Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]2[NH:9][C:8]3=[CH:10][S:11][CH:12]=[C:7]3[C:6](O)=[N:5]2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:6]1[C:7]2[C:8](=[CH:10][S:11][CH:12]=2)[NH:9][CH:4]([CH:1]2[CH2:3][CH2:2]2)[N:5]=1
Reactant: OC1=NC(C2CC2)Nc2cscc21
Reactant: O=P(Cl)(Cl)Cl
Product: ClC1=NC(C2CC2)Nc2cscc21

Procedure:
2-Cyclopropyl-4-hydroxydihydrothieno[3,4-d]pyrimidine (2.4 g, 0.0123M) was refluxed in phosphorus oxychloride (40 ml) for 11/2 hours. The mixture was cooled, concentrated under vacuum, the residue dissolved in chloroform, poured over ice, and basified with ammonia. The layers were separated and the organic solution dried (MgSO4) and concentrated. The residue, chromatographed on silica eluting with ethyl acetate/hexane, (1/6) gave 2.2 g of product, m.p. 86.5°-88.5° C. the structure of which was confirmed by NMR.
Reaction SMILES: [C@H:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].C([N+]1(C)[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)C>C(O)C.O>[C@H:1]1([N:11]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCN([C@@H]2CCCc3ccccc32)CC1

Procedure:
(R)-1,2,3,4-Tetrahydro-1-naphthylamine (16 mmol) was dissolved in ethanol (30 ml). Potassium carbonate (9.3 mmol) and 1-ethyl-1-methyl-4-oxo-piperidinium iodide (23 mmol) dissolved in water (30 ml) were added and the mixture was refluxed for 1 h. Water was added, ethanol was removed in vacuo and the residue was extracted with ethyl acetate. Organic phases were pooled, dried with sodium sulfate and concentrated. Chromatography on silica gel (ethyl acetate) yielded (R)-1-(1,2,3,4-tetrahydro-naphtalen-1-yl)-piperidine-4-one which was dissolved in acetic acid (11 ml). Aniline (14 mmol) and trimethylsilylcyanide (13 mmol) were added and the mixture was stirred for 1.5 h at room temperature. The reaction mixture was poured into cold ammonia solution (water/28% ammonia, 70 ml/30 ml). The solution was adjusted to pH 10 and extracted with methylene chloride. Organic phases were pooled, dried with sodium sulfate and concentrated. Crystallization from diethylether yielded the desired product as a solid. 8.1 g (80%) of (R)4-phenylamino-1-(1,2,3,4-tetrahydro-naphtalen-1-yl)-piperidine-4-carbonitrile, m.p. 152-153° C. and MIS: m/e=332.3 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:5]=[C:4]2[N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:23]=[CH:24][C:3]=12.[CH3:31][NH:32][CH3:33]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([N:32]([CH3:33])[CH3:31])=[C:3]3[CH:24]=[N:23][N:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:4]3=[N:5][C:6]=2[C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2nc3c(cnn3-c3ccccc3)c(Cl)c2-c2ccc(Cl)cc2)cc1
Reactant: CNC
Product: CN(C)c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)nc2c1cnn2-c1ccccc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
4-Chloro-5,6-bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine from step A (15 mg, 0.033 mmol) is treated with dimethylamine (2 M in THF, 1 mL, 2 mmol) in a sealed tube at 100° C. for 14 h. After cooling down to room temperature, the mixture is concentrated and the residue is purified by flash column chromatography (silica gel, 0%˜15% EtOAc/hex) to provide the titled compound [5,6-Bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-dimethyl-amine (11 mg, 73%). 1H NMR (CDCl3) δ(ppm) 8.35 (s, 1H), 8.32 (d, 2H), 7.47(t, 2H), 7.27(t, 1H), 7.23(d, 2H), 7.16(d, 2H), 7.11(d, 2H), 7.03(d, 2H), 2.91(s, 6H); HPLC-MS calculated for C26H20Cl2N4 (M+H+): 459.1. Found: 459.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](Br)[N:16]=2)[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=1)=[O:8])[CH3:5].I[C:28]1[N:32]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:31]2=[N:30][CH:29]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:28]3[N:32]4[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:31]4=[N:30][CH:29]=3)[N:16]=2)[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=1)=[O:8])[CH3:5]
Reactant: N#Cc1ccn2c(I)cnc2c1
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cnc4cc(C#N)ccn34)nc12
Temperature: 95 °C

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (100 mg, 0.196 mmol) and hexamethyltin (72 mg, 0.22 mmol) were combined in a nitrogen sparged toluene (5 ml) solution. Tetrakis(triphenylphosphine)palladium(0) (19.5 mg, 0.17 mmol) was added and the solution heated to 95° C. for 2 h. The reaction was cooled and 3-iodo-imidazo[1,2-a]pyridine-7-carbonitrile (54 mg, 0.2 mmol) was added with additional tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol). The mixture was heated at 100° C. for 14 h, cooled and directly purified by silica gel chromatography to afford 2-(7-cyano-imidazo[1,2-a]pyridin-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=c1[nH]c2nccc(Oc3cccc(NS(=O)(=O)c4cccc5ccccc45)c3)c2[nH]1
Yield: 57 %

Procedure:
Method K was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and naphthalene-1-sulfonyl chloride to afford the title compound as a brown solid (32 mg, 57%). 1H-NMR (δ, ppm, DMSO-d6): 6.09 (d, 1H, HPy,5, J=6.0 Hz), 6.68 (m, 2H, Harom), 6.87 (d, 1H, Harom, J=8.5 Hz), 7.20 (ps t, 1H, Harom, J=8.0 Hz), 7.60 (ps t, 1H, Harom, J=7.5 Hz), 7.65-7.73 (m, 3H, Harom+Py,6), 8.08 (d, 1H, Harom, J=8.0 Hz), 8.12 (d, 1H, Harom, J=7.5 Hz), 8.23 (d, 1H, Harom, J=8.5 Hz), 8.67 (d, 1H, Harom, J=8.5 Hz), 10.83 (s, 1H, NHSO2), 11.08 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 106.48, 108.98, 113.81, 114.02, 114.77, 124.06, 124.40, 127.03, 127.33, 128.21, 129.13, 129.97, 130.73, 133.74, 133.92, 134.60, 139.14, 141.21, 143.88, 147.15, 154.13, 155.01. HRMS (EI): m/z [M+H] calcd for C22H17N4O4S: 433.0971; found: 433.0969.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.C[O:17][C:18]1O[C:21]([C:23]([O:25][CH3:26])=[O:24])=[N:20][CH:19]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10]3[C:21]([C:23]([O:25][CH3:26])=[O:24])=[N:20][CH:19]=[C:18]([OH:17])[C:9]=3[C:8]2=[O:13])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ncc(OC)o1
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 120 °C
Reaction time: 24 h

Procedure:
In a sealed tube, 1-(4-fluorobenzyl)-5,6-dihydropyridin-2-(1H)-one (3.84 g, 18.7 mmol), and methyl 5-methoxy-1,3-oxazole-2-carboxylate prepared in Step 5 (2.94 g, 18.7 mmol), were combined. The reaction mixture was heated at 120° C. After 24 hours, the resultant mixture was cooled and methanol saturated with HCl (2 mL) was added. The product mixture stirred at room temperature for 40 minutes, then was concentrated under vacuum. The residual crude material was diluted with DMSO (6.0 mL) and filtered to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[H-].[Na+].I[CH3:15]>CN(C=O)C>[CH3:15][NH:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CI
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(C)ccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
To a solution of 5-methyl-2-nitro-phenylamine (3.04 g, 20.0 mmol) in anhydrous DMF (20 mL) at 0° C. was portionwise added 95% NaH (528 mg, 22.0 mmol) and the resulting mixture stirred for 10 min. A solution of iodomethane (1.25 mL, 20.0 mmol) in anhydrous DMF (10 mL) was then added. The ice bath was removed and the resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water, the solid was collected by filtration, washed with H2O and hexanes to yield methyl-(5-methyl-2-nitro-phenyl)-amine MS 167 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[C:16](=[O:18])=[O:17]>O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]([OH:18])=[O:17])=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-3-methyl-benzonitrile (10.008 g, 51.05 mmol) (commercially available) in tetrahydrofuran (“THF”) (350 ml) was added n-butyl lithium (1.6M in THF) (35 ml, 56.16 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 hour. Then carbon dioxide (24.933 g, 566.66 mmol) was added. The reaction mixture was allowed to warm to ambient temperature. The reaction mixture was quenched by addition of water (300 ml), and extracted with diethyl ether (3×300 ml). The phases were separated. The aqueous phase was acidified by addition of aqueous hydrochloric acid (concentrated) and extracted with chloroform (3×200 ml). The combined organic phases were concentrated and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N:6][C:7]=1[Cl:8].Br[CH:11]([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH:11]([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: Oc1cnc(Cl)c(Cl)c1
Reactant: CCC(Br)C(=O)OC
Product: CCC(Oc1cnc(Cl)c(Cl)c1)C(=O)OC

Procedure:
5,6-Dichloropyridin-3-ol was reacted with methyl 2-bromobutyrate using a similar procedure to that described in Example 1, Stage 1 to give methyl 2-(5,6-dichloro-3-pyridyloxy)butyrate, orange liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC([O-])(C)C.[K+].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-amino-3-nitrophenol (0.8 g, 5.34 mmol, 1.2 eq) in DMSO (3.8 mL, 5×) was treated with KOt-Bu (0.6 g, 5.34 mmol, 1.2 eq), and the mixture was stirred at RT for 2 h. The contents were treated with 4-chloro-6,7-dimethoxyquinazoline (1.0 g, 4.45 mmol, 1.0 eq) and K2CO3 (0.33 g, 2.4 mmol, 0.53 eq) then heated at 110° C. for 16 h. The mixture was cooled to RT, diluted with EtOAc and washed with NaHCO3 (sat). To remove the emulsion, the mixture was filtered through Celite, then the organic layer was washed with brine, 1N NaOH, then brine again. The organic portion was dried with Na2SO4, filtered and evaporated to give the title compound as a brown solid. MS(MH+)=343.1; Calc'd 342.31 for C16H14N4O5.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[CH2:17][CH2:16][C:15]([F:19])([F:18])[CH2:14][CH2:13]2)(=O)=O)=CC=1.O.[Br-:22].[Li+].O>CC(C)=O>[Br:22][CH2:11][CH:12]1[CH2:17][CH2:16][C:15]([F:19])([F:18])[CH2:14][CH2:13]1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(F)(F)CC2)cc1
Agent: [Li+]
Solvent: CC(C)=O
Solvent: O
Product: FC1(F)CCC(CBr)CC1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
In 15 ml of acetone, 1.5 g of 4,4-difluorocyclohexylmethyl p-toluenesulfonate was dissolved. Thereto 1.6 g of lithium bromide monohydrate was added and the mixture was heated under reflux for 8 hours. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.76 g of 4-bromomethyl-1,1-difluorocyclohexane.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:12][CH2:13]Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C.CCOC(C)=O>[N:22]([CH2:13][CH2:12][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:23]=[N-:24]
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)(CCCl)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC(O)(CCN=[N+]=[N-])c1ccccc1

Procedure:
A solution of 1-{[tert-butyl(dimethyl)silyl]oxy}-5-chloro-3-phenylpentan-3-ol ((5.2 g, 15.7 mmol) and NaN3 (7.8 g, 120 mmol) in 50 mL DMF was stirred for 24 h at 65° C. The reaction mixture was then diluted with EtOAc, washed with water, dried, filtered and evaporated in vacuo to provide 1-azido-5-{[tert-butyl(dimethyl)silyl]oxy) 3-phenylpentan-3-ol in quantitative yield as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.40-7.32 (m, 4H), 7.24 (m, 1H), 4.89 (s, 1H), 3.72 (dt, 1H, J=10.3, 3.9 Hz), 3.47-3.36 (m, 2H), 2.97 (ddd, 1H, J=12.3, 10.1, 5.5 Hz), 2.24-2.10 (m, 2H), 2.07-1.93 (m, 2H), 0.86 (s, 9H), −0.02, (s, 3H), −0.09 (s, 3H); ESI-MS 358 (M+Na).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNS(=O)(=O)c3ccc(C(C)(C)C)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-tert-butylbenzenesulfonyl chloride: ESMS m/e: 500.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[H-].[Na+].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH2:10][C:14]([O:15][CH2:16][CH3:17])=[O:18]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2′,5′-dichloroacetophenone (10.0 g), sodium hydride (60%, oil, 2.12 g) and diethyl carbonate (80 ml) was stirred at 80° C. for 20 min. Water was added to the reaction mixture, and the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(2,5-dichlorophenyl)-3-oxopropionate was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). A mixture of this oil and N,N-dimethylformamide dimethylacetal (9.46 g) was refluxed for 1 hr. The reaction mixture was concentrated, and the residue was dissolved in ethanol (80 ml). To the obtained solution was added hydroxylamine hydrochloride (7.35 g), and the mixture was refluxed for 2 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 5-(2,5-dichlorophenyl)isoxazole-4-carboxylate (6.40 g, yield 42%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio). NMR (CDCl3) δ: 1.23 (3H, t, J=7 Hz), 4.25 (2H, q, J=7 Hz), 7.4–7.6 (3H, m), 8.68 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41](O)=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:44]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH2:47][CH2:46][CH2:45]1>CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([NH:51][S:48]([C:44]3([CH3:45])[CH2:46][CH2:47]3)(=[O:50])=[O:49])=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Reactant: NS(=O)(=O)C1CCC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Yield: 53.6 %

Procedure:
Prepared from 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid etherate (114 mg, 0.192 mmol) and cyclobutanesulfonic acid amide (34 mg, 0.25 mmol) as described in the general procedure above. Flash chromatography (2% methanol/methylene chloride) gave 73 mg (58%) of [18-(isoquinolin-1-yloxy)-4-(1-methyl-cyclopropanesulfonylaminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: LC-MS (Method A, retention time: 3.55 min), MS m/z 710 (M++1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:25][C:26]([F:31])([CH2:29][NH2:30])[CH2:27][NH2:28]>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[NH:28][CH2:27][C:26]([F:31])([F:25])[CH2:29][NH2:30]
Reactant: O=S1CCN(c2cc(Cl)c3cc(Cl)ccc3n2)Cc2ccccc21
Reactant: NCC(F)(F)CN
Product: NCC(F)(F)CNc1cc(N2CCS(=O)c3ccccc3C2)nc2ccc(Cl)cc12

Procedure:
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and 2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.21 (s, 1 H), 7.86-7.81 (m, 2 H), 7.77-7.74 (m, 2 H), 7.58 (m, 2 H), 6.32 (s, 1 H), 5.45 (d, 1 H), 5.05 (d, 1 H), 4.75 (m, 1 H), 4.48 (m, 1 H), 4.20 (m, 2 H), 3.68 (t, 2 H), 3.50 (m, 2 H).
Reaction SMILES: O1CCOCC1.[OH-].[Li+].[CH:9]1([C:14]([N:16]2[CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH2:19][CH:18]([C:33]([O:35]CC)=[O:34])[CH2:17]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1>O>[CH:9]1([C:14]([N:16]2[CH2:21][CH:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)[CH2:19][CH:18]([C:33]([OH:35])=[O:34])[CH2:17]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
37 ml of dioxane, 18.5 ml of water and 0.51 g (21.4 mmol) of lithium hydroxide were added to 2.30 g (5.34 mmol) of ethyl 1-(cyclopentylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylate. The mixture was stirred overnight at RT. For work-up, the dioxane was removed under reduced pressure, water was added to the reaction mixture and the mixture was acidified using aqueous 1 N hydrochloric acid solution. The mixture was extracted with dichloromethane. The organic phase was dried with sodium sulphate and concentrated under reduced pressure. Yield: 2.17 g (99% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[CH3:22][C:23]1([CH3:35])[CH2:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][CH2:33]Cl)[C:25]=2[O:24]1>O>[CH3:22][C:23]1([CH3:35])[CH2:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][CH2:33][O:1][C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[CH:4][CH:3]=3)[C:25]=2[O:24]1
Reactant: CC1(C)Cc2cccc(CCCl)c2O1
Reactant: CON(C)C(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)Nc1ccc(OCCc2cccc3c2OC(C)(C)C3)cc1
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
2.6 g of 1-(4-hydroxyphenyl)-3-methoxy-3-methylurea was dissolved into 20 ml of dried N,N-dimethylformamide, and 0.6 g of 60% sodium hydride was added thereto. After the mixture was stirred for 30 minutes, 1.7 g of 2-(2,3-dihydro-2,2-dimethyl-7-benzofuranyl)ethyl chloride was added dropwise thereto under cooling with ice. After the mixture was stirred at room temperature for 5 hours, it was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/1) as a developer to obtain 2.0 g of Compound No. 10 shown in Table 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[O:11])=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCc1ccc(OCc2ccccc2)cc1)OCc1ccccc1
Yield: 89.3 %

Procedure:
3-(4-Hydroxyphenyl)propionic acid (5 g), potassium carbonate (16 g) and tetrahydrofuran (50 ml) were placed in a three-necked flask, 8.5 ml of benzyl bromide was added dropwise through a syringe under stirring, and the mixture was heated under reflux overnight. After filtering off the solid matters, the solvent was distilled off, and the residue was purified by column chromatography on silica gel (50 g), affording 9.25 g (89.3%) of pure benzyl 3-(4-benzyloxyphenyl)propionate.