Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[S:8][C:7]=1N)=[O:5])[CH3:2].N(OC(C)(C)C)=O.[Cl-].[NH4+]>[Cu](Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[S:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C2CCOCC2)sc1N
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCOCC2)c1
Reaction time: 0.25 h
Yield: 60.6 %

Procedure:
2-Amino-5-(tetrahydro-pyran-4-yl)-thiophene-3-carboxylic acid ethyl ester (1.79 g, 7 mmol) was added to a suspension of tert-butyl nitrite (10.5 mmol) and copper (II) chloride (7 mmol) in IMS (70 mL). The reaction was stirred for 15 minutes then saturated aqueous ammonium chloride (7 mL) was added and the mixture stirred for a further 15 minutes. The solvent was removed under vacuum and the residue partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulphate, filtered and the solvent evaporated to give the title compound (1.02 g). LCMS m/z 241 [M+H]+ RT=3.44 min (Analytical Method 4).
Reaction SMILES: [I:1]I.[C:3]([O:7][C:8](=[O:20])[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[O:18][CH3:19])([CH3:6])([CH3:5])[CH3:4]>C(Cl)Cl>[C:3]([O:7][C:8](=[O:20])[NH:9][CH2:10][C:11]1[CH:16]=[C:15]([I:1])[C:14]([NH2:17])=[CH:13][C:12]=1[O:18][CH3:19])([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1cc(N)ccc1CNC(=O)OC(C)(C)C
Reactant: II
Solvent: ClCCl
Product: COc1cc(N)c(I)cc1CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a suspension of iodine and AgNO2 in methylene chloride was added a solution of (4-amino-2-methoxy-benzyl)-carbamic acid tert-butyl ester (1.3 g, 5.15 mmol) in methylene chloride at 0° C., and the mixture was stirred for 30 min at 0° C. and more stirred for 30 min at ambient temperature. The reaction was quenched with Na2S2O3. The reaction solution was extracted with methylenechloride, washed with water and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (hexane/ethylacetate=2/1) to yield (4-amino-5-iodo-2-methoxy-benzyl)-carbamic acid tert-butyl ester (925 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([N+:13]([O-])=O)[CH:7]=1.[Cl-].[NH4+].O.[OH-].[Na+]>CO.[Fe]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1
Reactant: COC(=O)COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)COc1ccc(Cl)c(N)c1
Temperature: 60 °C
Yield: 53.2 %

Procedure:
A solution of (4-chloro-3-nitrophenoxy)acetic acid methyl ester (30 g) in methanol (100 mL) was added to a mixture of iron (26 g), ammonium chloride (33 g) and water (400 mL) at room temperature, and the resulting mixture was heated in an ultrasonic bath at 60° C. for 4 hours. The mixture was basified by the addition of sodium hydroxide, extracted with ethyl acetate, and the combined extracts were washed with 1.0 M aqueous hydrochloric acid solution. The pH of the combined aqueous phases was adjusted to 7-8 by the addition of sodium hydroxide, and the resulting precipitate was collected by filtration and then dried to afford title compound (14 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.[NH:20]1[C:28]2[C:23](=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.C(=O)([O-])O.[Na+].C(O)(C)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.O>[NH:20]1[C:28]2[C:23](=[C:24]([C:2]3[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]4[C:9]([CH:10]=3)=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:6]=4)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Temperature: 150 °C
Yield: 310.2 %

Procedure:
Five reactions were set up with 6-bromo-4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (500 mg, 1.53 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (125 mg, 0.153 mmol), 1H-indol-4-ylboronic acid (370 mg, 2.3 mmol), saturated aqueous sodium hydrogen carbonate (3 ml) and isopropyl alcohol (12 ml) in each. They were all heated at 150° C. for 10 minutes in the microwave. The reaction mixtures were combined and water (250 ml) and ethyl acetate (250 ml) added. The mixture was filtered and the organic layer collected. The organic layer was washed with water followed by brine. The organic layer was dried over magnesium sulphate, filtered and solvent removed in vacuo. The residue was dissolved in dichloromethane and pre-absorbed onto silica. Purification was carried out using chromatography on silica eluting with 0-25% ethyl acetate in cyclohexane. The desired fractions were collected and combined and solvent removed in vacuo to give the title compound as a yellow solid (1.72 g).
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([CH:9]=[CH:10][CH:11]=[CH:12][C:13]([O:15]CC)=[O:14])=[CH:7][N:8]=1)[CH2:2][CH3:3].[H][H]>>[CH2:1]([C:4]1[S:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][N:8]=1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCCc1ncc(C=CC=CC(=O)OCC)s1
Product: CCCc1ncc(CCCCC(=O)O)s1

Procedure:
Using the procedure of Example 10, ethyl 5-(2-propyl-5-thiazolyl)2,4-pentadienoate was reacted with hydrogen in the presence of activated carbon containing 10% palladium and the resulting product was saponified to obtain 2-propyl-5-thiazole-pentanoic acid. The latter product was reacted with α,β-ethanedisulfonic acid to obtain the hemi-α,β-ethane disulfonate of 2-propyl-5-thiazole-pentanoic acid melting at 124°C.
Reaction SMILES: C1COCC1.C([O:14][CH2:15][C:16]1([CH3:26])[O:25][CH2:24][C:19]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:18][O:17]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[CH3:26][C:16]1([CH2:15][OH:14])[O:17][CH2:18][C:19]2([O:20][CH2:21][CH2:22][O:23]2)[CH2:24][O:25]1
Reactant: CC1(COC(=O)c2ccccc2)OCC2(CO1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(CO)OCC2(CO1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a THF (10 ml) and methanol (5 ml) solution of the (8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)methyl benzoate (1.92 g, 6.52 mmol) obtained in the step (5b), a 1N aqueous sodium hydroxide solution (10 ml, 10 mmol) was added and stirred at room temperature for one hour. The reaction mixture was extracted with dichloromethane (50 ml) four times, dried over anhydrous sodium sulfate, and then, concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/1-0/1 gradient) and desired fractions were concentrated to obtain the title compound (1.12 g, 90.0% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3(O)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)=[O:23])=[CH:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:17]1[CH2:16][CH:15]=[C:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:21][C:22]([C:24]3[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=3)=[O:23])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:31])([CH3:1])[CH2:3][CH:4]=3)[CH:13]=2)[CH2:19][CH2:18]1
Reactant: CC1(C)CC=C(c2cc(C3(O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CC=C(c2cc(C3=CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Temperature: 60 °C
Yield: 50 %

Procedure:
To a suspension of 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (16.0 mg, 38.1 μmol, as prepared in the previous step) in 0.3 mL of toluene was added p-toluenesulfonic acid (14.0 mg, 74.0 mmol) and the mixture heated to 60° C. for 2 h. The solvent was evaporated and the title compound purified by RP-HPLC, eluting with a linear gradient of 40% CH3CN in 0.1% TFA/H2O to 100% CH3CN over 20 min to give 8.0 mg (50%) of a white solid: 1H-NMR (400 MHz, CD3OD) δ 8.23 (d, J=8.6 Hz, 1H), 8.02 (s, 1H), 7.38 (dd, J=8.6, 2.2 Hz, 1H), 7.26 (d, J=2.2 Hz, 1H), 6.20 (m, 1H), 5.78 (m, 1H), 4.32 (m, 2H), 3.94 (t, J=5.5, 5.5 Hz, 2H), 2.53 (m, 2H), 2.34 (m, 2H), 2.10 (m, 2H), 1.62 (t, J=6.3, 6.3 Hz, 2H), 1.12 (s, 6H). Mass spectrum (ESI, m/z) calcd. for C24H26N4O2 403.2 (M+H), found 403.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[C:5]([C:10]([O:12]C)=O)=[CH:4][CH:3]=1.Cl.[O:15]1[CH2:18][CH:17]([NH2:19])[CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:19]([CH:17]3[CH2:18][O:15][CH2:16]3)[C:10](=[O:12])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1CCl
Reactant: NC1COC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(Cl)nc2CN1C1COC1

Procedure:
Methyl 6-chloro-2-(chloromethyl)pyridine-3-carboxylate (Example 1, Step 4) (0.15 g, 0.68 mmol), oxetan-3-amine hydrochloride (0.15 g, 1.36 mmol) and potassium carbonate (0.38 g, 2.7 mmol) were stirred in DMF (10 mL) at room temperature overnight. Water and ethyl acetate were added and the biphasic mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (6-50% EtOAc/hexanes) gave the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:25][NH:26][CH3:27].O>CS(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([N:26]([CH3:27])[CH3:25])=[N:3][CH:4]=[CH:5]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Nc1ccc2c(Cl)nccc2c1)c1ccc(Cl)cc1
Reactant: CNC
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: CN(C)c1nccc2cc(NS(=O)(=O)c3ccc(Cl)cc3)ccc12
Temperature: 80 °C
Reaction time: 10 h

Procedure:
In dimethyl sulfoxide (1 ml) was dissolved 60 mg of 1-chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (Example 61). To the mixture was added 50% dimethylamine methanol solution (0.04 ml), followed by heating under stirring at 80° C. for 10 hours. After standing to cool, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by preparative TLC and solidified from isopropyl ether, to give the title compound (17 mg).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:29])=O>>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([Cl:29])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
This ester was dissolved in 50 ml of a 10% by weight solution of sodium hydroxide in a methanol/water mixed solvent (1/1 volume ratio). The solution was refluxed for 6 hours and, subsequently, the reaction mixture was dropped in an ice-cooled aqueous hydrochloric acid solution to form a white powdery precipitate. The precipitate was recovered by filtration, washed with water and then dried to obtain 2.0 g of 4-n-decyloxybiphenyl-4'-carboxylic acid. 2.0 g of the 4-n-decyloxybiphenyl-4'-carboxylic acid was incorporated with 10 ml of thionyl chloride, and the mixture was refluxed for 2 hours. Unreacted thionyl chloride was removed under a reduced pressure to obtain 2.2 g of 4-n-decyloxybiphenyl-4'-carboxylic acid chloride.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: O=C(c1cc([N+](=O)[O-])ccc1F)N1CCN(c2ccccc2)CC1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccccc2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 1 from (2-Fluoro-5-nitro-phenyl)-(4-phenyl-piperazin-1-yl)-methanone and morpholine (87%, yellow solid, MS (m/e): 397.3 (M+H, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Li]CCCC.CN([CH:30]=[O:31])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[C:12]([CH:30]=[O:31])=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: COc1cccc(-c2cncn2COCC[Si](C)(C)C)c1
Agent: [Li]CCCC
Product: COc1cccc(-c2cnc(C=O)n2COCC[Si](C)(C)C)c1
Yield: 21.5 %

Procedure:
Reaction of 5-(3-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (470 mg, 1.55 mmol), 2.5 M n-BuLi (800 uL, 2.00 mmol), and DMF (479 uL, 6.18 mmol) for 2 h at −40° C. followed by column chromatography on silica gel (EtOAc/hexane 9:1) gave the title compound (111 mg, 22%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.95 (t, 2H, J=9.0 Hz), 3.61 (t, 2H, J=9.0 Hz), 3.89 (s, 3H), 5.8s (s, 2H), 6.90 (d, 2H, J=9.0 Hz), 7.34-7.42 (m, 3H), 9.89 (s, 1H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29](C(OC(C)(C)C)=O)[CH3:30])[CH:24]=2)[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[CH:1]([N:14]1[CH2:15][C:16](=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][CH3:30])[CH:24]=2)[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(C(=C2CN(C(c3ccccc3)c3ccccc3)C2)S(C)(=O)=O)c1
Solvent: C1COCCO1
Product: CNc1cccc(C(=C2CN(C(c3ccccc3)c3ccccc3)C2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.1 %

Procedure:
A mixture of 0.3 g of 1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methyl-sulfonyl)methylene}azetidine, 4 cm3 of a 4.7 N solution of hydrochloric dioxane and 4 cm3 of dioxane is stirred for 18 hours at room temperature. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 100 cm3 of water and 20 cm3 of diethyl ether. The aqueous phase is alkalinized with 30 cm3 of an aqueous sodium bicarbonate solution. The organic phase is extracted with twice 40 cm3 of ethyl acetate, washed with twice 30 cm3 of water, decanted off, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 20 cm3 of diethyl ether. 0.16 g of 1-benzhydryl-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a solid melting at 161° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (250 MHz): 2.65 (3H, d, J=5 Hz, NCH3), 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 5.80 (1H, q, J=5 Hz, NH), 6.60 (3H, m, 3CH arom.), 7.15 (1H, t, J=7 Hz, CH arom.), 7.22 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz, 4CH arom.), 7.48 (4H, d, J=7 Hz, 4 CH arom.)].
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O.Cl.CCOCC>[C:18]([C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:4]=1[CH:3]=[O:2])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1C(=O)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=Cc1cc(OCc2ccccc2)ccc1C(=O)c1ccccc1

Procedure:
A solution of crude ketone from Step 1 in acetone (250 mL) and HCl 10% (25 mL) was stirred for 6 hours, diluted with Et2O, washed with a saturated NH4Cl solution, H20 (3×), brine and dried (MgSO4). After evaporation of the solvent, the residue was saturated with hexane and filtered to afford the title compound as pale yellow solid.
Reaction SMILES: [P].[Ca:2].C(=O)([O-])[O-].[Ca+2].C([O-])(=O)[CH2:9][C:10](CC([O-])=O)([C:12]([O-:14])=[O:13])[OH:11].[Ca+2].C([O-])(=O)[CH2:23][C:24](CC([O-])=O)([C:26]([O-:28])=[O:27])[OH:25].[Ca+2].[Ca+2]>>[Ca:2].[C:12]([O-:14])(=[O:13])[CH:10]([CH3:9])[OH:11].[Ca+2:2].[C:26]([O-:28])(=[O:27])[CH:24]([CH3:23])[OH:25]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Ca]
Product: CC(O)C(=O)[O-]

Procedure:
Eggshell powder is used in the food industry, including animal and human nutritional supplements. Eggshells provide approximately 36-37 percent elemental calcium in addition to traces of phosphorous and other trace elements. Thus, for example, 500 mg of dried powdered eggshell provides approximately 180 mg elemental calcium. This compared vary favorably to other calcium salts. For example, calcium carbonate provides 40 percent elemental calcium, calcium citrate provides 21 percent elemental calcium, calcium lactate provides 13 percent elemental calcium, calcium gluconate provides 9 percent elemental calcium, dicalcium phosphate provides 23 percent elemental calcium (and 19 percent phosphorus), and bone meal provides 20 percent elemental calcium (and 17 percent phosphorus). A single large eggshell has a mass of approximately 6 g and provides approximately 2200 mg of calcium.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>[Pd].CO>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3
Reaction time: 24 h

Procedure:
10% Palladium on carbon (84 mg, 0.08 mmol) was added to a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[[4-(methylsulfonyl)-1-piperazinyl]carbonyl]- (84 mg, 0.14 mmol) in MeOH (6 mL) and the reaction mixture was vacuum flushed with nitrogen (3×) and then with hydrogen (3×). The reaction mixture was stirred under a balloon of hydrogen for 1 d. Additional 10% palladium on carbon (100 mg, 0.9 mmol) was added and the reaction mixture was vacuum flushed with nitrogen (3×), with hydrogen (3×) and then stirred under a balloon of hydrogen for 3 d. The reaction mixture was filtered through a pad of celite and concentrated. The residue was purified by preparative HPLC (MeOH/H2O with an NH4OAc buffer) to yield 5H-indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6,7-dihydro-6-[[4-(methylsulfonyl)-1-piperazinyl]carbonyl]- (39 mg, 0.06 mmol, 44%) as a yellow solid. Mixture of atrope diastereomers: 1HNMR (500 MHz, CD3OD) δ 8.10 (s. 0.3H), 8.02 (s. 0.7H), 7.92 (d, J=8.6 Hz, 0.3H), 7.90 (d, J=8.6 Hz, 0.7H), 7.63 (d, J=8.5 Hz, 0.3H), 7.58 (d, J=8.5 Hz, 0.7H), 7.53-7.31 (m, 4H), 4.64-4.47 (m, 1H), 4.15-3.64 (m, 5H), 3.55-3.27 (m, 5H), 3.04-2.96 (m, 9H), 2.94-2.76 (m, 3H), 2.19-1.23 (m, 10H). LCMS: m/e 654 (M−H)−, ret time 1.73 min, column A, 3 minute gradient.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].[I:11]I>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([I:11])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]n1
Reactant: II
Solvent: CC#N
Product: CCOC(=O)c1n[nH]cc1I
Temperature: 0 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
A suspension of Intermediate 74a (5.00 g, 35.7 mmol) in acetonitrile (90 mL) was treated with iodine (9.10 g, 35.7 mmol) then ceric ammonium nitrate (19.6 g, 35.7 mmol) and the mixture was stirred at RT overnight. Another portion of iodine (2.28 g, 9.0 mmol) was added and the mixture was stirred for a further 24 h then treated with ice-cold aqueous sodium hydrogensulphite solution (5%, 100 mL). The mixture was filtered through Celite rinsing with EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting solid was triturated with ether/cyclohexane, filtered off, washed with cyclohexane and dried at 50° C. in vacuo to give the title compound (3.70 g, 39%). LCMS (Method 3): Rt 2.88 min, m/z 267 [MH+](weak).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=2)[O:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:22][N:23]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24]1.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[CH3:22][N:23]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24]1.[CH2:1]1[O:9][C:8]2[C:3](=[C:4]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:5]=[CH:6][CH:7]=2)[O:2]1
Reactant: Cc1cc(C)n(CCl)n1
Agent: Cl
Agent: NS(=O)(=O)c1cccc2c1OCO2
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)n(C)n1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of Hoc methylenedioxybenzenesulfonamide free phenol (0.010 g, 0.020 mmol) in DMF (1 mL) was combined with anhydrous cesium carbonate (0.015 g, 0.047 mmol). Freshly prepared 1-chloromethyl-3,5-dimethylpyrazole hydrochloride (0.006 g, 0.033 mmol) in DMF (0.5 ml) was added dropwise. The solution was heated to 60° C. with stirring for 15 minutes, and was cooled and dried in vacuo to give a green oil. Flash column chromatography (1:1 ethyl acetate/hexane) gave Doc methylenedioxybenzenesulfonamide 1-methyl-3,5-dimethylpyrazole tethered product (0.002 g, 17%) as a colourless oil: Rf=0.25 (1:1 ethyl acetate/hexane); coupled LCMS showed the product as a single major peak with m/z 645 [M+H]+ at RT of 1.68 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: C1COCCN1
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCN1CCOCC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 6) and morpholine following the procedure outlined in Example 15 (modifications: 25° C., 16 h; then 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 8.40 (s, 1H), 8.39 (s, 2H), 7.88 (d, 1H), 7.01 (d, 1H), 4.51 (s, 1H), 3.96 (t, 2H), 3.89 (s, 3H), 3.53 (m, 4H), 2.29 (br, 4H), 2.22 (t, 2H), 2.13 (s, 6H), 1.74 (m, 2H), 1.39 (m, 4H), 1.31 (m, 2H); MS (ESI): 481.4.
Reaction SMILES: [CH:1]([OH:3])=O.[CH3:4][N:5]([CH2:7][CH2:8][CH2:9][NH2:10])[CH3:6].C1(C)C=CC=CC=1>O>[CH3:4][N:5]([CH3:6])[CH2:7][CH2:8][CH2:9][NH:10][CH:1]=[O:3]
Reactant: CN(C)CCCN
Reactant: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCCNC=O
Yield: 59 %

Procedure:
Formic acid (23 g., 0.5 mole), dimethylaminopropylamine (51 g., 0.5 mole) and toluene (50 ml) were azeotroped together with continual removal of water using a Dean and Stark separator until no more water was formed. Toluene was distilled off and the pale yellow residue distilled in vacuo. The colourless liquid product of low smell (N-(3-dimethylaminopropyl)formamide) was obtained in a yield of 59% of theory, b.p. 140° C/15 mm Hg.