1 H), 7.44 (d, J=8.59 Hz, 1 H), 7.38-7.31 (m, 1 H), 7.28 (dd, J=8.59, 1.77 Hz, 1 H), 6.04 (s, 1 H), 5.13 (brs, 2 H), 3.56 (t, J=4.67 Hz, 2 H), 3.52-3.41 (m, 4 H), 3.37 (s, 1 H), 2.41 (s, 3 H), 1.38 (d, J=6.06 Hz, 3 H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([N:16]2[C:20]([CH3:21])=[C:19]([C:22]([OH:24])=[O:23])[C:18]([CH3:25])=[N:17]2)[CH:13]=[CH:14][CH:15]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/B(O)O)=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH3:21])=[C:19]([C:22]([OH:24])=[O:23])[C:18]([CH3:25])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:29][CH:28]=1
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: Cc1nn(-c2cccc(Br)c2)c(C)c1C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(C)c1C(=O)O
Yield: 63 %

Procedure:
In analogy to the procedure described in Example 14C], but with 2.8 eq of K3PO4, 1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and trans-2-(4-chlorophenyl)vinylboronic acid gave after suspending in CH2Cl2 and filtration the title compound in 63% yield as light yellow solid. MS: 352.2 (M+, 1 Cl).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][I:12])[CH2:10][CH2:9]O[CH2:7][CH2:6]1)=[O:4].[CH3:13]OC(C1CCCCC1)=O>>[CH3:1][O:2][C:3]([C:5]1([CH2:11][I:12])[CH2:10][CH2:9][CH2:13][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCCCC1
Reactant: COC(=O)C1(CI)CCOCC1
Product: COC(=O)C1(CI)CCCCC1
Yield: 100 %

Procedure:
Prepared according to the method for the preparation of 4-iodomethyltetrahydropyran-4-carboxylic acid methyl ester, from cyclohexane-carboxylic acid methyl ester (10 ml), to give the title compound as a brown gum (20 g, 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:29])[C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[CH:18]=1.COC[C@H]1[C@@H](C=O)[C@@]1(C)C1C=C(C(C)C)C=C(C(C)C)C=1>>[CH3:1][O:2][CH2:3][C@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@:5]1([CH3:29])[C:17]1[CH:18]=[C:19]([CH:26]([CH3:27])[CH3:28])[CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: COC[C@H]1[C@@H](C=O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CCOC(=O)/C=C(C)/C=C/[C@@H]1[C@H](COC)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 76 %

Procedure:
Following a procedure similar to that for the preparation of Compound 24 but using Intermediate 46 as the starting material afforded the title compound (15 mg, 76% yield) as a white solid:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5](/[CH:9]=[N:10]/[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[N+:29]([CH3:32])([O-:31])=[O:30]>C(OCC)(=O)C>[N+:29]([CH2:32][CH:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:4]=1)([O-:31])=[O:30]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)/N=C/c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Of the compound from Example 11A, 3.6 g (13.17 mmol) were introduced in 26 ml of nitromethane and admixed with 0.69 ml (3.95 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 2 h. The reaction mixture was diluted with ethyl acetate and washed in succession twice each with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, and then with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. The residue (about 5 g) was dissolved in 15 ml of isopropanol at reflux. After cooling, the precipitated product was isolated by filtration, washed with a little isopropanol and sucked dry. After further drying in an HV, the title compound was obtained: 2.26 g (51% of theory).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18](Br)[CH:19]=3)[CH:12]=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[C:23]([O:26][CH2:27][C:28]1[C:29]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:30][CH:31]=[CH:32][C:33]=1B(O)O)(=[O:25])[CH3:24].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:23]([O:26][CH2:27][C:28]1[C:29]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:30][CH:31]=[CH:32][C:33]=1[C:18]1[CH:19]=[C:14]([NH:13][C:11]2[CH:12]=[C:6]3[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8][N:7]3[N:10]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C(C)=O)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 56.4 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 3-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 209c (185 mg, 0.50 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (200 mg, 0.50 mmol), Pd(dppf)Cl2 (41 mg, 0.050 mmol), sodium acetate (82 mg, 1.0 mmol), K3PO4 (212 mg, 1.0 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 212a (180 mg, 56%) as a yellow solid. MS-ESI: [M+H]+ 639.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]=[CH:7][C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].[C:23](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH3:23])[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cnc2cc(-n3cccc3)c(F)cc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 60 °C
Yield: 76.4 %

Procedure:
A mixture of 1.5 g (0.005 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-4-hydroxyquinoline-3-carboxylate and 1.4 g (0.01 mol) of potassium carbonate in 10 ml of dimethylformamide is heated for 30 minutes at 60° C. and left to cool, 2.15 g (3×0.005 mol) of methyl iodide are added, the mixture is heated at 80°-90° C. for 4 hours and left to cool, 25 ml of a water/ice mixture are added and the precipitate formed is filtered off and washed with water. The precipitate is receystallized from ethanol to give 1.2 g of a solid melting at 253°-254° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Na].[Cl:26][C:27]1[N:32]=[C:31]([NH:33][CH:34]([CH2:42][CH3:43])[C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[CH:30]=[C:29]([CH2:44][CH3:45])[N:28]=1.Br[C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1.O.C1(C)C=CC=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:26][C:27]1[N:32]=[C:31]([NH:33][CH:34]([CH2:42][CH3:43])[C:35]2[CH:40]=[CH:39][C:38]([O:41][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[CH:37][CH:36]=2)[CH:30]=[C:29]([CH2:44][CH3:45])[N:28]=1
Reactant: Brc1cccnc1
Reactant: CCc1cc(NC(CC)c2ccc(O)cc2)nc(Cl)n1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: [Na]
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc(NC(CC)c2ccc(Oc3cccnc3)cc2)nc(Cl)n1
Reaction time: 8 h
Yield: 33.6 %

Procedure:
To a solution of 2.2 g of dl-5-chloro-6-ethyl-4-(α-ethyl-4-hydroxybenzyl)aminopyrimidine sodium salt dissolved in 25 ml of dried pyridine were added 1.1 g of 3-bromopyridine and 1 g of cuprous chloride, and the mixture was refluxed under nitrogen atmosphere by heating and stirring for 8 hours. After completion of the reaction, the reaction product was poured into water and extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid and water, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure The oily product obtained was isolated by chromatography (Wako Gel C-200, trade name, eluted with toluene:ethyl acetate=4 : 1) to give 0.8 g of the desired product as colorless oily liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][NH2:33]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28][O:27][CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: COCCNCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: COCCNCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 3-1 1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-(2-methoxyethyl)ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm 8.06-8.04 (d, J=7.6 Hz, 1 H), 7.88-7.86 (m, 2 H), 7.73-7.70 (m, 2 H), 7.59-7.56 (m, 2 H), 6.01 (s, 1 H), 5.33 (s, 2 H), 4.55 (s, 2 H), 3.88-3.78 (m, 2 H), 3.72 (s, 2 H), 3.67-3.65 (t, J=4.8 Hz, 2 H), 3.45-3.42 (t, J=6 Hz, 2 H), 3.38 (s, 3 H), 3.30-3.28 (m, 2 H), 2.45 (s, 3 H).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]1([N:40]=[C:41]=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C=Nc1ccccc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccccc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 30.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, phenyl isocyanate (0.33 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 7:3) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(phenylamino)carboxamide (0.23 g, 31%) as a white solid: mp 212-214° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 8.78 (s, 1H), 7.88-7.76 (m, 3H), 7.37 (d, J=7.7 Hz, 2H), 7.21 (t, J=7.7 Hz, 2H), 6.89 (t, J=7.3 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 5.20-5.13 (dd, J=5.3 and 12.5 Hz, 1H), 4.72 (d, J=5.9 Hz, 2H), 2.97-2.84 (m, 1H), 2.65-2.49 (m, 2H), 2.09-2.05 (m, 1H); 13C NMR (DMSO-d6) δ 172.72, 169.79, 167.58, 166.99, 155.22, 140.25, 134.69, 133.63, 131.59, 128.60, 127.18, 121.83, 121.18, 117.70, 48.86, 38.71, 30.92, 21.97; Anal. Calcd. For C21H18N4O5: C, 62.07; H, 4.46; N, 13.79. Found: C, 62.14; H, 4.49; N, 13.49.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:12]2=[N:13][C:14]([NH:17]CC3C=CC(OC)=CC=3)=[CH:15][CH:16]=[C:11]2[C:10]([C:27](=[O:29])[CH3:28])=[CH:9]1)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[C:27]([C:10]1[C:11]2[C:12](=[N:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[N:8]([CH2:7][C:6]([OH:30])=[O:5])[CH:9]=1)(=[O:29])[CH3:28]
Reactant: COc1ccc(CNc2ccc3c(C(C)=O)cn(CC(=O)OC(C)(C)C)c3n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cn(CC(=O)O)c2nc(N)ccc12

Procedure:
A solution of [3-acetyl-6-(4-methoxy-benzylamino)-pyrrolo[2,3-b]pyridin-1-yl]-acetic acid tert-butyl ester (51 mg, 0.125 mmol) and TFA (191 μL, 2.49 mmol) in CH2Cl2 (0.6 mL) was stirred at RT for 24 h. Volatils were removed under reduced pressure and the brown solid thus obtained was used without further purification in the next step. MS (UPLC/MS): 234.1 [M+H]+, 232.1 [M−H]−. 1H-NMR (400 MHz, DMSO): δ (ppm): 8.08 (d, 1H), 8.02 (s, 1H), 6.83 (m, 2H), 6.44 (d, 1H), 4.90 (s, 2H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1C(O)=O>C1(C)C=CC=CC=1>[N:13]12[CH2:20][CH2:19][CH2:18][CH:14]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC3CCCN3C2C1

Procedure:
8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated under reflux overnight with 5.8 g (50 mmol) of proline in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC(C)=CC=1.[C:13]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][C:14]1=[CH2:15].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:17](=[O:18])[CH2:16][C:14](=[CH2:15])[C:13]([OH:19])=[O:20])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: C=C1CC(=O)OC1=O
Reactant: Clc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccc(Cl)cc1
Product: C=C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 40 °C
Yield: 70 %

Procedure:
21.2 g of anhydrous aluminum chloride are introduced into 50 g of p-chlorotoluene and the mixture is heated to 40° C. with stirring. A solid mixture of 8.3 g of itaconic anhydride and 13.2 g of 4-chlorobiphenyl is added in portions in the course of one hour. The reaction mixture is stirred at 40° C. for 30 minutes and then added to 100 g of ice water. The solid reaction product is filtered off and washed twice with water (50 ml). The product is dried at room temperature and about 100 mbar until free of solvent and water. 4-(4′-Chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid is obtained in a yield of 70% as a colorless, finely crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:55]1[CH2:60][CH2:59][S:58](=[O:62])(=[O:61])[CH2:57][CH2:56]1>CN(C=O)C.O>[O:61]=[S:58]1(=[O:62])[CH2:59][CH2:60][N:55]([C:21]([C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:16][CH:17]=2)=[O:23])[CH2:56][CH2:57]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Reactant: O=S1(=O)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.64 mmol) in DMF (8 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (227 mg, 0.70 mmol), N,N-diisopropyl ethyl amine (550 μL, 3.2 mmol) and thiomorpholine 1,1-dioxide (0.104 g, 0.77 mmol). The resulting reaction mixture was stirred for 30 min at room temperature and diluted with water. The mixture was then extracted with ethyl acetate and the combined organic layers washed with aqueous sodium carbonate (saturated) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 6:4) afforded the title compound (176 mg, 63%) as a white solid. MS: m/e=429.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[OH-].[Li+]>>[OH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([N:10]([C:11]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:21][CH2:22]1
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [Li+]
Agent: [OH-]
Product: C[C@H]1CC[C@H](C(=O)N(c2ccsc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1

Procedure:
The product from step I (30 mg) was hydrolyzed with lithium hydroxide as described earlier (example 3, step VIII) to afford after column purification on silica gel (CH2Cl2-MeOH) 16 mg (57%) of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24]>>[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)=[CH:27][CH:26]=1)=[O:24]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C=O)cc4)ccc3o2)CC1
Yield: 34.9 %

Procedure:
Following the General Procedure-1, the titled compound (100 mg) was prepared from Intermediate 13 (270 mg, 0.73 mmol) and 4-formylphenylboronic acid (132 mg, 0.88 mmol) as an off-white solid. M.P.: 167-170° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 10.07 (S, 1H), 7.96 (dd, J 1.7, 6.6, 2H), 7.93 (s, 1H), 7.76 (d, J 8.2, 2H), 7.58 (s, 2H), 4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.1, 2H), 3.22-3.13 (m, 1H), 3.04 (t, J 11.3, 2H), 2.18 (dd, J 2.8, 13.3, 2H).