Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH2:20].C(NCC)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13](=[S:20])[NH2:14])=[CH:11][C:10]=1[CH2:17][CH2:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cc(C#N)ccc1OCc1ccccc1
Reactant: S
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCCc1cc(C(N)=S)ccc1OCc1ccccc1
Temperature: 60 °C

Procedure:
Through a solution of 4-(benzyloxy)-3-propylbenzonitrile (1.23 g, 4.91 mmol) (Example 30) in DMF (35 mL) was passed H2S for 30 min at rt. Diethyl amine (0.76 mL, 7.36 mmol) was added and the solution was heated to 60° C. for 4 h. The mixture was cooled to rt, and the residual H2S was removed by passing argon through the solution for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was filtered through a plug of silica and washed with EtOAc. Concentration of the filtrate under reduced pressure resulted in a yellow solid which was used in the next step without further purification.
Reaction SMILES: [NH2:1][OH:2].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])/[CH:4]=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]>>[OH:2][NH:1][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][C:3]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NO
Product: CCOC(=O)C[C@H](NO)C(=O)OCC
Reaction time: 1 h

Procedure:
Hydroxylamine free base (50% aqueous solution, 2.0 g, 30.3 mmol) is added dropwise to diethyl maleate (4.41 g, 25.6 mmol) and stirred for 60 minutes to give diethyl N-hydroxyaspartate. Toluene (25.02 g) and p-toluenesulfonic acid (0.05 g, 0.26 mmol) are added to the reaction mixture and refluxed for 4.5 hours to afford diethyl 2-aminomaleate. The reaction mixture is cooled to room temperature and added acetic acid (7.0 g) and 2-ethylacrolein (2.13 g, 25, 0 mmol). The reaction mixture is stirred at 80°-90° C. for 24 hours. It is concentrated under reduced pressure and analyzed by GLC using an external standard. The analysis showed the yield of diethyl 5-ethylpyridine-2,3-dicarboxylate is about 35%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27]#[CH:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[OH:29][CH2:30][C:31]([NH:34][S:35]([C:38]1[S:42][C:41](Cl)=[N:40][CH:39]=1)(=[O:37])=[O:36])([CH3:33])[CH3:32]>>[OH:29][CH2:30][C:31]([NH:34][S:35]([C:38]1[S:42][C:41]([C:28]#[C:27][C:26]2[CH:25]=[N:24][N:17]3[C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:11])[F:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:15][C:16]=23)=[N:40][CH:39]=1)(=[O:37])=[O:36])([CH3:33])[CH3:32]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC)c3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ncc(S(=O)(=O)NC(C)(C)CO)s4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-Ethoxy-4-trifluoromethyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.3) (400 mg, 1.0 mmol) and 2-chloro-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.14) (244 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (80 mg, 12%). MS (ISP) 634.1 [(M+H)+]; mp 209-211° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([NH:21][OH:22])=[NH:20])[CH2:14]2)=[CH:9][CH:8]=1.[C:26](Cl)(=O)[CH3:27].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][C@H:15]([C:19]3[N:20]=[C:26]([CH3:27])[O:22][N:21]=3)[CH2:16][C:17]2=[O:18])=[CH:11][CH:12]=1
Reactant: N=C(NO)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc([C@@H]2CC(=O)N(c3ccc(OCc4cccc(F)c4)cc3)C2)no1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-N-hydroxy-5-oxo-pyrrolidine-3-carboxamidine (0.020 g, 0.58 mmol) was dissolved in a mixture of 0.4 ml pyridine and acetyl chloride (0.01 ml, 0.116 mmol) was slowly added at 0° C. The mixture was then stirred at 70° C. overnight. Iced water was added and the mixture was stirred for one hour. Extraction with a saturated solution of ammonium chloride and dichloromethane gave the crude product that was purified by column cromatography on silica gel using a 19:1-mixture of dichloromethane and methanol as the eluent to obtain the title compound as a light yellow solid (0.0197 g, 92% of theory). MS (m/e)=368.4 (M+H)+.
Reaction SMILES: Cl.[C:2]1([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OO)(=[O:21])C>O>[C:2]1([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N+:11]([O-:21])=[CH:10][CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OO
Reactant: O=C(O)c1cnccc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1c[n+]([O-])ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Phenylnicotinic acid hydrochloride (2.4 g, 0.01 mol) is dissolved in water (50 ml) and the pH is adjusted to pH 10-11 by the addition of 5N aqueous NaOH solution. A solution of peracetic acid (40% w/v, 15.2 g) is added cautiously at ambient temperatures. When the addition is complete, the reaction mixture is stirred at ambient temperature for 15 min and then heated at 50° for 4 h. After this period, the mixture is allowed to cool and evaporated in vacuo to dryness. The residue is slurried in hot ethanol (20 ml), then filtered, and the filtrates are evaporated to dryness in vacuo to yield 4-phenylnicotinic acid N-oxide.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH2:23])#[N:11].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O1CCCC1>[C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH:23][C:25](=[O:26])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)#[N:11]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#Cc1ccc2[nH]cc(CCN)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reaction time: 1.5 h
Yield: 75.2 %

Procedure:
A solution of diisopropylethylamine (6.11 g), in dry tetrahydrofuran (20 ml) was added to a stirred solution of 5-cyano-1H-indole-3-ethanamine (7.3 g) in dry tetrahydrofuran (250 ml). A solution of benzyl chloroformate (7.73 g) in dry tetrahydroguran (20 ml) was then added at room temperature. After stirring for 1.5 h the reaction mixture was partitioned between water (100 ml). The aqueous layer was separated and extracted with ethyl acetate (4×50 ml). The combined organic solutions were washed with water (100 ml), dried (MgSO4) filtered and evaporated to afford an oily solid which was washed with petroleum spirit (b.p. 60°-80°, 100 ml) and then recrystallised from a mixture of ethyl acetate (50 ml) and petroleum spirit (b.p. 60°-80°, 35 ml) to afford the title compound (9.46 g), m.p. 127.5°-129°.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.I[CH2:30][CH3:31].C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1>[CH2:30]([O:28][C:26]1[CH:25]=[CH:24][C:23]2[N:19]([CH2:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)[CH:20]=[N:21][C:22]=2[CH:27]=1)[CH3:31]
Reactant: Oc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.4 %

Procedure:
A mixture of 1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (80 mg, 0.20 mmol) from Example 147, iodoethane (47 mg, 0.30 mmol) and Cs2CO3 (196 mg, 0.6 mmol) in NMP (3.5 mL) was stirred at rt for 5 h. The mixture was added to water and extracted with DCM. The organic layer was separated, washed sequentially with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to afford (1R,2R)-2-((6-((5-ethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (35 mg, 42%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.62 (s, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.14-7.19 (m, 2H), 6.82 (d, J=9.0 Hz, 1H), 5.41 (s, 2H), 4.72 (d, J=4.8 Hz, 1H), 3.97-4.04 (m, 2H), 3.43-3.54 (m, 2H), 2.03 (m, 1H), 1.87 (m, 1H), 1.60-1.65 (br m, 2H), 1.32 (t, J=13.8 Hz, 3H), 1.15-1.24 (m, 4H). LCMS (ESI) m/z 423 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7])[CH3:3].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[CH3:1][N:2]([CH2:4][C:5](=[CH2:9])[C:6]([O:8][CH2:15][CH3:16])=[O:7])[CH3:3]
Reactant: C=C(CN(C)C)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: C=C(CN(C)C)C(=O)OCC

Procedure:
A solution of the 2-dimethylaminomethylacrylic acid (35 g) compound prepared as in Example 1 in ethanol (350 ml) and concentrated sulphuric acid (60 ml) were boiled under reflux for three hours. The solution was evaporated to half volume and poured into water (1 liter). The aqueous solution was neutralised by the addition of solid sodium carbonate and extracted with ether. Evaporation of the ether solution gave a pale brown oil which was distilled to give a colourless oil (boiling point 84° C/20 mm). The product was identical with that obtained in Example 4.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH:10]1([C:13]([C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[O:14])[CH2:12][CH2:11]1.[Cl-].[NH4+]>O1CCCC1>[CH:10]1([C:13]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:9])([C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[OH:14])[CH2:11][CH2:12]1
Reactant: Cn1cccc1C(=O)C1CC1
Reactant: Cc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)(c1cccn1C)C1CC1
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a suspension of magnesium turnings (1.72 g, 0.071 mole) in anhydrous tetrahydrofuran (20 ml), 2-bromotoluene (12.1 g, 0.071 mole) in tetrahydrofuran (100 ml) was added dropwise under nitrogen. The reaction mixture was heated at reflux for 1 h after the initial exotherm had subsided before cyclopropyl-(N-methylpyrrol-2-yl)ketone (7.1 g, 0.047 mole) (J. Org. Chem., (1971), 36, 2897; J.Org.Chem. (1980), 45, 3172) in anhydrous tetrahydrofuran (100 ml) was introduced. After heating the reaction mixture at reflux for 2 h it was left overnight at room temperature. Saturated, aqueous ammonium chloride solution (100 ml) was added, and the mixture was extracted with diethyl ether (3×200 ml). The combined extracts were dried (MgSO4) and the solvents evaporated. The residue was flash chromatografied on silica gel eluting with n-heptane/tetrahydrofuran (19:1) providing the title compound as a solid (10.9 g).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1>[F:13][C:14]([F:22])([F:23])[CH2:15][CH:16]([CH3:1])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)CCC(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of diisopropylamine (19.5 mL) in tetrahydrofuran (200 mL) at 0° C. was treated with n-butyllithium (71 mL, 1.5M in hexanes). The resulting solution was stirred for 30 minutes at 0° C., then was cooled to -70° C. A solution of ethyl 4,4,4-trifluorobutyrate (14 mL) in tetrahydrofuran (150 mL) was slowly added to the lithium diisopropylamide solution and the resulting mixture was stirred at -70° C. for 30 minutes. A solution of iodomethane (11.5 mL) in tetrahydrofuran was added in one portion, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with water and evaporated. The residue was dissolved in methylene chloride, washed (10% (w/v) hydrochloric acid, water, and brine), dried (MgSO4), filtered, and evaporated. The resulting pale yellow liquid was purified by distillation to yield ethyl 4,4,4-trifluoro-2-methylbutyrate as a colorless liquid (7.8 g, 46%); bp 125°-128 ° C.; partial NMR: (300 MHz, CDCl3): 1.30 (m, 6H, CH3), CH2CH3), 2.15 (m, 1H, H-C(3)), 2.64 (m, 1H, H-C(3)), 2.72 (m, 1H, H-C(2)), 4.16 (q, 2H, OCH2).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:38])[N:35]([OH:37])[CH3:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:39])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:42][O:43][C:44]([CH3:60])([CH3:59])[C:45]([NH:47][NH:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([OH:57])[CH:51]=1)=[O:46]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:42]/[O:43][C:44]([C:45](=[O:46])[NH:47][NH:48][C:49](=[O:58])[C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([OH:57])[CH:51]=2)([CH3:59])[CH3:60])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:38])[N:35]([OH:37])[CH3:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:39])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)N(C)O)nc2n1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NNC(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)N(C)O)nc2n1
Reaction time: 20 h
Yield: 28.3 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(N-hydroxy-N-methylcarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (40 mg) (0.066 mmol) and 29 mg (0.086 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 1 ml of absolute dimethylacetamide. After stirring for 20 hours the solution is concentrated at room temperature in a high vacuum. The residue is crystallized from ethanol. There are obtained 16 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[2-(N-hydroxy-N-methylcarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a brown powder.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])C(=O)OC(C)(C)C)[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1.C(=O)([O-])O.[Na+].[CH2:46]([O:49][CH2:50][CH2:51]Br)[CH2:47]Br.O>C1(C)C=CC=CC=1>[CH3:39][N:9]1[CH:10]=[C:11]([NH:12][C:13]([C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:34][C:35]([F:36])([F:37])[F:38])[CH:21]=3)[O:18][CH:19]=2)=[O:14])[C:7]([N:5]2[CH2:6][C@@H:2]([N:1]3[CH2:51][CH2:50][O:49][CH2:46][CH2:47]3)[CH2:3][C:4]2=[O:40])=[N:8]1
Reactant: BrCCOCCBr
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](N)CC2=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)c(N2C[C@@H](N3CCOCC3)CC2=O)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (4-(4-((3-((4S)-4-amino-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (79 mg) and sodium hydrogen carbonate (70 mg) in toluene (0.70 mL) was added 2,2′-dibromodiethyl ether (0.035 mL), and the mixture was stirred overnight at 100° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in TFA (0.70 mL), and the solution was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/hexane to give the title compound (3.3 mg).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]32[S:16][CH2:15][CH2:14][S:13]3)=[C:4]([CH3:17])[CH:3]=1.C([Li])CCC.[C:23](=[O:25])=[O:24]>O1CCCC1.CCCCCC>[CH3:17][C:4]1[CH:3]=[C:2]([C:23]([OH:25])=[O:24])[C:11]([CH3:12])=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]12[S:16][CH2:15][CH2:14][S:13]1
Reactant: Cc1cc(Br)c(C)c2c1CCCC21SCCS1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C(=O)O)c(C)c2c1CCCC21SCCS1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
A solution of 12.7 g of the title compound of Step B in 300 mL of tetrahydrofuran under a nitrogen atmosphere was cooled to -78° C. To this solution was slowly added 19.2 mL of a 2.5M solution of n-butyllithium in hexane (purchased from Aldrich Chemical Co.). The reaction mixture was maintained below -60° C. during the addition of n-butyllithium and stirring 30 min after addition was complete. The mixture was then cooled to -78° C. and 35.0 g of crushed dry ice was added. The resulting mixture was stirred and allowed to warm to room over 1.5 h. The mixture was then concentrated under reduced pressure, and to the resulting residue was added 300 mL of water. The mixture was then cooled to 0° C., acidified to pH 2 with concentrated hydrochloric acid, and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting solid was crystallized from 1-chlorobutane to gave 3.2 g of the title compound of Step C as a white solid melting at 215° C. (dec.). 1H NMR ((CD3)2SO): δ 1.90 (m, 2H), 2.16 (s, 3H), 2.34 (m, 2H), 2.61 (t, 2H), 2.75 (s, 3H), 3.40-3.70 (m, 4H), 7.29 (s, 1H), 12.75 (br s, 1 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:16]1[C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=[C:12]([O:11][C:9]([O:1][CH2:2][C:3]2[S:7][CH:6]=[N:5][CH:4]=2)=[O:10])[CH:17]=1
Reactant: OCc1cncs1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of 3.11 g (27 mmol) of 5-(hydroxymethyl)thiazole and excess N-methyl morphcline in 100 ml of methylene chloride was cooled to 0° C. and treated with 8.2 g (41 mmol) of 4-nitrophenyl chloroformate. After being stirred for 1 h, the reaction mixture was diluted with CHCl3, washed successively with 1N HCl, saturated aqueous NaHCO3, and saturated brine, dried over NaSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2, 1-2% MeOH/CHCl3, Rf=0.5 in 4% MeOH/CHCl3) to yield 5.9 g (78%) of the desired compound as a yellow solid. NMR (CDCl3) δ5.53 (s, 2H), 7.39 (dt, J=9, 3 Hz, 2H), 8.01 (s, 1H), 8.29 (dt, J=9, 3 Hz, 2H), 8.90 (s, 1H). Mass spectrum: (M+H)+ =281.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CN(C=O)C.S(Cl)([Cl:22])=O>ClC1C=CC=CC=1>[OH:1][C:2]1[C:3]([C:12]([Cl:22])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2cc1O
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2cc1O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 723 %

Procedure:
99.0 g (0.52 mol) of 3-hydroxy-2-naphthoic acid and 1 ml of N,N'-dimethylformamide are initially introduced into 600 ml of chlorobenzene and 68.5 g=42 ml (0.58 mol) of thionyl chloride are added at 40° C. The mixture is subsequently stirred at 40° C. for 1.5 h and excess thionyl chloride is then distilled off in vacuo. 776.8 g of 3-hydroxy-2-naphthoyl chloride are obtained as a clear solution in chlorobenzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([F:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:13]([F:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(F)c(I)cc2C1
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N1Cc2cc(F)c(N3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-fluoro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and morpholine. Yellow solid. MS (m/e): 323.4 ([M+H]+, 100%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[OH:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: OCc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(CO)cccc21
Yield: 77.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 173 mg of 4-(hydroxymethyl)indoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 288 mg of 2-{2-[4-(hydroxymethyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:35])=[C:4]([C:8]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[C:17]3[C:9]=2[C:10]2[CH2:11][CH2:12][CH:13]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:14][C:15]=2[NH:16]3)[CH:5]=[CH:6][CH:7]=1.Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43](Cl)=[O:44]>C(Cl)Cl>[C:21]([C:18]1[CH:19]=[CH:20][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:43](=[O:44])[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=3)[C:3]=2[CH3:35])=[C:9]2[C:17]=1[NH:16][C:15]1[CH2:14][CH:13]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:12][CH2:11][C:10]2=1)(=[O:23])[NH2:22]
Reactant: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3c(c12)CCC(NC(=O)OCc1ccccc1)C3
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: Cc1c(NC(=O)c2ccccn2)cccc1-c1ccc(C(N)=O)c2[nH]c3c(c12)CCC(NC(=O)OCc1ccccc1)C3

Procedure:
A solution of benzyl 5-(3-amino-2-methylphenyl)-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazol-2-ylcarbamate, TFA salt (Example 51-1, 55 mg, 0.094 mmol), TEA (0.066 mL, 0.472 mmol), and picolinoyl chloride hydrochloric acid salt (50.4 mg, 0.283 mmol) in DCM (8 mL) was stirred at rt overnight. The mixture was concentrated and purified by preparative HPLC to provide benzyl 8-carbamoyl-5-(2-methyl-3-(picolinamido)phenyl)-2,3,4,9-tetrahydro-1H-carbazol-2-ylcarbamate, isolated as the TFA salt, as a white solid (26 mg, 39%). 1H NMR (400 MHz, methanol-d4) δ 8.59 (1H, t, J=4.8 Hz), 8.14 (1H, d, J=8.3 Hz), 7.89-7.99 (1H, m), 7.85 (1H, dd, J=9.9, 8.1 Hz), 7.50 (2H, dd, J=7.7, 2.0 Hz), 7.11-7.32 (6H, m), 7.01 (1H, d, J=7.9 Hz), 6.74 (1H, d, J=7.5 Hz), 4.96 (2H, s), 3.68-3.87 (1H, m), 2.96-3.10 (1H, m), 2.49-2.66 (1H, m), 1.82-2.11 (5H, m), 1.73 (1H, br. s.), 1.34-1.62 (1H, m). Mass spectrum m/z 575.1 (M+H)+.