Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH:35]1[CH2:40][CH:41]([CH3:43])[CH3:42])(OC(C)(C)C)=O>CN(C=O)C.CCOC(C)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:40]([C@@H:35]1[NH:34][CH2:39][CH2:38][N:37]([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][N:9]=3)[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=2)[CH2:36]1)[CH:41]([CH3:43])[CH3:42]
Reactant: FC(F)(F)c1ccc(Cl)nc1-c1n[nH]c2ncccc12
Reactant: CC(C)CC1CNCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H]1CN(c2ccc(C(F)(F)F)c(-c3n[nH]c4ncccc34)n2)CCN1
Temperature: 90 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A mixture of 3-(6-chloro-3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine (50 mg, 0.1674 mmol), K2CO3 (46.27 mg, 0.3348 mmol) and N—BOC isobutyl piperazine (81.14 mg, 0.3348 mmol) in DMF (1.786 mL) were heated at 90° C. for 100 mins in the microwave. The reaction was worked up by diluting with EtOAc, washing with bicarb and brine. This was dried over MgSO4, filtered and evaporated to dryness to give an orange residue. The residue was taken up in TFA/DCM (1 ml/3 ml) and stirred at RT for 2 hours. Reaction mixture was concentrated and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (39 mg, 36% Yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)CCC>O1CCOCC1.C(OCC)C.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>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Yield: 40.7 %

Procedure:
To a solution of 0.5 g (1.6 mmol) of material from Example 27 and 0.6 g (1.7 mmol) of 2-(tributylstannyl)-furan in 5 mL of dioxane was added 0.1 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0). The mixture was heated to reflux for 16 hours, cooled to ambient temperature and diluted with 5 mL of ethyl ether. The mixture was washed once with 5 mL of saturated aqueous potassium fluoride, the organic layer was separated and the aqueous portion was extracted three times with 5 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (25 g of silica gel, 25% ethyl acetate/hexane) of the residue afforded a yellow oil which was recrystallized from ethyl ether/hexane to afford 0.2 g (51%) of the title compound.
Reaction SMILES: [CH:1](O)=[O:2].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[F:28][C:29]1[C:41]([F:42])=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:30]=1[O:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)(O)[O-].[Na+]>C(OCC)C.O>[CH:1]([N:35]1[CH2:36][CH2:37][CH:32]([O:31][C:30]2[C:38]([F:45])=[C:39]([F:44])[C:40]([F:43])=[C:41]([F:42])[C:29]=2[F:28])[CH2:33][CH2:34]1)=[O:2]
Reactant: O=CO
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 1.5 ml of formic acid and 3.5 ml of acetic anydride was stirred at 55° C. for one hour, cooled, and treated with a solution of 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 50 ml of diethyl ether. The reaction mixture was then stirred at ambient temperature for three hours. Thereafter, the mixture was poured into 100 ml of water, adjusted to pH 10 by the addition of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated solution of chloride and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the solvent afforded an oil which was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to yield 4.0 g (91%) of 1-formyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 32°-34° C.
Reaction SMILES: COCCOC.Br[C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([CH2:16][OH:17])=[CH:13][C:12]=2[CH:18]=1.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[Na+].[Na+]>CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C(Cl)Cl>[OH:17][CH2:16][C:14]1[O:15][C:11]2[CH:10]=[CH:9][C:8]([C:26]3[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=3)=[CH:18][C:12]=2[CH:13]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: OCc1cc2cc(Br)ccc2o1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc3oc(CO)cc3c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
To 4 mL DME under Ar was added (5-bromo-1-benzofuran-2-yl)methanol (Example 3, 250 mg, 1.10 mmol) and Ar was bubbled through the mixture for 2 minutes to remove any dissolved oxygen. To this mixture was then added 37.6 mg (0.033 mmol) tetrakis(triphenylphosphine) palladium(0) and the reaction was stirred for 10 minutes at rt. 4-(Methoxycarbonyl)phenyl boronic acid (218 mg, 1.21 mmol) and 2.64 mL of 1 M Na2CO3 were then added, and the mixture was then heated to 100° C. for 2.5 hours under Ar. At the end of this time, TLC (5% MeOH/CH2Cl2) revealed complete reaction. The mixture was then filtered and the DME removed under reduced pressure. The thick paste was then transferred to a separatory funnel with 80 mL water and 100 mL EtOAc. The EtOAc was separated and the aqueous phase extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and solvent removed in vacuo to provide a dark brown solid. The solid was dissolved in a minimal amount of MeOH, fused to silica gel, and purified by flash chromatography (2.5% MeOH/CH2Cl2). The desired product (247.7 mg, 80%) was obtained as a white solid. 1H-NMR (acetone-d6, δ: 3.91 (s, 3H), 4.71 (s, 2H), 6.82 (s, 1H), 7.62 (m, 2H), 7.83 (d, 2H), 7.94 (m, 1H), 8.09 (d, 2H); LRMS (GC/MS/EI) 282 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH2:34]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][OH:45])[CH2:38][CH2:37]1)[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:45][CH2:44][CH2:43][CH2:42][N:39]4[CH2:38][CH2:37][N:36]([CH2:34][CH3:35])[CH2:41][CH2:40]4)=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: COCCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CCN1CCN(CCCO)CC1
Product: CCN1CCN(CCCOc2cc3ncc(C#N)c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c3cc2OCCOC)CC1
Yield: 39.3 %

Procedure:
Following the procedure of Example 15, 4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-fluoro-6-(2-methoxyethoxy)-3-quinolinecarbonitrile (300 mg, 0.62 mmol) and 1-ethyl-4-(3-hydroxypropyl)piperazine (540 mg, 3.1 mmol) provides 155 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[3-(4-ethyl-1-piperazinyl)propoxy]-6-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 188-190° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.S(Cl)([Cl:16])=O>ClCCCl>[Cl:16][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-n2cccn2)cc1
Solvent: ClCCCl
Product: ClCc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
To a solution of [4-(1H-pyrazol-1-yl)phenyl]methanol (24.0 g) in 1,2-dichloroethane (200 mL) was added dropwise thionyl chloride (26.3 g) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with tert-butyl methyl ether to give the title compound (23.5 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][SH:9])[CH2:3][CH2:2]1.[Na].C1(C)C=CC=CC=1.Br[CH2:19][C:20](=[O:42])[C@@H:21]1[C@:38]2([CH3:39])[C@H:24]([C@H:25]3[C@H:35]([C:36](=[O:40])[CH2:37]2)[C@:33]2([CH3:34])[C@H:28]([CH2:29][C@H:30]([OH:41])[CH2:31][CH2:32]2)[CH2:27][CH2:26]3)[CH2:23][CH2:22]1>C(O)(C)C>[OH:41][C@@H:30]1[CH2:31][CH2:32][C@@:33]2([CH3:34])[C@@H:28]([CH2:27][CH2:26][C@@H:25]3[C@@H:35]2[C:36](=[O:40])[CH2:37][C@@:38]2([CH3:39])[C@H:24]3[CH2:23][CH2:22][C@@H:21]2[C:20](=[O:42])[CH2:19][S:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:29]1
Reactant: SCCN1CCOCC1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Agent: [Na]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CSCCN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 0.08 h

Procedure:
2-Morpholinoethanethiol (1 ml.) was added to a warm solution of sodium (0.6 g.) in a mixture of dry toluene (30 ml.) and isopropyl alcohol (25 ml.). After 5 min., 21-bromo-3α-hydroxy-5α-pregnane-11,20-dione (2.0 g.) was added and the resulting mixture was stirred at 40° for 30 min. The mixture was then partitioned between water and ether and the organic layer was washed with water, dried (Na2SO4) and evaporated. The residue was subjected to preparative t.l.c. (EtOAc) to give title compound (150 mg.) as a white foam, [α]D + 73° (c 0.9); λmax. 243 nm. (ε 570).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4]([CH3:13])[N:3]=1.[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH2:18]>O1CCCC1>[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: COC(CN)OC
Reactant: Cc1nc(Cl)c2c(C)cccc2n1
Solvent: C1CCOC1
Product: COC(CNc1nc(C)nc2cccc(C)c12)OC
Temperature: 5 °C

Procedure:
4. 14.15 g of crude 4-chloro-2,5-dimethylquinazoline are suspended in 300 ml of tetrahydrofuran, cooled to 5° C. and treated with 16.5 ml of 2,2-dimethoxyethylamine while stirring. The mixture is stirred at room temperature for 24 h., a further 10 ml of 2,2-dimethoxyethylamine are added thereto and the mixture is stirred for a further 40 h. The reaction mixture is evaporated in vacuum and the residue is partitioned between chloroform and saturated aqueous sodium hydrogen carbonate solution. The chloroform solution is evaporated in a vacuum. The residue (21 g) is chromatographed over 150 g of silica gel. 1.85 g of 4-(2,2-dimethoxyethylamino)-2,5-dimethylquinozoline are eluted with ethyl acetate. These are recrystallized from hexane. There are obtained 18.3 g of 4-(2,2-dimethoxyethyl-amino)-2,5-dimethylquinazoline of m.p. 48°-49° C.
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2.[Cl:34]C1C=C2C(=CC=1)C=NC(OS(C(F)(F)F)(=O)=O)=C2>>[ClH:4].[ClH:34].[ClH:1].[Cl:15][C:12]1[CH:11]=[C:6]2[C:5](=[CH:14][CH:13]=1)[CH:10]=[N:9][C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH:26]=3)[CH:21]=1)=[CH:7]2
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Reactant: O=S(=O)(Oc1cc2cc(Cl)ccc2cn1)C(F)(F)F
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2cc(Cl)ccc2cn1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 6-chloroisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.14-2.31 (m, 4H), 3.04-3.16 (m, 2H), 3.33-3.41 (m, 2H), 4.47-4.62 (m, 3H), 7.83 (dd, J=8.8, 2.0 Hz, 1H), 8.15 (s, 1H), 8.21 (d, J=1.8 Hz, 1H), 8.34 (d, J=8.8 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 8.73 (s, 1H), 8.84 (d, J=2.0 Hz, 1H), 9.22 (br. s., 1H), 9.34 (br. s., 1H), 9.52 (s, 1H), MS(ES+): m/z=404.90/406.78 [MH+]. HPLC: tR=1.80 min (ZQ2, polar—5 min).
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[C:21]([I:30])=[N:20]2)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1>>[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[C:21]([I:30])=[N:20]2)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(Cl)cc1C(F)(F)F
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(c2)c(I)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and 1-[4-chloro-2-(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-carbaldehyde following General Procedure F.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>CS(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2ccccc12
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCOc1cnc(Cl)c2ccccc12
Temperature: 25 °C

Procedure:
1-chloro-4-hydroxyisoquinoline (50 mg, 0.28 mmol, 1.0 equiv), Cs2CO3 (454 mg, 1.39 mmol, 5.0 equiv.), and tert-butyl (2-bromoethyl)carbamate (2-2) (94 mg, 0.42 mmol, 1.5 equiv.) were suspended in anhydrous DMSO (2 mL) and stirred at room temperature. When LCMS indicated the reaction was complete, the crude reaction mixture was purified with reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA present) to yield the product (2-3). LRMS m/z (M+H) 323.1 found, 323.1 required.
Reaction SMILES: [N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][NH:11][CH2:12][C:13]3[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=3)[O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=1>ClCCl>[N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][N:11]([CH2:12][C:13]3[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=3)[O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[S:42]([C:38]3[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=3)(=[O:44])=[O:43])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
A solution of isopropyl [3-({[4-(1H-pyrazol-1-yl)benzyl]amino}methyl)-phenoxy]acetate (0.28 g, 0.75 mmol), triethylamine (0.53 mL, 0.37 mmol) and pyridine-3-sulfonyl chloride (268 mg, 1.50 mmol) in dichloromethane (7 mL) was stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane, and the combined organic layers were washed with water, brine and dried over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography (0-5% methanol in dichloromethane) afforded the desired product (180 mg, 69% based on the recovered amine starting material) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=5.56 Hz, 6H) 4.37 (s, 2H) 4.42 (s, 2H) 4.50 (s, 2H) 5.06-5.25 (m, 1H) 6.49 (s, 1H) 6.65-6.75 (m, 2H) 6.77-6.84 (m, 1H) 7.17-7.23 (m, J=8.59 Hz, 3H) 7.46 (dd, J=7.83, 4.80 Hz, 1H) 7.60 (d, J=8.34 Hz, 2H) 7.74 (s, 1H) 7.92 (s, 1H) 8.08 (d, J=7.83 Hz, 1H) 8.83 (d, J=4.29 Hz, 1H) 9.09 (s, 1H). LRMS m/z calcd. for C27H28N4O5S ([M+H]+): 520.2. Found: 521.2.
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:31][CH2:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]1[C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)/[CH:3]=[CH:4]/[C:5]1[CH:18]=[CH:17][C:8]([CH2:9][O:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:7][CH:6]=1>CCO>[O:1]=[C:2]([N:19]1[CH2:31][CH2:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]1[C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:17][CH:18]=1
Reactant: CCOC(=O)COCc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Solvent: CCO
Product: O=C(O)COCc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 40 %

Procedure:
The same method as employed in the preparation of Example 79 but starting from a solution of (E)-(4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzyloxy)acetic acid, ethyl ester in EtOH gave after recrystallization from MeOH:H2O the title compound as an off-white solid in a 40% yield. MP: 162-163° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:20][CH3:21])[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2[C:5](=[C:6]([CH:17]([CH3:19])[CH3:18])[CH:7]=[C:8]([C:15]#[CH:16])[CH:9]=2)[O:4]1)[CH3:2].[CH3:22][O:23][C:24](=[O:53])[C:25]([C:28]1[CH:33]=[CH:32][C:31](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:30][CH:29]=1)([CH3:27])[CH3:26].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:22][O:23][C:24](=[O:53])[C:25]([C:28]1[CH:29]=[CH:30][C:31]([C:16]#[C:15][C:8]2[CH:9]=[C:10]3[C:5](=[C:6]([CH:17]([CH3:19])[CH3:18])[CH:7]=2)[O:4][C:3]([CH2:1][CH3:2])([CH2:20][CH3:21])[CH2:12][C:11]3([CH3:14])[CH3:13])=[CH:32][CH:33]=1)([CH3:27])[CH3:26]
Reactant: C#Cc1cc(C(C)C)c2c(c1)C(C)(C)CC(CC)(CC)O2
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC1(CC)CC(C)(C)c2cc(C#Cc3ccc(C(C)(C)C(=O)OC)cc3)cc(C(C)C)c2O1

Procedure:
Following General Procedure B and using 2,2-diethyl-6-ethynyl-8-isopropyl-4,4-dimethyl chroman (Intermediate 29, 0.069 g, 0.24 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.146 g, 0.48 mmol), triethyl amine (3 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.107 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 5% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (0.070 g, 62%).
Reaction SMILES: [N:1]#[N:2].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([NH:16][C@H:17]([C:25]([N:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][C:29]([OH:31])=[O:30])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14].O.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43]([OH:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1>C(O)C1C=CC=CC=1.C1C=CC=CC=1>[N:1]#[N:2].[C:37]1([CH3:47])[CH:38]=[CH:39][C:40]([S:43]([OH:46])(=[O:44])=[O:45])=[CH:41][CH:42]=1.[CH2:47]([O:30][C:29](=[O:31])[CH2:28][N:27]([C:25](=[O:26])[C@H:17]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])[NH:16][S:13]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1)(=[O:14])=[O:15])[CH2:32][CH2:33][CH2:34][CH3:35])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: c1ccccc1
Solvent: OCc1ccccc1
Product: CCCCN(CC(=O)OCc1ccccc1)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2ccccc2c1
Yield: 94.9 %

Procedure:
A mixture of 1.2 g of N2 -(2-naphthylsulfonyl)-L-arginyl-N-butylglycine and 1.0 g of p-toluenesulfonic acid monohydrate in 5 ml of benzyl alcohol and 30 ml of benzene was refluxed for 5 hours, while removing water by azeotropic distillation. At the end of this period, the solvent was evaporated and then 100 ml of ethyl ether was added to the residue to give 1.73 g (93%) of N2 -(2-naphthylsulfonyl)-L-arginyl-N-butylglycine benzyl ester p-toluenesulfonate in the form of a powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:21]([OH:23])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.CN(C=O)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])[C:21]1=[O:23])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)N1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 48 h

Procedure:
Dissolve 4.76 g of the lysine derivative, 1.64 g. of N-hydroxysuccinimide and 3.24 g dicyclohexylcarbodiimide in 250 ml. of DMF. Store this reaction mixture at 0° C. for two days. Concentrate the reaction in vacuo and dissolve the residue in ethyl acetate. Filter and purify the product by silica gel chromatography. Isolate the purified 3-(S)-t-butoxycarbonylamino-1-(1-methoxycarbonylethyl)perhydroazepin-2-one.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([OH:12])=[O:11])[CH3:6].[CH2:17](O)[CH3:18]>>[CH2:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([O:12][CH2:17][CH3:18])=[O:11])[CH3:6]
Reactant: CCc1cc(C(=O)O)ccc1O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(O)c(CC)c1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
Thionyl chloride (3 ml) was added dropwise over a period of 2 minutes to ethanol (50 ml) at -10° C. whilst under an atmosphere of argon. The reaction mixture was stirred at -10° C. for 20 minutes and then allowed to warm to ambient temperature. A solution of 3-ethyl-4-hydroxybenzoic acid (3.5 g) in ethanol was added to the reaction mixture dropwise, with cooling (ice-bath). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The ethanol was removed by evaporation and the residue was partitioned between ethyl acetate (100 ml) and 1M aqueous sodium hydroxide solution (50 ml). The phases were separated and the aqueous phase washed with ethyl acetate (50 ml). The ethyl acetate extracts were combined, washed with water (50 ml) brine (50 ml), dried (MgSO4) and evaporated. The residue, an oil, crystallised on standing to give a solid which was triturated with 10% diethyl ether/pentane to give ethyl 3-ethyl-4-hydroxybenzoate as a solid (1.4 g), m.p. 73°-74° C.; microanalysis, found: C, 68.4; H, 7.7%; C11H14O3 requires: C, 68.0; H, 7.3%; NMR: 1.15(3H,t), 1.3(3H,t), 2.55(2H,q), 4.25(2H,q), 6.85(2H,d), 7.65(2H,m), 10.15(1H,s).