Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
4-Bromophenol (1.00 g) was dissolved in N,N-dimethylformamide (20 ml) to prepare a solution. Imidazole (0.95 g) and tert-butylchlorodimethylsilane (1.05 g) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give (4-bromo-phenoxy)-tert-butyl-dimethyl-silane (1.586 g, yield 96%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1.[CH:11]1([N:17]=[C:18]=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[N:6][C:7]([NH:10][C:18]([NH:17][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:19])=[N:8][CH:9]=1
Reactant: O=C=NC1CCCCC1
Reactant: Nc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(Br)cn1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
NaH (230 mg) was suspended in DMF (10 ml), and a solution of 5-bromopyrimidine-2-amine in DMF (5 ml) and a solution of cyclohexyl isocyanate (791 mg) in DMF (5 ml) were added dropwise thereto in this order under ice-cooling, followed by stirring at the same temperature for 30 minutes. The obtained solid was collected by filtration and washed with diethyl ether to obtain 1-(5-bromopyrimidin-2-yl)-3-cyclohexylurea (1.47 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](Cl)=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][CH:7]=2)=[O:31])=[CH:26][CH:25]=1
Reactant: COC(=O)CCCC=C(c1cccnc1)c1cccc(N)c1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCC=C(c1cccnc1)c1cccc(NC(=O)COc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.25 g of methyl 6-(3-aminophenyl)-6-(3-pyridyl)-hex-5-enoate are dissolved in 30 ml of methylene chloride. At 0° C., 1.65 g of 4-chlorophenoxyacetic acid chloride and 2.5 ml of triethylamine are added successively to this solution which is then stirred for 2 hours at ambient temperature. The reaction mixture is washed with water and then evaporated down. The residue is dissolved in a mixture of 20 ml of ethanol and 16 ml of 0.5N sodium hydroxide solution and stirred for 24 hours at ambient temperature. The reaction mixture is evaporated down at ambient temperature, water is added and the resulting mixture is washed with ethyl acetate. The aqueous phase is neutralised by the addition of citric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated down and the residue is recrystallised from ethyl acetate/diisopropyl ether.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].[ClH:18].CCOCC>S1(CCCC1)(=O)=O>[ClH:18].[CH3:14][C:13]([NH:17][CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[I:1])([CH3:16])[CH3:15]
Reactant: Ic1ccccc1OCC1CO1
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)NCC(O)COc1ccccc1I
Yield: 53 %

Procedure:
A solution of 30.0 g (0.108 mole) of [(2-iodophenoxy)methyl]oxirane and 110 ml (1 mole) of t-butylamine in 62 ml of sulfolane was heated in an autoclave for two hours. The excess t-butylamine was evaporated in vacuo. The residue was dissolved in ether and the ether solution washed with water and brine. The solution was dried (K2CO3), and the solvent was evaporated in vacuo. A hydrochloride salt was prepared by adding ethereal hydrogen chloride to an ether solution of the residue. There was obtained 25 g (53% yield) of crystalline 1-[(1,1-dimethylethyl)amino]-3-(2-iodophenoxy)-2-propanol hydrochloride, mp 184° to 185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6](CC)[CH2:7]C)=[O:5].NC1C(C(NC)=O)=C([F:35])C(Br)=CC=1>>[NH2:1][C:2]1[C:3]([C:4]([NH:6][CH3:7])=[O:5])=[C:11]([F:35])[C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Reactant: CNC(=O)c1c(N)ccc(Br)c1F
Product: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1F
Yield: 34 %

Procedure:
Prepared analogously to Compound 3C replacing Compound 3D with 6-amino-3-bromo-2-fluoro-N-methylbenzamide (Compound 27D, 700 mg, 2.83 mmol) to afford 281 mg of the title compound (34%). 1H NMR (400 MHz, CD3OD) δ=7.88 (d, J=1.8 Hz, 1H), 7.76 (d, J=1.0 Hz, 1H), 7.38 (t, J=8.6 Hz, 1H), 6.59 (d, J=8.6 Hz, 1H), 4.26 (t, J=7.0 Hz, 2H), 3.54 (t, J=6.2 Hz, 2H), 2.92 (s, 3H), 1.98-2.13 (m, 2H). MS (ESI): m/z=293.87 [M+H]+. UPLC: tR=0.60 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH2:1]([S:5]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>O1CCOCC1>[CH2:1]([S:5]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(S(=O)(=O)CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)CS(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 105.8 %

Procedure:
A mixture of methyl 4-isobutylsulfonylbenzoate (1.0 g, 3.9 mmol), NaOH solution (10 mL of 1 M, 10.00 mmol), and dioxane (10 mL) was heated at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature, then concentrated in vacuo. The solid residue was dissolved in water and washed with ethyl acetate (1×10 mL). The aqueous layer was acidified with 1N HCl solution and was extracted with ethyl acetate (2×10 mL) and layers were separated. The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography using (0-100%) ethyl acetate/hexanes as eluent to give 4-isobutylsulfonylbenzoic acid (1.0 g, 98%). ESI-MS m/z calc. 242.1. found 243.2 (M+1)+; Retention time: 1.73 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J=8.3 Hz, 2H), 8.05 (d, J=8.3 Hz, 2H), 3.03 (d, J=6.5 Hz, 2H), 2.27 (dt, J=13.3, 6.6 Hz, 1H), 1.08 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:20])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[CH3:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:20])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22][CH3:21])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(I)cc1
Reactant: CSc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(-c2ccccc2SC)cc1
Reaction time: 3 h

Procedure:
Combine 5-amino-4-cyano-3-(4-iodo-phenyl)-thiophene-2-carboxylic acid ethyl ester (0.829 mmol) in dioxane and add 2-(methylthio)phenylboronic acid, tetrakis(triphenylphosphine)palladium (0), and 1.4 ml of 2M sodium carbonate solution and heat to reflux. After 3 hours, purification by radial chromatography (6000 micron Si plate) eluting with 10-20% ethylacetate/methylene chloride provides the title compound: 1H NMR (400 MHz, CDCl3) δ 7.49-7.19 (m, 8H), 5.26 (s, 2H), 4.17 (q, 2H, J=7.2 Hz), 2.38 (s, 3H), 1.18 (t, 3H, J=7.0 Hz), MS found (M+1) 395.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:36])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=3)=[N:10][C:9]=2[N:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH2:30]3)[CH:26]=1)=O)C.[CH3:37][NH2:38]>CO>[CH3:37][NH:38][C:4]([C:6]1[C:7](=[O:36])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:23])[CH3:24])[CH:16]=3)=[N:10][C:9]=2[N:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH2:30]3)[CH:26]=1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(CN(C)C)c3)ncc2c1=O
Solvent: CO
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(CN(C)C)c3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 15.3 %

Procedure:
2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (15 mg, 0.032 mmol) was dissolved in MeOH (1 mL) and methylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 2.3 mg of 2-(3-dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 9.51 (s, 1H), 9.35 (s, 1H), 8.75 (s, 1H), 7.01-7.50 (m, 7H), 3.90 (br s, 2H), 2.90-3.02 (m, 7H), 2.60 (s, 6H), 2.11-2.19 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H28N6O2: 468.23, Found: 469.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.CO[C:12]1[C:21](=[O:22])[C:16]2[N:17]=[C:18]([CH3:20])[S:19][C:15]=2[C:14](=[O:23])[CH:13]=1>C(O)C>[CH3:20][C:18]1[S:19][C:15]2[C:14](=[O:23])[CH:13]=[C:12]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)[C:21](=[O:22])[C:16]=2[N:17]=1
Reactant: COC1=CC(=O)c2sc(C)nc2C1=O
Reactant: NCCN1CCOCC1
Solvent: CCO
Product: Cc1nc2c(s1)C(=O)C=C(NCCN1CCOCC1)C2=O

Procedure:
51.2 μl (0.39 mmol; 3 equivalents) of 4-(2-aminoethyl)morpholine is added to 27 mg (0.129 mmol) of 5-methoxy-2-methyl-4,7-dioxobenzothiazole in solution in 2 ml of anhydrous ethanol. The reaction mixture is stirred under reflux for 18 hours then the solvent is evaporated off under reduced pressure. The residue is purified on a silica column (eluent: 5% methanol in dichloromethane). The expected compound is obtained in the form of a red powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3Cl)c2)CC1
Yield: 97.8 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 2-chlorobenzoyl chloride (87 μl, 0.687 mmol), 79.9 mg (98%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH3:15])[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.[N+](=[CH2:28])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:16]([O:18][CH3:28])=[O:17])[CH3:15])[CH2:9][N:8]=[C:7]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:6]=2[CH:25]=1
Reactant: C=[N+]=[N-]
Reactant: CC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O
Product: COC(=O)C(C)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
To this solution of 7-chloro-2-[(1-carboxyethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine under nitrogen, is added with stirring, 50 ml. (0.015 mole) of an ethereal 0.3 molar solution of diazomethane. After 10 minutes the solution is evaporated giving 7-chloro-2-[[1-(methoxycarbonyl)ethylidene]-hydrazino]-5-phenyl-3H-1,4-benzodiazepine is obtained.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])C)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.S(=O)(O)[O-:17].[Na+].Cl>O>[CH2:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:17])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=S([O-])O
Reactant: CC(=O)c1ccc2c(c1)CCC2
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCC2
Temperature: 55 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred 6% aqueous sodium hypochlorite solution in an oil bath to 55° C. is added 1-indane-5-yl-ethanone (1.0 g, 6.2 mmol). The solution is stirred at 55° C. for 2 h, followed by cooling to rt. Solid sodium bisulfite is added until the solution becomes clear. The mixture is diluted with water, followed by aqueous hydrochloric acid (6.0 M). The solid that forms is filtered and washed several times with water. The solid is dried under high vacuum at 60° C. for 5 h to afford 5-indancarboxylic acid as a white solid (0.96 g, 95%): 1H NMR (CDCl3) δ 8.0, 7.9, 7.3, 3.0, 2.1.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[I-:32].[Cs+].COCCOC.N(OCCC(C)C)=O>CO.[Cu]I>[I:32][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reactant: [I-]
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: [Cs+]
Solvent: COCCOC
Solvent: CO
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4I)ncn3)cccc2s1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To N-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 151), (0.25 g, 0.56 mmol) was added CsI (0.15 g, 0.56 mmol, Aldrich), 12 (0.071 g, 0.28 mmol, Aldrich), CuI (0.032 g, 0.17 mmol, Aldrich) and ethylene glycol dimethyl ether (6 mL). To the mixture was added isoamyl nitrite (0.45 mL, 3.4 mmol, Aldrich) and the reaction was stirred for 1 h at room temperature, at 65° C. for 3 h, and then at room temperature for 18 h. The reaction mixture was diluted with MeOH (2 M in NH3) and concentrated. The residue was taken up in MeOH and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 0.4 to 1.3% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a white solid. Mp: 242-243° C. MS (ESI, pos. ion) m/z: 557.0 (M+1).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:71])[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][C@H:19]([CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:51]([C:52]#[N:53])=[C:50]([S:54][CH2:55][C:56]3[N:57]=[C:58]([C:61]4[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=4)[O:59][CH:60]=3)[N:49]=[C:48]([NH2:68])[C:47]=2[C:69]#[N:70])=[CH:42][CH:41]=1)[O:20][C:21](=[O:37])[CH2:22][CH2:23][NH:24][C:25](=[O:36])[C@H:26]([CH3:35])[NH:27]C(=O)OC(C)(C)C)=[O:16])=[O:11])=O)(C)(C)C.[ClH:72]>ClCCl>[ClH:67].[ClH:72].[NH2:8][C@@H:9]([CH3:71])[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][C@@H:19]([O:20][C:21](=[O:37])[CH2:22][CH2:23][NH:24][C:25](=[O:36])[C@@H:26]([NH2:27])[CH3:35])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:51]([C:52]#[N:53])=[C:50]([S:54][CH2:55][C:56]3[N:57]=[C:58]([C:61]4[CH:62]=[CH:63][C:64]([Cl:67])=[CH:65][CH:66]=4)[O:59][CH:60]=3)[N:49]=[C:48]([NH2:68])[C:47]=2[C:69]#[N:70])=[CH:42][CH:41]=1)=[O:16])=[O:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCC(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)CCNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@H](N)C(=O)NCCC(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)CCNC(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An amount of 200 mg (0.196 mmol) of the compound from example 46A was introduced in 60 ml of dichloromethane, and hydrogen chloride gas was passed into this solution. After one hour of stirring at RT, the solution was concentrated under reduced pressure to a volume of approximately 30 ml and was admixed with 50 ml of ethyl acetate. The precipitated solid was isolated by suction filtration, washed with ethyl acetate and dried under a high vacuum at 100° C. for 5 hours. This gave 151 mg (86% of theory) of the target compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.FC(F)(F)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.O>CN(C)C=O>[F:23][C:22]([F:25])([F:24])[CH2:21][O:3][CH:4]1[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(OCC(F)(F)F)C1
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
Sodium hydride (60 wt % dispersion in liquid paraffin, 151 mg, 3.46 mmol) in N,N-dimethylformamide (5 mL) was mixed with tert-butyl 3-hydroxyazetidine-1-carboxylate (500 mg, 2.89 mmol) in N,N-dimethylformamide (3 mL) under cooling with ice and stirred for 30 minutes, and the resulting reaction mixture was mixed with 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.499 mL, 3.46 mmol) under cooling with ice and then stirred at room temperature for 5 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→1/1(v/v)) to give the title compound as a colorless solid (350 mg, yield 48%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:58][CH3:59])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([O:52][Si](C)(C)C)[CH2:51][CH2:50][S:49][CH2:48][CH2:47]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:60])[CH:28]=1.O>O1CCCC1>[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([OH:52])[CH2:47][CH2:48][S:49][CH2:50][CH2:51]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:58][CH3:59])=[CH:31][C:30]=2[CH3:60])[CH:28]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)(c1ccc(C#CC2(O)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.2 mL, 0.2 mmol) was added to a solution of [5-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-thiopyran-4-ylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 137-(1); 82 mg, 0.13 mmol) in tetrahydrofuran (1 mL) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:3) to give the target compound as a colorless oil (50 mg, 69%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[P:29]([O-:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>CN(C)C=O.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>[CH3:28][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1
Reactant: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Reactant: CCOP([O-])OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1ccc2c(c1)/C(=C/Nc1ccc(N3CCN(C)CC3)cc1)C(=O)NC2=O
Temperature: 120 °C

Procedure:
To a solution of (4Z)-6-bromo-4-({[4-(4-methylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (67 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) is added diethyl phosphite (22 μL) and tetrakis(triphenylphosphine)palladium(0) (9 mg, 8 μmol, 0.05 mol %). The mixture is heated in a 120° C. oil bath for 6 hour and then purified by reverse phase high performance liquid chromatography to give diethyl [(4Z)-4-({[4-(4-methylpiperazin-1-yl)phenyl]amino}methylene)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl]phosphonate as its ditrifluoroacetate salt (8.8 mg, 3.1%).
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.[Cl:25][C:26]1[N:30]=[C:29](Cl)[S:28][N:27]=1.C(N(CC)CC)C>ClCCl>[Cl:25][C:26]1[N:30]=[C:29]([N:22]2[CH2:23][CH2:24][CH:19]([N:5]([CH:2]3[CH2:4][CH2:3]3)[C:6](=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([C:13]4[O:17][CH:16]=[N:15][CH:14]=4)=[CH:11][CH:12]=3)[CH2:20][CH2:21]2)[S:28][N:27]=1
Reactant: Clc1nsc(Cl)n1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(Cl)ns2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrogen chloride salt (696 mg), 3,5-dichloro-1,2,4-thiadiazole (372 mg), and triethylamine (0.42 mL) in dichloromethane (30 mL) is stirred overnight at room temperature. More triethylamine (0.40 mL) is added and the mixture is stirred until the conversion is complete (1 h). The solvent is partly evaporated and the residue is triturated with water. The precipitate is filtered off, washed with dichloromethane and dried to yield the title compound. LC (method 5): tR=2.08 min; Mass spectrum (ESI+): m/z=430/432 (Cl) [m+H]+.