Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[CH3:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[OH:26].[OH-].[Na+]>C(#N)C.O.[Cl-].[Na+].O>[CH2:11]([O:10][C:8]([N:3]1[CH2:4][CH2:5][C@@H:6]([O:26][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:19]=2[CH3:18])[C@H:1]([OH:7])[CH2:2]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(O)c1C
Reactant: O=C(OCc1ccccc1)N1CCC2OC2C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1cccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)c1C
Temperature: 25 °C
Yield: 51.4 %

Procedure:
Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (21.0 g, 92.0 mmol) was added to a stirred solution of 2,3-dimethylphenol (23.0 g, 188 mmol) and aqueous sodium hydroxide (100 ml, 2N, 200 mmol) in acetonitrile (400 ml). The reaction mixture was heated at reflux for 14 h. On cooling to room temperature, the reaction mixture was concentrated in vacuo before dilution with water (500 ml). Extraction with dichloromethane (4×100 ml) was followed by washing of the combined organics with aqueous sodium hydroxide (100 ml, 3N, 300 mmol), water (100 ml) and brine (100 ml). The organics were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to furnish a crude product. Purification was carried out by silica gel chromatography using a gradient eluent system of iso-hexanes and ethyl acetate (100% iso-hexanes to 80:20 iso-hexanes:ethyl acetate) to furnish trans-benzyl-4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate as a pale yellow syrup (16.8 g, 50%).
Reaction SMILES: [C:1]([Si:5]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[CH:21][CH:20]=1)([C:12]1[CH:17]=CC=C[CH:13]=1)[C:6]1[CH:11]=CC=C[CH:7]=1)(C)([CH3:3])[CH3:2].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[O:42][N:41]=[C:40]([CH2:43][S:44]([C:47]3[CH:55]=[CH:54][C:50]([CH2:51][CH2:52][NH2:53])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[N:39]=2)=[CH:34][CH:33]=1>>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[O:42][N:41]=[C:40]([CH2:43][S:44]([C:47]3[CH:48]=[CH:49][C:50]([CH2:51][CH2:52][NH:53][CH2:29][C@H:27]([OH:28])[CH2:26][O:25][C:22]4[CH:23]=[CH:24][C:19]([O:18][Si:5]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:11])[CH3:7])[CH:12]([CH3:13])[CH3:17])=[CH:20][CH:21]=4)=[CH:54][CH:55]=3)(=[O:45])=[O:46])[N:39]=2)=[CH:36][CH:37]=1
Reactant: COc1ccc(-c2nc(CS(=O)(=O)c3ccc(CCN)cc3)no2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1)(c1ccccc1)c1ccccc1
Product: COc1ccc(-c2nc(CS(=O)(=O)c3ccc(CCNC[C@H](O)COc4ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc4)cc3)no2)cc1
Yield: 72.9 %

Procedure:
This material was prepared as described in Example 11 from tert-butyl{4-[(2S)oxiranylmethoxy]phenoxy}diphenylsilane (0.45 g, 1.124 mmol) and 4-({[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}sulfonyl)phenethylamine (0.70 g, 1.875 mmol). This procedure afforded 0.570 g of the title compound as a white foam.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:16]1[C:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[NH:22][C:21](=[O:27])[CH:20]=[CH:19]2)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:42][CH2:43][NH:44][C:45](=[O:53])[O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:16]1[C:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[N:22]([CH2:42][CH2:43][NH:44][C:45](=[O:53])[O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:21](=[O:27])[CH:20]=[CH:19]2)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)CCOC(=O)NCCBr
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc(=O)n2CCNC(=O)OCC[Si](C)(C)C)c(-c2ccc(Cl)cc2)c1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-6-(1-tert-butoxy-2-(tert-butyldimethylsilyloxy)ethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(1H)-one (0.4061 g, 0.812 mmol) in DMF (8.0 mL) was added potassium tert-butoxide (0.137 g, 1.22 mmol) and the mixture stirred for 30 minutes. A solution of 2-(trimethylsilyl)ethyl 2-bromoethylcarbamate (0.327 g, 1.22 mmol) in DMF (1 mL) was added and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was cooled to 0° C., potassium tert-butoxide (0.200 g) was added and the resulting reaction mixture was stirred for 30 minutes. A solution of 2-(trimethylsilyl)ethyl 2-bromoethylcarbamate (0.5 g) in DMF (1 mL) was added and the reaction mixture was warmed to room temperature overnight. Reaction mixture was diluted with ethyl acetate and washed with 5% lithium chloride solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 10 to 50% ethyl acetate/hexanes) to give desired product a yellow foam (0.2725 g). Some O-alkylation side-product was also observed.
Reaction SMILES: Cl.[O:2]=[S:3]1(=[O:22])[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][NH:13]2.CCN(CC)CC.[C:30](OC(=O)C)(=[O:32])[CH3:31]>CCOC(C)=O>[C:30]([N:13]1[C:14]2[C:10](=[C:9]([N:4]3[CH2:5][CH2:6][CH2:7][CH2:8][S:3]3(=[O:2])=[O:22])[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=2)[CH2:11][CH2:12]1)(=[O:32])[CH3:31]
Reactant: COC(=O)c1cc2c(c(N3CCCCS3(=O)=O)c1)CCN2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(c(N3CCCCS3(=O)=O)c1)CCN2C(C)=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-2,3-dihydro-1H-indole-6-carboxylate hydrochloride salt (D234) (350 mg, 1.0 mmol, 1 equiv) in AcOEt (5 ml) were added NEt3 (140 ml, 1.0 mmol, 1 equiv) and acetic anhydride (0.5 ml, 5.6 mmol, 5.6 equiv) and the resulting mixture was stirred at 50° C. for 30 min then cooled to room temperature and washed with a 2N aqueous HCl solution followed by a saturated aqueous NaHCO3 solution, then dried over MgSO4 and concentrated in vacuo to give methyl 1-acetyl-4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-2,3-dihydro-1H-indole-6-carboxylate (D235) as a white solid which was used in the next step without further purification. [M+H]+=353.2, RT=2.24 min.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1ccn[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 26 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)nicotinamide (Stage 24.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford a yellow solid. UPLC-MS (Condition 3) tR=1.02 min, m/z=452.2 [M+H]+, m/z=450.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.09 Hz, 3H) 3.17-3.27 (m, 2H) 3.35-3.43 (m, 2H) 3.43-3.53 (m, 2H) 4.59 (br. s, 1H) 6.53 (d, J=1.96 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.76 (br. s, 1H) 7.82-7.95 (m, 2H) 8.13 (d, J=2.45 Hz, 1H) 8.72 (d, J=2.45 Hz, 1H) 10.29 (s, 1H) 12.98 (br. s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]3[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=3[CH2:21][CH2:22][CH3:23])=[O:12])[CH:10]=1)[N:7]([CH3:26])[CH:6]=[C:5]2[CH:27]([CH3:29])[CH3:28].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>>[CH3:26][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:40]3[CH:41]=[N:42][C:37]([N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)=[CH:38][CH:39]=3)=[CH:10][C:9]=2[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=2[CH2:21][CH2:22][CH3:23])=[O:12])[C:5]([CH:27]([CH3:29])[CH3:28])=[CH:6]1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c(C(C)C)cn(C)c12
Reactant: CN1CCN(c2ccc(B(O)O)cn2)CC1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C)CC3)nc2)cc2c(C(C)C)cn(C)c12
Yield: 59.2 %

Procedure:
The title compound was prepared in the same manner as described for Example 2 using 5-bromo-1-methyl-3-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indole-7-carboxamide (480 mg, 1.05 mmol) and [6-(4-methyl-1-piperazinyl)-3-pyridinyl]boronic acid (320 mg, 1.45 mmol). Obtained 345 mg of the title compound (59% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (s, 1H), 8.41-8.48 (m, J=2.53 Hz, 2H), 7.86 (dd, J=2.53, 8.84 Hz, 1H), 7.76 (d, J=1.77 Hz, 1H), 7.26 (d, J=1.52 Hz, 1H), 7.08 (s, 1H), 6.92 (d, J=8.84 Hz, 1H), 5.90 (s, 1H), 4.37 (d, J=4.80 Hz, 2H), 3.68 (s, 3H), 3.48-3.56 (m, 4H), 3.20 (quin, J=6.76 Hz, 1H), 2.52-2.58 (m, 2H), 2.44 (br. s., 4H), 2.25 (s, 3H), 2.13 (s, 3H), 1.57 (qt, J=7.36, 7.56 Hz, 2H), 1.30 (d, J=6.82 Hz, 6H), 0.93 (t, J=7.33 Hz, 3H). MS (ES) [M+H]+ 555.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[P:13]([O-:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[K+].CCOC(C)=O>C1COCC1>[C:21]([O:20][P:13]([O:25][CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1
Temperature: 70 °C
Yield: 45 %

Procedure:
To a stirred solution of methyl-3-(bromomethyl)benzoate (0.5 g, 2 mmol) in THF (10 mL) was added potassium ditertiary butyl phosphate (0.5 g, 2 mmol). The reaction flask was heated to 70° C. for 2 h. After the flask was cooled to rt, EtOAc (50 mL) was added to the mixture. The organics were washed with brine (2×10 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to yield methyl 3-((di-tert-butoxyphosphoryloxy)methyl)benzoate (0.35 g, 0.9 mmol). 1H NMR (400 MHz, CHCl3-d): δ 1.47 (s, 18H), 3.91 (s, 3H), 5.03 (d, 2H, J=7.6 Hz), 7.44 (t, J=7.6 1H), 7.60 (dd, J=1.2 and 7.2), 7.98 (ddd, J=1.2, 2.8 and 7.6, 1H), 8.05 (t, J=0.4, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:24]#[N:25])=[CH:11][C:12]2[N:13]([C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:16][N:17]=2)[CH:14]=1.B.C1COCC1>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH2:24][NH2:25])=[CH:11][C:12]2[N:13]([C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:16][N:17]=2)[CH:14]=1
Reactant: N#Cc1cc2nnc(N3CCOCC3)n2cc1-c1ccc(Cl)cc1Cl
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: NCc1cc2nnc(N3CCOCC3)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 5 %

Procedure:
In a sealed flask, a solution of the crude 6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile in THF (1 mL) was cooled to 0° C. (ice bath) then treated with BH3.THF complex (1.0 M solution in THF, 0.73 mL, 0.73 mmol). The reaction mixture was heated at 40° C. for 1 h, cooled to RT, and diluted in MeOH (large excess). The mixture was concentrated under vacuum, and the remaining residue was suspended in 2.0 M HCl, and shaken for 15 min. After evaporation to dryness, the remaining residue was purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 5 mg, 0.008 mmol, 5%) as a white solid. MS: 378 [M+1]+; HPLC: AtRet=1.15.
Reaction SMILES: N1C=CC=[CH:3][C:2]=1CN.N1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[CH2:24](Cl)Cl>>[CH:2]([N:16]([CH2:15][C:10]1[CH:24]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:3]
Reactant: ClCCl
Reactant: NCc1ccccn1
Reactant: c1ccc(CNCc2ccccn2)nc1
Product: C=CN(Cc1ccccc1)Cc1ccccn1

Procedure:
The procedure described in Example 1 above was carried out with 43.3 g (0.4 mole) of 2-picolylamine substituted for the bis-2-picolylamine. Concentration of the methylene chloride gave 82.5 g of the N-vinylbenzyl-N-2-picolylamine monomer.
Reaction SMILES: [NH2:1][CH:2]([CH:18]([CH3:20])[CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[NH:31][N:30]=[C:29]([C:32](O)=[O:33])[CH:28]=2)[CH:22]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH:2]([NH:1][C:32]([C:29]3[NH:30][N:31]=[C:27]([C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)[CH:28]=3)=[O:33])[CH:18]([CH3:20])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CC(C)C(N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc(-c2cccnc2)[nH]n1
Product: CC(C)C(Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cccnc2)n[nH]1
Yield: 12 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 4-(1-(2-amino-3-methylbutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.060 g; 0.21 mmol) and 5-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (0.039 g; 0.21 mmol). The crude product was purified by flash chromatography using cyanocolumn and EtOAc/heptane as eluent. Yield 12%. 1H-NMR (400 MHz; MeOD): δ 1.14 (m, 6H), 1.95 (m, 1H), 4.35 (m, 2H), 4.55 (m, 1H), 6.71 (s, 1H), 7.02 (m, 1H), 7.53 (m, 1H), 7.72 (m, 3H), 7.95 (s, 1H), 8.25 (m, 1H), 8.54 (m, 1H), 8.88 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH2:34][O:35][CH3:36])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[O:33][N:32]=[C:31]([CH2:34][O:35][CH3:36])[CH:30]=4)[CH:24]=3)[CH2:20][C:19](=[O:37])[NH:18][C:9]=2[CH:10]=1
Reactant: COCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-chloro-5-dimethylamino-2-{3-[3-(3-methoxymethyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example M20) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (157 mg).
Reaction SMILES: C([O:3][P:4]([CH2:13][C@@H:14]([OH:27])[CH2:15][NH:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH3:18])([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])C>Cl>[ClH:25].[Cl:26][C:21]1[CH:20]=[C:19]([CH:17]([NH:16][CH2:15][C@H:14]([OH:27])[CH2:13][P:4]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)(=[O:3])[OH:5])[CH3:18])[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CNC(C)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC(NC[C@H](O)CP(=O)(O)CC1CCCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 4.1 g of 3-{N-[1-(3,4-dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester in 30 ml of 5N hydrochloric acid is heated at reflux for 24 hours, during which time two phases are formed. The reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure; the residue is taken up in absolute ethanol and the residual water is distilled off azeotropically. The white solid that remains behind is crystallised from isopropanol, yielding 3-{N-[1-(3,4-dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid hydrochloride having a melting point of 174°-180°.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8](O)[CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:2]([CH:1]1[O:10][CH2:9][CH2:8][O:7]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCO
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCC1OCCO1
Temperature: 25 °C

Procedure:
30 g (0.29 mole) of hexanol, 31 g (0.5 mol) of ethylene glycol, 100 mg of p-toluenesulfonic acid (p-Ts) in 100 ml of benzene are placed in 250 ml round-bottomed flask equipped with a Dean-Stark trap, a condenser and a mechanical stirrer. The mixture is heated to reflux until no more water has separated from the benzene phase. The mixture is then cooled to room temperature, washed with 100 ml of 5% sodium bicarbonate, 100 ml of saturated NaCl solution, and finally water. The solution is dried over sodium sulfate. After removing the solvent, the oil is fractionated. A yield of 19.6 g of colorless oil (46%) is obtaind nD20 =1.4554.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH2:13])=[CH:6][CH:5]=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:35]Br)=[CH:30][C:29]=1[NH:45][CH:46]=[O:47])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(=O)C>O.CS(C)=O>[NH2:13][C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][CH2:35][C@@H:34]([C:31]2[CH:32]=[CH:33][C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:29]([NH:45][CH:46]=[O:47])[CH:30]=2)[O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Reactant: NCCc1ccc(NC[C@H](N)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(NC[C@H](N)c2ccccc2)cc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 100 °C
Reaction time: 1.42 h

Procedure:
Under nitrogen, (R)—N2-[4-(2-aminoethyl)phenyl]-1-phenylethane-1,2-diamine (Example 5) (22.4 g, 1.4 equiv), N-[2-benzyloxy-5-((R)-2-bromo-1-(tert-butyldimethylsilanyloxy)ethyl)phenyl]formamide (29.2 g, 1.0 equiv), potassium carbonate (34.7 g, 4.0 equiv) were combined with dimethyl sulfoxide (35 mL). The resulting slurry was stirred at 100° C. for 85 minutes. The mixture was cooled to room temperature and water (200 mL) and isopropyl acetate (200 mL) were added. The layers were separated and the organic layer was washed with water (200 mL) followed by aqueous saturated sodium chloride (150 mL) and dried over anhydrous magnesium sulfate (20 g). The solids were removed by filtration and the filtrate concentrated to yield crude title intermediate as an amber colored oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[S:11][C:12]#[N:13].[N:14]1([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH:20]([CH3:22])[CH3:21])[CH:18]=[CH:17][N:16]=[CH:15]1>CC(=O)C>[C:1]([NH:13][C:12]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([CH:19]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:20]([CH3:22])[CH3:21])=[CH:28][CH:27]=1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CSN
Reactant: CC(C)C(c1ccc(N)cc1)n1ccnc1
Solvent: CC(C)=O
Product: CC(C)C(c1ccc(NC(=S)NC(=O)c2ccccc2)cc1)n1ccnc1
Temperature: 80 °C
Yield: 72.1 %

Procedure:
Benzoyl chloride (0.067 mol) was added to a solution of aminothiocyanate (5.09 g) in 2 propanone (150 ml) and the mixture was stirred and refluxed for 20 minutes. A solution of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.0557 mol) in 2-propanone (150 ml) was added and the mixture was stirred and refluxed at 80° C. overnight. The mixture was cooled, filtered through celite and the filtrate was evaporated. The residue was taken up in CH2Cl2. The organic layer was dried, filtered off and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH98/2/0.1). The pure fractions were collected and the solvent evaporated, yielding 15.2 g (72%) of (±)-N-benzoyl-N′-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]thiourea (interm. 1).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[O:45]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[C:47](B2OC(C)(C)C(C)(C)O2)=[CH:46]1>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:45]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[C:47]([C:2]2[C:7]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])[CH2:10][C:6]=3[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=2)=[CH:46]1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: CC1(C)OB(c2coc3ccccc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4coc5ccccc45)c3C2=O)c(OC)c1
Temperature: 120 °C
Yield: 48.8 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (65 mg, 0.118 mmol), aqueous sodium carbonate (2 N, 0.237 mL, 0.474 mmol), 2-(benzofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (43 mg, 0.178 mmol) and bis(triphenylphosphine)palladium chloride (17 mg, 0.024 mmol) in DME (2 mL) was placed in a vial. The vial was purged with nitrogen, sealed, and the reaction mixture heated at 120° C. for 1 h. The mixture was filtered through a pad of Celite, which was rinsed with MeOH. The solvent was removed in vacuo and the residue diluted with MeOH, passed through a microfiltration frit, and purified via preparative HPLC. The fractions were collected and concentrated in vacuo to give the title compound as a tan oil (36.3 mg, 48%). [M+H] calc'd for C35H39FN4O6, 632. found, 632.
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.[C:21](#[N:23])[CH3:22]>>[O:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([CH2:22][C:21]#[N:23])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(Oc2ccccc2)c1
Reactant: CC#N
Agent: C[O-]
Agent: [Na+]
Product: N#CCC(=O)c1cccc(Oc2ccccc2)c1
Yield: 65 %

Procedure:
A solution of sodium methoxide (from 1.2 g sodium in 25 ml methanol) was added dropwise over 2 hours to a refluxing solution of methyl-3-phenoxybenzoate (11 g) in acetonitrile (100 ml) under a nitrogen atmosphere while distilling off methanol and excess acetonitrile. After complete removal of methanol the reaction mixture was poured onto ice-water (200 g) and acidified with 50% HCl. The solid was filtered off and dried to give the title compound (7.5 g, 65%) as a white solid of m.p. 95°-96° C.