Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:21])[CH:7]([O:18][CH2:19][CH3:20])[CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[CH3:4].Cl[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=2)[O:27][C:28]=1[CH3:29]>CN(C)C=O.O>[CH2:3]([O:5][C:6](=[O:21])[CH:7]([O:18][CH2:19][CH3:20])[CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=2)[O:27][C:28]=1[CH3:29])[CH3:4]
Reactant: COc1cc(OC)cc(-c2nc(CCl)c(C)o2)c1
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2cc(OC)cc(OC)c2)oc1C)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
0.048 g (1.10 mmol) Sodium hydride (55% in mineral oil) was added in one portion below 5° C. and under argon to a stirred solution of 0.261 g (1.00 mmol) rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester and 0.321 g (1.20 mmol) 4-chloromethyl-2-(3,5-dimethoxy-phenyl)-5-methyl-oxazole in 15.0 ml N,N-dimethylformamide. The reaction mixture was warmed up to room temperature and then stirred for 16 hours at ambient temperature. It was then diluted with cold water and extracted two times with ethyl acetate. The combined organic phases were dried over MgSO4, filtered and evaporated. The residue formed was purified by flash-chromatography (silica gel; eluent: gradient of hexane and ethyl acetate) to give 0.413 g (84%) rac-3-{1-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid ethyl ester as light yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([F:17])[F:16])[CH3:12]>[Cu].CS(C)=O>[CH2:11]([O:13][C:14](=[O:19])[C:15]([F:17])([F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 15 h

Procedure:
According to the Kumadaki method (supra) and the above-described scheme, 2-iodonitrobenzene (Compound 1c; 250.0 mg, 1.0 mmol), bromodifluoroacetic acid ethyl ester (203 mg, 1.0 mmol), copper powder (128 mg, 2.0 mmol) and DMSO (2.0 mL) were put into a two-neck reaction tube, and the mixture was stirred under argon atmosphere at 55° C. for 15 hours. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2,2-difluoro-2-(2-nitrophenyl)acetic acid ethyl ester (Compound 2c) was obtained with a yield of 13%.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=2)([OH:18])[CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[C:31]([O:11][CH2:10][CH2:9][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:23][CH:24]=1)[OH:18])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCOc1ccc(C(O)(c2ccccc2)C(CCO)c2ccccc2)cc1
Product: CC(=O)OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCCN(C)C)cc1
Temperature: 90 °C

Procedure:
The reaction is performed under dry conditions. 40.5 g of either (RR,SS)- or (RS,SR)-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]butane-1,4-diol and 150 ml of acetic acid anhydride are placed in a flask. The temperature is raised to 90° C., where it is kept until the primaryOH-group is completely acetylated. [4-acetoxy-1,2-diphenyl-1-[4-[2-(N ,N-dimethylamino)ethoxy]phenyl]butan-1-ol is obtained as intermediate: m.p. of the (RR,SS)-isomer pair is 97°-9° C⟧ While stirring the reaction mixture, 30 ml of acetyl chloride in 50 ml of aceticacid anhydride are added at 90° C. The stirring is continued at thistemperature for 2 h. The solvent is evaporated. Then 1M sodium carbonate solution is added in excess, after which the product is extracted in toluene. The solution is dried over sodium sulfate, and the solvent is evaporated. The yield of the pure isomer mixture (Z:E 2:1) is quantitative. The m.p. of the (Z)-isomer is 88° -90° C. prepared from the corresponding (Z)-alcohol by refluxing in acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:40])[CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([O:40][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:15][CH:16]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(F)cc3)CC2)c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OC(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(F)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 533.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15](C2C=CC=CC=2)(O)[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1(C)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([O:8][C:9]1[C:14]([CH:15]=[CH:16][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1-c1cccc(C(C)(O)c2ccccc2)c1OCc1ccccc1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1ccccc1-c1cccc(C=Cc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 18 (from above), toluene (75 mL) and a crystal of p-toluenesulfonic acid monohydrate was refluxed with H2O removal (Dean-Stark trap) for 2 hr. The mixture was cooled to room temperature and stirred overnight. The mixture was washed with saturated NaHCO3 solution (25 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure to give a brown oil. The crude product was absorbed onto silica gel using DCM and dry-loaded on a column of silica gel (60 g) packed in hexanes. The column was eluted with hexanes (300 mL), 0.4% MTBE/hexanes (500 mL), 0.8% MTBE/hexanes (500 mL) and 1% MTBE/hexanes (1000 mL). Product fractions were concentrated under reduced pressure to give 0.6 g of an inseparable mixture of 19 and 2-(benzyoxy)-2′-methoxybiphenyl as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>[Pd](Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10]([C:33]3[CH:32]=[N:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2cc3c(C)nc(N)nc3n([C@H]3CC[C@H](O)CC3)c2=O)cn1
Temperature: 100 °C

Procedure:
A flask containing 2-amino-6-bromo-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (105 mg, 0.297 mmol), potassium carbonate (123 mg, 0.892 mmol), and 2-methoxy-5-pyridine boronic acid (52 mg, 0.34 mmol) was evacuated and back-filled with nitrogen (2×). A solution of 5:1 dimethylformade:water (1.8 mL) was bubbled with argon for 15 min then added to the flask followed by bis(tripehnylphosphine) palladium (II) chloride (10 mg, 0.015 mmol). The flask was fitted with a cold finger, evacuated and back filled with nitrogen (2×) then heated to 100° C. for 4 hr. The mixture was cooled overnight, diluted with methanol and chloroform then filtered through a glass fiber filter to filter out palladium. The filtrate was concentrated and the residue was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0.5-6%) to afford the title compound (80, 71%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(CN)OCC
Reactant: O=Cc1ccccc1
Product: CCOC(CNCc1ccccc1)OCC
Yield: 42.5 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2, 2,2-diethoxyethanamine (72.7 ml, 500 mmol) was reacted with benzaldehyde (50.7 ml, 500 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=50:50 and 0:100) to obtain the title compound (47.5 g, 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:9]#[N:10].Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH3:29]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])([CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH3:29])[C:9]#[N:10]
Reactant: CC(C)N(CCC(C#N)c1ccccc1F)C(C)C
Reactant: CC1CCCCN1CCCl
Product: CC1CCCCN1CCC(C#N)(CCN(C(C)C)C(C)C)c1ccccc1F

Procedure:
Substitution of equivalent quantities of α-(o-fluorophenyl)-α-[2-(diisopropylamino)ethyl]acetonitrile and 1-(2-chloroethyl)-2-methylpiperidine in the procedure of Example 2, Method B and substantial repetition of the procedure detailed therein, affords α-(o-fluorophenyl)-α-[2-(diisopropylamino)ethyl]-α-[2-(2-methyl-1-piperidinyl)ethyl]acetonitrile, as an oil boiling at about 170°-175° C. at 0.5 mm. pressure.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH3:2].[NH4+:31].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[NH2:31][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NCCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl {3-[(2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}carbamate (1.39 g, 3.35 mmol) in 35 mL of CHCl3 was treated with 15 mL of concentrated NH4OH solution and p-toluenesulfonyl chloride (0.67 g, 3.51 mmol). After 15 min, the reaction mixture was diluted with water and CHCl3 and the phases were separated. The organic portion was washed with 10% Na2CO3 solution and water. The combined aqueous washes were back-extracted with CHCl3. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl {3-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}carbamate (1.30 g) as an orange foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5](Cl)=[N:6][CH:7]=1.[C:10](#[N:12])[CH3:11].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([CH2:11][C:10]#[N:12])=[N:6][CH:7]=1
Reactant: CC#N
Reactant: Clc1cc(Br)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCc1ncc(Br)cc1Cl
Yield: 84.9 %

Procedure:
27.0 g of 5-bromo-2,3-dichloropyridine was dissolved in 450 ml of anhydrous tetrahydrofuran and 7.33 g of acetonitrile was added at ambient temperature under argon. 262 ml of lithium hexamethyldisilazide (1N solution in tetrahydrofuran) was added dropwise over a period of 45 min, during which the temperature rose to 35° C. Subsequently, the reaction mixture was stirred at ambient temperature for 1h, then the reaction mixture was poured into 800 ml of cold water and was extracted with two 1 L portions of diethyl ether. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. 29.4 g of crude material was obtained as a brown oil. It was purified by chromatography on silica gel, using heptane/ethyl acetate (9:1) as a eluent. Thus, 23.4 g of (5-bromo-3-chloro-pyridin-2-yl)-acetonitrile was obtained as a orange oil. 1H-NMR (CDCl3): 8.60 ppm (s, 1H), 7.92 ppm (s, 1H), 4.00 ppm (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cn1cccc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)c2cccn2C)cc1
Reaction time: 0.75 h
Yield: 28.5 %

Procedure:
A solution of 5 g (0.06 mole) N-methylpyrrole and 13.3 g (0.078 mole) of 4-methoxybenzoyl chloride in 50 mL of dry toluene was heated under reflux overnight with an argon stream bubbling through the reaction mixture. After cooling, 40 mL of 20% 3-dimethylaminopropylamine in H2O was added and the mixture stirred for 45 minutes. Diethyl ether was added and the organic solution was washed with 1N HCl, NaHCO3, water, brine and dried (MgSO4). The solvent was evaporated in vacuo and the residue recrystallized from ethanol to give 3.68 g of product: mp. 66-68° C.; mass spectrum (CH4-Cl) m/z=216 (M+1); NMR (CDCl3) d 7.85 (d, 2H); 6.9-7.1 (d,s, 3H); 6.7 (d, 1H); 6.15 (d, 1H); 4.1 (s, 3H); 3.9 (s, 3H). Anal Calcd for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.59; H, 6.06; N. 6.43.
Reaction SMILES: N1C=CN=C1.[CH2:6]1[O:8][C@@H:7]1[CH2:9][OH:10].[CH3:11][C:12]([Si:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([Si:15]([O:10][CH2:9][C@@H:7]1[CH2:6][O:8]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:14])([CH3:11])[CH3:13]
Reactant: OC[C@@H]1CO1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H]1CO1)(c1ccccc1)c1ccccc1
Yield: 37 %

Procedure:
Imidazole (6.6 g, 97.2 mmol) and DMF (75 ml) were added to (R)-glycidol (2.7 ml, 40.5 mmol) (13a), and the resulting mixture was stirred. Then, TBDPSCl (12.6 ml, 48.6 mmol) was added and reacted at 0° C. overnight. Next day, after disappearance of the spots of the raw material was observed by thin-layer chromatography (TLC) (hereinafter referred to as TLC), the product was extracted with ethyl acetate and distilled water, to recover an organic layer. The organic layer was washed with saturated sodium hydrogen carbonate and a saturated salt solution, and dried with anhydrous sodium sulfate. The solvent was evaporated using a vacuum evaporator, and the residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=50:1). Thus, a compound (13b) (S)-tert-butyl(oxiran-2-ylmethoxy)diphenylsilane (4.5664 g, 15 mmol, 37%) was obtained as a colorless and transparent liquid.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:8]([CH:10]=1)[NH2:9].[CH3:22][S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>ClCCl>[CH3:22][S:23]([NH:9][C:8]1[CH:10]=[C:4]([CH:5]=[CH:6][C:7]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH:3]=[O:2])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COC(OC)c1ccc(OCCN2CCOCC2)c(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C=O)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.7 %

Procedure:
A solution of 5-dimethoxymethyl-2-(2-morpholinoethoxy)aniline obtained in Step 3 (0.27 g, 0.91 mmol) in dichloromethane (2.00 mL) was added with methanesulfonyl chloride (0.11 mL, 1.42 mmol) and pyridine (0.50 mL, 6.18 mmol), followed by stirring at room temperature for 10 hours. The reaction mixture was added with hydrochloric acid (3 mol/L, 3.00 mL), was stirred at room temperature for 20 minutes, was neutralized with a saturated aqueous sodium hydrogencarbonate solution (50 ml) and was extracted with ethyl acetate (50 mL×3). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. the crude product was purified by silica gel column chromatography (chloroform, then methanol/chloroform=1/6) to obtain 3-methanesulfonylamino-4-(2-morpholinoethoxy)benzaldehyde (0.28 g, 95%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH:21]3[CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:8]([O:10]C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([CH2:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH:21]3[CH2:23][CH2:22]3)(=[O:19])=[O:20])=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of methyl 3-cyclopentyl-2-[4-(cyclopropylsulfonyl)phenyl]propanoate (1.95 g) in a mixed solvent of tetrahydrofuran (40 mL) and methanol (20 mL) was added 2N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-diethyl ether to give the title compound (1.67 g, 89%) as colorless crystals. MS: 323 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:40][CH3:41])[C:23]([Cl:42])=[CH:22][N:21]=1>>[Cl:42][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:40][CH3:41])=[N:25][C:20]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: COc1cc2c(cc1N)CCN(CC(N)=O)CC2
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)CCN(CC(N)=O)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.010 g, 10%). MP: 219-221° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.16 (d, 1H, J=8.3 Hz), 8.13 (s, 1H), 8.01 (s, 1H), 7.47-7.43 (m, 2H), 7.26-7.20 (m, 1H), 6.63 (s, 1H), 6.58-6.55 (m, 1H), 6.53-6.49 (m, 1H), 5.55-5.49 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.32-3.27 (m, 1H), 3.22-3.17 (m, 4H), 3.11 (s, 2H), 2.96-2.90 (m, 1H), 2.89-2.85 (m, 2H), 2.81-2.87 (m, 2H), 2.74-2.67 (m, 4H), 2.64-2.58 (m, 4H), 2.38 (s, 3H). MS: 581.26 (MH)+.
Reaction SMILES: [C:1](Br)(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.[NH2:12][C@H:13]([C:18]([OH:20])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15].C(=O)=O.CC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:8]=[C:7]1[NH:9][C:2]([C:1]([NH:12][CH:13]([CH:14]([CH3:15])[CH2:16][CH3:17])[C:18]([OH:20])=[O:19])=[O:10])=[CH:3][C:4](=[O:5])[NH:6]1
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: O=C(Br)c1cc(=O)[nH]c(=O)[nH]1
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCC(C)C(NC(=O)c1cc(=O)[nH]c(=O)[nH]1)C(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the orotoyl bromide solution, 9.84 g (75 mmol) of Isoleucine is suspended, with stirring, in 100 mL of dry DCM. To this suspension a catalytic amount (˜0.1 mmol) of DMAP is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of about −15° C. When the target temperature is reached the drop wise addition of orotoyl bromide is commenced. Addition of orotoyl bromide continues, with constant cooling and stirring, until all of the orotoyl bromide is added, after which the reaction is allowed to warm to room temperature with constant agitation. The solution is then filtered to remove any remaining Isoleucine and the volatile DCM is removed from the filtrate under reduced pressure, the remainder is then purified by flash chromatography (ethyl acetate/hexanes; 1/5), yielding 2-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-3-methylpentanoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[C:31]2[O:30][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][C:27](=[O:37])[C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OC(=O)C)C>[C:32]([C:29]1[O:30][C:31]2[C:22]([CH2:21][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)=[CH:18][CH:19]=3)=[CH:23][CH:24]=[CH:25][C:26]=2[C:27](=[O:37])[CH:28]=1)([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)c1cc(=O)c2cccc(CBr)c2o1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(=O)c2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Yield: 28.2 %

Procedure:
1.8 g of 2-(4-hydroxyphenoxy)methylquinoline, 2.2 g of 8-bromomethyl-2-carboethoxy-4-oxo-4H-1-benzopyran and 1.0 g of potassium carbonate are combined in 100 ml of acetone and refluxed for 18 hours. The mixture is cooled, diluted with ethylacetate and filtered. The filtrate is concentrated and the crude product purified by flash chromatography on silica gel in 5% ethanol in chloroform/hexane (1:1) to give 0.96 g 2-carboethoxy-8-(4- (quinolin-2-yl-methoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran: m.p. 124°-27° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[N:5]([CH:15]([CH3:17])[CH3:16])[C:4]1=[O:18])[CH3:2]>CO.O1CCCC1.[Pd]>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH:15]([CH3:16])[CH3:17])[C:4](=[O:18])[C:3]2([CH2:19][CH3:20])[CH2:1][CH3:2]
Reactant: CCC1(CC)C(=O)N(C(C)C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCC1(CC)C(=O)N(C(C)C)c2ccc(N)cc21
Reaction time: 4 h
Yield: 86.3 %

Procedure:
To a solution of 3,3-diethyl-1-isopropyl-5-nitro-1,3-dihydro-indol-2-one (12.6 g, 45.60 mmol) in methanol/tetrahydrofuran (THF) (1:1, 80 ml) palladium on charcoal (10%, 1.2 g) was added and the mixture hydrogenated at room temperature for 4 h. After filtration of the catalyst the solvent was evaporated and the residue triturated with iso-hexane to yield 9.7 g 5-amino-3,3-diethyl-1-isopropyl-1,3-dihydro-indol-2-one (39.37 mmol, 86%).