Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@:4]1([C:10]([O:12]CC2C=CC=CC=2)=[O:11])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2]>CO.[Pd]>[CH:1]([C@:4]1([C:10]([OH:12])=[O:11])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)OCc2ccccc2)CCC(=O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@]1(C(=O)O)CCC(=O)C1
Reaction time: 2 h
Yield: 84.8 %

Procedure:
Benzyl (1S)-1-isopropyl-3-oxocyclopentanecarboxylate (1.27 g, 4.88 mmol) was combined with Pd/C (10% Degussa, 500 mg) in 20 mL of methanol and stirred under a hydrogen atmosphere (balloon) for 2 h. The reaction had only proceeded part way (˜30% conversion) so the reaction mixture was filtered, another portion of Pd/C (500 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 5 h. Since the reaction had now gone to completion, the reaction mixture was filtered through celite and concentrated to afford 704 mg of (1S)-1-isopropyl-3-oxocyclopentanecarboxylic acid that did not require further purification. Note that the large quantities of catalyst were used because the ester obtained after chiral separation must have been poisoned by an impurity. This was unique to this particular sample. Normally much smaller quantities of catalyst are used. 1H NMR was identical to that of the racemic acid above (Step D).
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:20]=[CH:19][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[CH:8][CH:7]=1)=[O:5])C.[CH:23]([Li])([CH2:25][CH3:26])[CH3:24].Cl>C1(C)C=CC=CC=1.CCCCCC.C1CCCCC1>[CH3:24][CH:23]([CH2:25][CH3:26])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[CH:19][CH:20]=1)=[O:5]
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2OC)cc1
Reactant: [Li]C(C)CC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CCC(C)C(=O)c1ccc(Cc2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
The 2-(4-diethylcarbamoylbenzyl)anisole (100 mg) obtained in the process of Reference Example 1(d) was dissolved in toluene (2 ml), added with a solution of sec-butyl lithium in n-hexane and cyclohexane (1.0 M, 0.47 ml) at 0° C. under argon atmosphere and stirred at room temperature for 1 hour. After the reaction mixture was slowly poured into 1 N aqueous hydrochloric acid (5 ml) with ice cooling to quench the reaction and the layers were separated, the aqueous layer was extracted with ether (10 ml). The organic layer was washed with saline and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=2:1) to obtain 58.3 mg of the title compound. Yield: 61%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:38]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:46][C:47]([NH2:49])=[O:48].O>CN(C=O)C>[C:47]([CH2:46][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:38]=2)=[CH:4][CH:3]=1)(=[O:48])[NH2:49]
Reactant: NC(=O)CI
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(O)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCC(N)=O)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reaction time: 0.83 h
Yield: 35.9 %

Procedure:
In DMF (1.6 ml) was dissolved 7-(4-hydroxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (131 mg). To the mixture was added potassium carbonate (41 mg), and the mixture was stirred for 50 minutes. To the mixture was added iodoacetamide (50 mg), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-carbamoylmethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 95) (52 mg).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:32]([F:35])([F:34])[F:33])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>ClCCl.CN(C=O)C>[CH2:28]([N:26]([CH3:27])[C:24]1[C:23]([C:32]([F:33])([F:34])[F:35])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:41]5[CH2:45][CH2:44][CH2:43][CH2:42]5)=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1)[CH:29]([CH3:30])[CH3:31]
Reactant: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: C1CCNC1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 117) (300 mg, 0.62 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light orange foam (80 mg, 24%).
Reaction SMILES: C([OH:9])CCCCCCC.[O-2].[Ba+2:11].[C:12]([OH:31])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[C:32](=[O:34])=[O:33]>O>[C:12]([O-:31])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[Ba+2:11].[C:12]([O-:31])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[C:32](=[O:9])([O-:34])[O-:33]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCCCCCCCO
Reactant: O=C=O
Agent: [Ba+2]
Agent: [O-2]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Product: O=C([O-])[O-]
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a mixture of 50 g of octanol and 150 g of process oil (PUREXX12 : Esso Petroleum) was added 122 g of barium oxide gradually to disperse it, 24 g of water and 117 g of oleic acid were added, the mixture was stirred for 30 minutes, and carbon dioxide (20 L/hour) was blown thereinto at 130° C. for 3 hours to progress reaction. The mixture was gradually heated to 190° C. to continue reaction while water was distilled off, and then filtered to give a brown solution of an overbased barium oleate-carbonate complex (Ba=21%; metal ratio=3.4) (this product is designated S-2).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][C@H:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([NH2:30])=[O:29])[CH2:20]1>CS(C)=O>[NH:13]1[C:10]2=[CH:11][N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:17][CH2:18][C@H:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]([C:28]([NH2:30])=[O:29])[CH2:20]4)[CH2:5][CH2:6]3)[CH:8]=[C:9]2[CH:15]=[CH:14]1
Reactant: NC(=O)N1C[C@@H](CCBr)c2ccccc21
Reactant: c1cc2cc(N3CCNCC3)ncc2[nH]1
Solvent: CS(C)=O
Product: NC(=O)N1C[C@@H](CCN2CCN(c3cc4cc[nH]c4cn3)CC2)c2ccccc21

Procedure:
from 5-piperazin-1-yl-1H-pyrrolo[2,3-c]pyridine and (S)-3-(2-bromoethyl)-2,3-dihydro-1H-indole-1-carboxylic acid amide. Assignment of the optical rotation was done in dimethyl sulfoxide.
Reaction SMILES: [Mg:1].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[Br-:10]>CCOCC>[Br:10][Mg:1][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1
Reactant: [Mg]
Reactant: [Br-]
Reactant: Fc1ccc(Br)cc1
Solvent: CCOCC
Product: Fc1ccc([Mg]Br)cc1
Temperature: 25 °C

Procedure:
Magnesium metal turnings (44.35 mmol, 1.08 g) were flame dried, then stirred under argon in 40 ml of anhydrous ether. With vigorous stirring, 1-bromo-4-fluorobenzene (40.3 mmol) was added dropwise to the magnesium. The reaction was initiated in an ultrasound device and then the halide was added dropwise at a rate sufficient to maintain reflux. After addition of the bromide was complete, the reaction mixture was stirred at room temperature for 20 minutes, then heated to reflux and finally cooled to room temperature. This procedure yielded a golden orange transparent Grignard solution containing 40.32 mmol of title Grignard as a 0.91M solution in ether.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[C:15]([C:19]([OH:21])=[O:20])=[CH:16][S:17][CH:18]=1.CN(P(N(C)C)(N(C)C)=O)C.CN([CH:36]=[O:37])C>C1COCC1>[Br:13][C:14]1[C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH:36]=[O:37])[S:17][CH:18]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cscc1Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=Cc1scc(Br)c1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a solution of (i-Pr)2NH (1.09 g, 10.8 mmol) in anhydrous THF (15 mL) was added dropwise n-BuLi (5.0 mL, 12.5 mmol, 2.5M in hexane) at −30° C. The mixture was stirred at the same temperature for 0.5 h. Then, the mixture was cooled to −78° C. and the solution of 4-bromothiophene-3-carboxylic acid from example 1.1 (1.0 g, 4.85 mmol) and HMPA (0.17 g, 0.95 mmol) in anhydrous THF (20 mL) was added slowly. The mixture was stirred at the same temperature for 1 h, anhydrous DMF (0.6 g, 8.22 mmol) was added dropwise into the stirring mixture at −78° C. The reaction mixture was stirred for another 45 min at room temperature and then quenched with water. The aqueous layer was acidified with 5% aq. HCl to pH 1-2, the precipitate was collected by filtration, the filtrate was extracted with DCM (3×50 mL). The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was washed with CH2Cl2 to give the title product (0.68 g, 60.2%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][N:39]=1)[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][C:18]([NH:20][C:21]2[N:25]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[N:24]=[C:23]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:22]=2)=[O:19])=[CH:9][CH:8]=1)=[O:6].CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][CH2:52][O:53][CH2:54][C:55](Cl)=[O:56]>C1COCC1>[C:33]([C:23]1[CH:22]=[C:21]([NH:20][C:18](=[O:19])[NH:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([C:5]([C:4]3[CH:37]=[CH:38][N:39]=[C:2]([NH:1][C:55](=[O:56])[CH2:54][O:53][CH2:52][CH2:51][O:50][CH3:49])[CH:3]=3)=[O:6])=[CH:8][CH:9]=2)[N:25]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[N:24]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C(=O)c3ccnc(N)c3)c3ccccc23)cc1
Reactant: COCCOCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCC(=O)Nc1cc(C(=O)c2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 0 °C

Procedure:
To a solution of 1-(4-(2-aminoisonicotinoyl)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea (38.0 mg, 0.073 mmol) and DIPEA (64 μL, 0.37 mmol) in dry THF (4.0 mL) under N2 at 0° C. was added 2-(2-methoxyethoxy)acetyl chloride (45.0 mg, 0.29 mmol). The reaction mixture was maintained at 0° C. for 30 min and was then warmed to RT for 1.5 hr. The reaction was quenched by the addition of a solution of NH3 (1% in MeOH, 3.0 mL) and after a further 45 min at RT was evaporated in vacuo. The residue was purified by SCX capture and release followed by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-60%, gradient elution) to afford the title compound, Example 22, as a yellow solid (21 mg, 44%); Rt 2.67 min (Method 2); m/z 635 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.39 (3H, s), 3.29 (3H, s), 3.50 (2H, m), 3.66 (2H, m), 4.14 (2H, s), 6.45 (1H, s), 7.35-7.37 (3H, overlapping m), 7.46 (2H, d), 7.67-7.73 (3H, overlapping m), 8.20 (2H, m), 8.37 (1H, s), 8.49 (1H, m), 8.54 (1H, d), 9.03 (1H, s), 9.47 (1H, s), 10.24 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][CH:28]=[CH:29][C:30](=[O:32])[CH3:31]>>[C:30]([C:29]1[CH:15]([CH2:14][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:27]([CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[Cl:19])[CH:28]=1)(=[O:32])[CH3:31]
Reactant: COc1ccc2c(c1)CCN(C/C=C/C=O)C2=O
Reactant: CC(=O)C=CNCc1ccccc1Cl
Product: COc1ccc2c(c1)CCN(CC1C=CN(Cc3ccccc3Cl)C=C1C(C)=O)C2=O

Procedure:
The title compound 41 is prepared according to the procedure reported in step D of Example 8 with aldehyde 44 (113 mg, 0.46 mmol) and enamine 45 (94 mg, 1 equiv) as reactants. (Yield 82.4 mg, 41%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[C:24]([C:26]#[N:27])[C:23]4[N:28]=[CH:29][NH:30][C:22]=4[CH:21]=3)=[CH:16][C:15]=2[C:31]([F:34])([F:33])[F:32])[CH2:7][CH2:6]1.[CH:35](N(C(C)C)CC)(C)C>C1COCC1>[C:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[C:24]([C:26]#[N:27])[C:23]4[N:28]=[CH:29][N:30]([CH3:35])[C:22]=4[CH:21]=3)=[CH:16][C:15]=2[C:31]([F:32])([F:34])[F:33])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)Cl
Reactant: N#Cc1nc(-c2ccc(OCCC3CCNCC3)c(C(F)(F)F)c2)cc2[nH]cnc12
Solvent: C1CCOC1
Product: CC(=O)N1CCC(CCOc2ccc(-c3cc4c(ncn4C)c(C#N)n3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetyl chloride (0.012 ml) was added dropwise to a solution of 1-methyl-(6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (25 mg) and diisopropylethylamine (0.051 ml) in THF (2 ml). The reaction mixture was stirred at room temperature for 18 hours. The product was then purified by acidic prep HPLC to give 6-(4-(2-(1-acetylpiperidine-4-yl)-ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (7.2 mg).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH2:17](N(CC)CC)C.CO.C([O:29][CH2:30][CH3:31])(=O)C>>[C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@:3]([CH:17]=[CH:31][CH:30]=[O:29])([OH:4])[CH2:2]1
Reactant: CCOC(C)=O
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCN(CC)CC
Solvent: CO
Product: O=CC=C[C@]1(O)C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Yield: 34 %

Procedure:
The procedure used in Example IV is followed utilizing 2'-deoxyuridine (456 mg; 2 mmole) triethylamine (280 μl; 2 mmole) and propargyl aldehyde (200 μl; 4 mmole) to obtain, after preparative TLC (eluant 5% methanol in ethyl acetate), the desired title compound as a pale yellow oil (190 mg; 34% yield) pure by TLC analysis. 1HNMR (DMSO) 5.88 (d, J=8.2 Hz, 1H, N--CH=CH--CO) 6.15 (t,J=6.1 Hz, 1H, N--CH--(O)), 7.04 (q, J1 =8.2 Hz, J2 =14.8 Hz, 1H, --CH=CH--CHO) 8.05 (d,J=8.2 Hz, 1H, N--CH=CH--CO) 8.15 (d,J=14.8, 1H, CH=CH--CHO) 9.60 (d,J=7.8 Hz, 1H, CHO). Mass spectrum m/z (intensity, % base peak), ion: 282 (0.1)M+, 253 (0- 1) (M-CHO)+, 137 (40) 117 (78) 73 (100).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([CH3:12])OC=2OCC)[CH2:3][CH2:2]1.[C:13]([O:21][CH3:22])(=[O:20])/[CH:14]=[CH:15]\[C:16]([O:18][CH3:19])=[O:17].[CH3:23][OH:24]>>[CH3:19][O:18][C:16]([C:15]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:5][C:6]([CH3:12])=[C:23]([OH:24])[C:14]=1[C:13]([O:21][CH3:22])=[O:20])=[O:17]
Reactant: CCOc1oc(C)nc1C1CC1
Reactant: CO
Reactant: COC(=O)/C=C\C(=O)OC
Product: COC(=O)c1c(C2CC2)nc(C)c(O)c1C(=O)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
2-Cyclopropyl-5-ethoxy-4-methyl-oxazole (164) (33.8 g, 0202 mmol) in neat dimethyl maleate (115.8 g, 807 mmol) was refluxed for 4 hours. The reaction was cooled to 0° C., added anhydrous methyl alcohol (500 mL) and bubbled hydrogen chloride gas into the suspension for 15 minutes. The reaction flask was sealed with a rubber septum and kept in a fridge for overnight. The solid was filtered off and washed with methanol and diethyl ether. The filtrate was evaporated to give 2-cyclopropyl-5-hydroxy-6-methyl-pyridine-3,4-dicarboxylic acid dimethyl ester (165) (35.2 g, 66% yield) as a colorless solids.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=1.[NH3:30]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:30])=[O:21])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: N
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCNCC3)c2c1C
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCNCC3)c12
Temperature: 120 °C
Yield: 36 %

Procedure:
A suspension of methyl 4-(4-fluoro-2-(piperidin-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.1 g, 0.2 mmol) in 7N ammonia in MeOH (6 mL) was heated in a sealed tube at 120° C. for 18 hours. After cooling to ambient temperature the precipitated solid was collected by filtration, washed with cold MeOH and dried under vacuum to give beige solid (0.035 g, 36%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].NC1C(C(O)=[O:16])=NNC=1.C(Cl)CCl.C1C=[CH:24][C:25]2[N:30]([OH:31])[N:29]=[N:28][C:26]=2[CH:27]=1>CN(C=O)C.CC(O)=O>[N+:30]([C:25]1[C:26]([C:27]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)=[N:28][NH:29][CH:24]=1)([O-:31])=[O:16]
Reactant: On1nnc2ccccc21
Reactant: Nc1ccccc1N
Reactant: Nc1c[nH]nc1C(=O)O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.5 %

Procedure:
A mixture of o-phenylenediamine (1.51 g, 14.0 mmol), 4-amino-1H-pyrazole-3-carboxylic acid (2.00 g, 12.7 mmol), EDC (2.93 g, 15.3 mmol) and HOBt (2.08 g, 15.3 mmol) in DMF (70 ml) was stirred at ambient temperature for 24 h. The mixture was reduced in vacuo and the residue dissolved in AcOH (150 ml) and heated at reflux for 3 h. The solvent was removed in vacuo, water (100 ml) added and the resultant solid collected by filtration washing with water. The solid was dried through azeotrope with toluene (3×150 ml) yielding 2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazole as a yellow solid (1.44 g, 50%). A 100 mg portion was purified by preparative LC/MS and following evaporation of product containing fractions gave 70 mg of the title compound. (LC/MS: Rt 1.72, [M+H]+ 229.61).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19][OH:20])=[O:5])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>ClCCl.O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH2:8][C@H:7]1[CH2:19][O:20][C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 89.1 %

Procedure:
To a cold (ice bath) mixture of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxymethyl-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, 250 mg), 4-chlorophenol (136 mg) and triphenylphoshine (256 mg) in dichloromethane (4 mL) and tetrahydrofuran (1.5 mL) was slowly added a solution of di-tert-butyl-azodicarboxylate (225 mg) in tetrahydrofuran (2.5 mL). The reaction mixture was stirred at room temperature for 2.5 days then concentrated in vacuo and the residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethylacetate (1:0 to 9:1 v/v) as eluant to afford the title compound (0.304 g, 89%) as light yellow oil. MS (EI): 413.2 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:15][O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][C:43]=1[NH:44][C:45]([NH:47][CH:48]1[CH2:50][CH2:49]1)=[O:46])[O:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([OH:40])=[C:34]([C:37]([NH2:39])=[O:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1.[CH2:51]([NH:53][CH2:54][CH3:55])[CH3:52]>O.C(OCC)(=O)C.CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][C:43]=1[NH:44][C:45]([NH:47][CH:48]1[CH2:50][CH2:49]1)=[O:46])[O:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH2:15][C@H:13]([OH:14])[CH2:12][N:53]([CH2:54][CH3:55])[CH2:51][CH3:52])=[C:34]([C:37]([NH2:39])=[O:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCNCC
Reactant: NC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(N)=O
Temperature: 60 °C
Reaction time: 6 h
Yield: 36.3 %

Procedure:
After adding (2R)oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate (308 mg, 1.35 mmol), potassium carbonate (149 mg, 1.08 mmol) and dimethylformamide (9 ml) to 4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide (372.0 mg, 0.90 mmol), the mixture was stirred at 60° C. for 6 hours. Next, diethylamine (2 ml) was added and the mixture was further stirred overnight at 50° C. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was subjected to silica gel column chromatography (eluent-ethyl acetate:methanol=95:5), the fraction containing the target substance was concentrated, and crystals were precipitated from diethyl ether, filtered out and blow-dried to obtain the title compound (177.5 mg, 0.327 mmol, 36.3%) as white crystals.