Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)(=[O:4])(=[O:3])[NH2:2].[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3([C:26]([NH:28][C:29]4[CH:30]=[N:31][C:32]([CH3:36])=[C:33](Br)[CH:34]=4)=[O:27])[CH2:25][CH2:24]3)=[CH:22][C:17]=2[O:16][CH2:15]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3([C:26]([NH:28][C:29]4[CH:30]=[N:31][C:32]([CH3:36])=[C:33]([C:7]5[CH:8]=[CH:9][CH:10]=[C:5]([S:1](=[O:4])(=[O:3])[NH2:2])[CH:6]=5)[CH:34]=4)=[O:27])[CH2:25][CH2:24]3)=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1cccc(S(N)(=O)=O)c1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-(3-sulfamoylphenyl)pyridin-3-yl)cyclopropanecarboxamide was prepared from 3-sulfamoylphenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2Cl)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=3)[NH:3][C:2]=1[CH3:1])[CH:22]=[CH:21]2)(=[O:15])=[O:14]
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: CS(=O)(=O)c1cccc2c(Cl)ccnc12
Product: Cc1ccc2[nH]c(C)c(-c3ccc4cccc(S(C)(=O)=O)c4n3)c2c1

Procedure:
The sub-title compound was prepared by the method of Example 40 step a, using 2,5-dimethyl indole and 8-methanesulphonyl-4-chloroquinoline.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[O:24]=[CH:25][C@@H:26]([C@H:28]([C@@H:30]([C@@H:32]([CH2:34][OH:35])[OH:33])[OH:31])[OH:29])[OH:27]>>[O:24]=[C:25]1[O:31][C@H:30]([C@H:32]([CH2:34][OH:35])[OH:33])[C:28]([OH:29])=[C:26]1[OH:27]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 0.29 h

Procedure:
Isolation and Culture of Growth Plate Chondrocytes: Six- to eight-week old broiler chickens were obtained commercially, sacrificed by cervical displacement, and the tibiae harvested. Epiphyseal growth plate chondrocytes were obtained from the tibiae as described (Ali et al., 1970, Proc. Natl. Acad. Sci. USA 67: 1513–1520). Briefly, cartilage slices were digested in 1% trypsin solution prepared in synthetic cartilage lymph (SCL). SCL contains 2 mM Ca2+ and 1.42 mM Pi, in addition to 104.5 mM Na+, 133.5 mM Cl−, 63.5 mM sucrose, 16.5 mM N-tris methyl-2-aminoethane sulfonic acid (TES), 12.7 mM K+, 5.55 mM D-glucose, 1.83 mM HCO3−, 0.57 mM Mg2+, and 0.57 mM SO4−. Cartilage slices were digested for 15 to 20 minutes at 37° C. After digestion, part of the trypsin solution was removed and 10 ml of SCL and 0.5 ml of 0.78% collagenase solution added to the tissue slices. After 30 minutes of collagenase/trypsin digestion at 34° C., the liquid was removed from the slices and replaced with 0.5 ml of 0.78% collagenase solution plus 15 ml DMEM, with 10% FBS. The collagenase-DMEM solution was removed from the cartilage digestate after 15 hours (overnight) of digestion. The chondrocytes were released from the residual tissues by vortexing for a total of 3 minuntes (1 minute each time) in fresh medium. Isolated cells were demineralized in iso-osmotic citrate buffer (8.0 mM citric acid in 80.5 mM sodium citrate, pH 6.0) for 15 minutes at 34° C. After demineralization cells were washed with fresh medium, resuspended in 10 ml of DMEM with 10% FBS, and counted using a hemocytometer. Cell viability was determined by trypan blue exclusion. Cells were plated at 3–4×105 cells per 35 mm dish in 2 ml of medium. The cells were initially cultured in DMEM with 10% FBS and 1% penicillin/streptomycin solution. The culture medium was changed twice a week for the duration of the experiments. On day 7, the cell cultures were changed into a 1:1 (v/v) mixture of DMEM with 10% FBS and serum-free HL-1 medium. Ascorbic acid was provided at 50 μg/ml medium after day 3. For treatment of endothelial cell cultures, the concentrated fusarochromanone solution was diluted in methanol to final concentrations of 0.6 mM, 3 mM, and 15 mM. On day 7, 2 μl samples of the FC solutions or pure methanol for the control were added to the cultures in 2 ml of media. FIGS. 5A to 5D show there is no appreciable change in the morphology of chondrocytes treated with FC101 for seven days. Note that there is little difference between the control cells (5A) and those treated with FC101 (B:0.6 μM; C:3 μM; D:15 μM FC101).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30]([N:32]4[CH2:37][CH2:36][C:35]([CH2:43][CH3:44])([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47])(=O)C.C1COCC1.[OH-].[Na+]>CO>[CH2:43]([C:35]1([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33][N:32]([C:30]([C@:14]23[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]2[C@@H:16]2[C@@:11]([CH3:45])([CH2:12][CH2:13]3)[C@@:10]3([CH3:46])[C@@H:19]([C@:20]4([CH3:23])[C@@H:7]([CH2:8][CH2:9]3)[C:6]([CH3:48])([CH3:47])[C@@H:5]([OH:4])[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)=[O:31])[CH2:37][CH2:36]1)[CH3:44]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
Ethyl 1-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)-4-ethylpiperidine-4-carboxylate (Example 72, 2.0 g) was taken in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (1.5 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure. The residue was taken in water and extracted with DCM; the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (1.45 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 10H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.15-4.18 (m, 2H); 4.56 (s, 1H); 4.71 (s, 1H); MASS: 624 (100%).
Reaction SMILES: [CH2:1](O)[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5](O)[C@@H:4](O)[C@@H:3]1O.P([O-])([O-])([O-])=O.[OH-].[K+]>CCCCCCCCCCCC>[C:6]([OH:7])(=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCCCCCCC
Product: CCCCCCCCCCCC(=O)O
Temperature: 30 °C
Reaction time: 72 h

Procedure:
Components for the fermentation medium described in Example 1 as well as 50 g sucrose were dissolved in 1 liter distilled water and adjusted to pH 5.5. Fifty milliliters of the medium were placed in a 500 ml shaking flask and inoculated with 2 loopsful of the Debaryomyces vanriji strain used in Example 1, and growth was maintained at 30° C. for 26 hours. The obtained culture broth was centrifuged in order to separate the cells (about 1 g dry weight). A reaction solution was prepared by mixing 100 ml of 0.5 M phosphate buffer (pH 7.0) with 10 ml of normal dodecane. A reaction was carried out between this reaction solution and the filtered cells at 30° C. for 72 hours. The reaction products were basified to pH 10 with potassium hydroxide and were analyzed using the same process as in Example 1. As a result, 4.8 mg/L of lauric acid and 3.7 mg/L of 1,10-decane dicarboxylic acids were produced in the reaction medium. For this experiment, the medium, substrate, and the equipment were autoclaved previously so that the experiment could be carried out under sterile conditions.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][CH:4]([CH3:11])[CH2:5][CH2:6][C:7](OC)=[O:8]>CO>[CH3:3][CH:4]([CH3:11])[CH2:5][CH2:6][C:7]([NH:1][NH2:2])=[O:8]
Reactant: NN
Reactant: COC(=O)CCC(C)C
Solvent: CO
Product: CC(C)CCC(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Under nitrogen, a solution of 53.8 g (1.68 mol) of anhydrous hydrazine in 300 mL of methanol was cooled to 0° C. and treated with 186 g (1.4 mol) of methyl 4-methylvalerate. The reaction was allowed to warm to ambient temperature and stir overnight prior to stirring at reflux for 4 h. The reaction was concentrated in vacuo giving 166 g (93%) of 4-methylvaleric acid hydrazide as a colorless solid: 49–51° C.; NMR (CDCl3) δ 0.89 (d, J=7 Hz, 6H), 1.48–1.64 (m, 3H), 2.15 (t, J=7 Hz, 2H), 3.91 (br s, 2H), 6.94 (br s, 1H). A 7.86 g (60 mmol) sample of the hydrazide was dissolved in 50 mL of methanol and treated with 7.8 g (60 mmol) of ethyl iminovalerate under nitrogen. The reaction was stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (40:60) gave 9.6 g (82.%) of 3-butyl-5-isopentyl-1H-1,2,4-triazole as a colorless solid which melts close to ambient temperature: NMR (CDCl3) δ 0.81–0.90 (m, 9H), 1.25–1.40 (m, 2H), 1.47–1.74 (m, 5H), 2.70 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 196 (100); HRMS. Calcd for M+H: 196.1814. Found: 196.1832.
Reaction SMILES: [CH2:1]([Si:4]([CH2:12][CH:13]=[CH2:14])([CH2:9][CH:10]=[CH2:11])[CH2:5][CH2:6][CH2:7]Br)[CH:2]=[CH2:3].C([O-])=[O:16].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([Si:4]([CH2:12][CH:13]=[CH2:14])([CH2:9][CH:10]=[CH2:11])[CH2:5][CH2:6][CH2:7][OH:16])[CH:2]=[CH2:3]
Reactant: O=C[O-]
Reactant: C=CC[Si](CC=C)(CC=C)CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: C=CC[Si](CC=C)(CC=C)CCCO

Procedure:
Triallyl(3-hydroxylpropyl)silane was prepared from triallyl-3-bromopropyl silane prepared in Example 7 via the formyloxypropyl intermediate. A 100 ml flask equipped with stir bar and reflux condenser was charged with 10.0 grams (36 millimoles) of triallyl 3-bromopropyl silane (prepared as described in Example 7), 4.90 grams (72 millimoles) sodium formate (commercially available from Aldrich Chemical Co. of Milwaukee, Wis.) and 0.60 grams of tetrabutyl ammonium bromide (commercially available from Aldrich Chemical Co.). The suspension was stirred at 110° C. for two days. The solution was then filtered and combined with equal volumes of deionized water and cyclohexane (commercially available as Omnisolve from E. Merck of Gibbstown, N.J.). The organic extract was flash chromatographed on silica using first cyclohexane, followed by 80/20 cyclohexane/acetone to collect the triallyl formyloxypropyl silane intermediate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.[ClH:12].[N:13]1([CH2:19][CH2:20][Cl:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>CO>[ClH:21].[ClH:12].[N:13]1([CH2:19][CH2:20][S:9][C:7]2[NH:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=3[N:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: ClCCN1CCCCC1
Reactant: Cc1ccc2[nH]c(=S)[nH]c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2nc(SCCN3CCCCC3)[nH]c2c1

Procedure:
4.87 g (30 mmoles) of 5-methyl-benzimidazoline-2-thione, 6.54 g (35.5 mmoles) of 2-(1-piperidyl)-ethylchloride hydrochloride, 2.78 g (33 mmoles) of sodium hydrogencarbonate are dissolvent in 60 ml of methanol and the mixture is refluxed for 6 hours. The inorganic salt is filtered off, the filtrate is evaporated, and the title compound is precipitated by adding ethyl acetate and hydrochloric ethyl acetate. Weight: 9.32 g (90%). Melting point: 229°-230° C., which does not change after recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].[CH2:29]([N:31](CC)CC)C.Cl.CN>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH:31][CH3:29])(=[O:27])=[O:26]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)NC)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)1H-indole-2-carboxylate (101 mg, 0.219 mmol) in 2 mL of dichloromethane was added triethylamine (0.157 mL, 1.09 mmol), followed by methylamine hydrochloride(44 mg, 0.66 mmol). After one hour, the mixture was partitioned between 100 mL of EtOAc and 100 mL of saturated aqueous NH4Cl solution. The organic phase was washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to give the titled product. ESI+MS: 457.0 [M+H]−.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C.O>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: NC1CCCCC1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Solvent: CC#N
Solvent: O
Product: CSc1nc(Cl)c(C=O)c(NC2CCCCC2)n1
Reaction time: 16 h
Yield: 99 %

Procedure:
4,6-Dichloro-2-methylsulfanylpyrimidine-5-carboxaldehyde (4.0 g, 0.018 mol) in acetonitrile (65 mL) was treated with rapid stirring with cyclohexylamine (3.76 g, 4.3 mL, 0.038 mol) over 1 min. Reaction stirred 16 h then diluted with 3 volumes of H2O. The precipitated solid was collected, washed with H2O and dried in vacuo to afford 5.1 g. (99%) of the title compound as a white solid. LC MS (m/e)=286 (MH+). Rt=2.85 min.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:16]2=[O:28])[CH2:3]1.[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:16]3=[O:28])[CH2:3][C@H:2]2[F:1])=[CH:9][CH:10]=1)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
To a solution of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.02 g, 0.052 mmol, example 1) in DCM (3 mL) was added (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.059 g, 0.272 mmol) followed by DCC (0.032 g, 0.157 mmol) and DMAP (6.39 mg, 0.052 mmol). The reaction mixture was stirred at room temperature for 18 h. Water (10 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (3×10 mL) and the organic layers were combined, dried over Na2SO4, and concentrated to a crude product. The crude product was purified by preparative TLC eluting with 35% ethyl acetate in petroleum ether to provide the purified product (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (27 mg, 79%). LC/MS (Conditions A) RT=2.523 min, (M+H)+=582.2. 1H NMR (400 MHz, methanol-d4) δ 7.36 (d, J=8.5 Hz, 2H), 7.18 (s, 4H), 7.08 (d, J=8.5 Hz, 2H), 4.80-4.59 (m, J=10.0, 10.0, 5.0 Hz, 1H), 4.51 (d, J=15.0 Hz, 1H), 4.39 (d, J=15.0 Hz, 1H), 4.23 (dd, J=8.3, 6.3 Hz, 1H), 3.72 (t, J=8.8 Hz, 1H), 3.56-3.40 (m, 1H), 3.32-3.22 (m, 2H), 2.86-2.61 (m, 2H), 2.47 (td, J=10.0, 5.0 Hz, 1H), 2.34 (s, 3H), 2.32-2.23 (m, 1H), 2.22-2.01 (m, 2H), 1.88 (dd, J=9.5, 4.0 Hz, 2H), 1.74 (dt, J=13.4, 3.8 Hz, 1H), 1.50 (s, 9H), 1.42-1.30 (m, 1H), 1.09 (dd, J=10.0, 7.0 Hz, 6H). 19F NMR (376 MHz, methanol-d4) δ −184.32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Br:11]Br>[Fe].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Br:11]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
Iron (0.35 g) was added to 1chloro-4-nitrobenzene (15.8 g) at 140° C., bromine (2.8 ml) was added dropwise and the mixture heated to 140° C. for 1 hour. Two further additions of iron and bromine were made at 1 hour intervals followed by a final addition of iron (0.07 g) and heating to 140° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, added to sodium metabisulfite solution (200 ml) and stirred for 30 min. The solution was extracted with dichioromethane (×4), washed with aqueous sodium metabisulfite and water then dried (MgSO4) to give an oil which was used in the next step without further purification.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1>C1(C)C=CC=CC=1>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[CH:9][C:10]#[N:11])[CH:13]=1
Reactant: O=Cc1cccnc1
Reactant: CCOP(=O)(CC#N)OCC
Solvent: Cc1ccccc1
Product: N#CC=Cc1cccnc1
Yield: 69.2 %

Procedure:
95 ml (0.60 mol) of cyanomethylphosphonic acid diethyl ester and 50 ml (0.55 mol) of pyridine-3-carbaldehyde are dissolved in 1 L of toluene and mixed with 55 g (0.55 mol) of KHCO3. The mixture is heated for 1 hour in a preheated oil bath. The cooled mixture is mixed with additional toluene and washed with 1M NaHCO3, twice with water and with saturated common salt solution. The organic phase is dried and concentrated by evaporation in a vacuum. The residue is recrystallized from ethyl acetate/hexane, and 49.5 g (69%) of product is obtained. Melting point 99.5-101° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: COc1ccc2c(c1/C=C\C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1/C=C\C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A solution of tert-butyl (Z)-4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)vinyl]piperidine-1-carboxylate (0.0374 g, 0.100 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0146 g, 0.100 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((Z)-2-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}vinyl)piperidine-1-carboxylate (0.0387 g, 77%).
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]>O.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:8]2[C:7]=1[NH:6][C:4]([CH:1]1[CH2:2][CH2:3]1)=[N:11][C:9]2=[O:10]
Reactant: O=CC1CC1
Reactant: NC(=O)c1cccc(Cl)c1N
Agent: Cl[Fe](Cl)Cl
Solvent: O
Product: O=c1nc(C2CC2)[nH]c2c(Cl)cccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
EDCI hydrochloride (22.0 g) and 1-hydroxybenzotriazole (11.4 g) were added to a solution of 2-amino-3-chlorobenzoic acid (12.8 g) in DMF (100 mL), and subsequently ammonia water (22.0 ml) was added thereto. The reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 2-amino-3-chlorobenzamide (9.7 g). Iron(III) chloride hexahydrate (6.3 g) and cyclopropanecarbaldehyde (1.3 ml) were added to a suspension of the obtained 2-amino-3-chlorobenzamide (2.0 g) in water (30 ml), and the mixture was stirred overnight at 100° C. After cooling, water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 8-chloro-2-cyclopropylquinazolin-4(1H)-one (2.0 g). Compound (115) was obtained as a yellow solid (yield based on 6 steps: 18%) according to Example 114(2) using the obtained 8-chloro-2-cyclopropylquinazolin-4(1H)-one instead of compound (114a).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[CH:4]=1)[CH3:2].[Cl:10]CCCl.P(Cl)(Cl)(Cl)=O>O>[Cl:10][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: ClCCCl
Reactant: CCc1cc(O)ncn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCc1cc(Cl)ncn1

Procedure:
To 12.4 g (0.1 mole) of 6-ethyl-4-hydroxypyrimidine was added 50 ml of 1,2-dichloroethane, and 18.4 g (0.12 mole) of phosphorus oxychloride was added thereto. The mixture was refluxed by heating for 3 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 10.38 g of 4-chloro-6-ethylpyrimidine as slightly red liquid.
Reaction SMILES: [C:1]([OH:14])(=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[N+:40]([C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:45][CH:44]=1)([O-:42])=[O:41].C(NC1CCCCC1)(NC1CCCCC1)=O>CN(C=O)C>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([C:1]([N:52]2[CH2:53][CH2:54][N:49]([C:46]3[CH:45]=[CH:44][C:43]([N+:40]([O-:42])=[O:41])=[CH:48][CH:47]=3)[CH2:50][CH2:51]2)=[O:14])[CH:12]=[C:9]([O:10][CH3:11])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(OC)c1O
Reaction time: 7 h

Procedure:
In a 100 ml flask, 0.99 g (5 mmoles) of syringic acid, 0.74 g (5.5 mmoles) of hydroxybenzotriazol, 1.10 g (5.5 mmoles) of dicyclohexylcarbodiimide and 1.04 g (5 mmoles) of 1-(4-nitrophenyl)piperazine are dissolved in 10 ml of DMF. After agitation at ambient temperature for 7 hours, the mixture is filtered and the precipitate rinsed with 20 ml of DMF followed by 100 ml of chloroform 2 g of a yellow powder is obtained, containing approximately 20% of dicyclohexylurea. The product is used as it is in the following stage.