Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([O:19]CC)=[O:18])=[CH:12][C:11]=3[CH:22]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][C:11]=3[CH:22]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)C1=Cc2cc(N3CCOCC3)ccc2OCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1=Cc2cc(N3CCOCC3)ccc2OCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.4 %

Procedure:
In methanol (8 ml) was dissolved ethyl 7-morpholino-2,3-dihydro-1-benzoxepine-4-carboxylate (800 mg, 2.64 mmol), and to the mixture was added 1N sodium hydroxide solution (8 ml). The mixture was stirred at room temperature for 12 hours, and to the mixture was added 1N hydrochloric acid (8 ml). The organic solvent was evaporated under reduced pressure, and the precipitated insoluble materials were filtered, which were washed with water and diisopropylether and dried under reduced pressure to give 7-morpholino-2,3-dihydro-1-benzoxepine-4-carboxylic acid (649 mg, 2.36 mmol, 89%).
Reaction SMILES: [Na].[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH2:16][CH2:17][CH3:18])[C:14]=1[OH:15])[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[C:8]2[CH3:24])(=[O:4])[CH3:3].[C:25](OCC)(=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27].Cl>C(O)C>[CH3:24][C:8]1[C:7]2[C:12](=[C:13]([CH2:16][CH2:17][CH3:18])[C:14]3[O:15][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][C:2](=[O:4])[C:5]=3[CH:6]=2)[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=1
Reactant: CCCc1c(O)c(C(C)=O)cc2c(C)cc(C(=O)OCC)nc12
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCc1c2nc(C(=O)OCC)cc(C)c2cc2c(=O)cc(C(=O)OCC)oc12

Procedure:
Sodium (2.925 g) was dissolved in dry ethanol (380 ml) and the product of step (b) (8 g) was added together with diethyl oxalate (8.7 ml). After 2 hours at reflux, the mixture was cooled and acidified with gaseous HCl, until the suspension was yellow and the pH about 2. The mixture was then refluxed 30 minutes, cooled and evaporated. The residue obtained was washed with dilute sodium bicarbonate solution, dried to give the sub-title compound, 7.8 g from ethanol, mp 183°-4°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10].[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:7][N:6]1[C:2]([NH:1][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:3]([NH:8][CH:9]=[O:10])[CH:4]=[N:5]1
Reactant: Cn1ncc(NC=O)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc(NC=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 52.7 %

Procedure:
The crude product of N-(5-amino-1-methyl-1H-pyrazol-4-yl)formamide (13.33 g) was dissolved in N,N-dimethylformamide (130 ml). To the solution were added trityl chloride (29.2 g), triethylamine (66.3 ml) and 4-dimethylaminopyridine (465 mg), and the mixture was stirred at 60° C. for 5 hours. To the reaction mixture was added water, and the whole mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a white solid. The solid was triturated with ethyl acetate/diisopropyl ether (1:1) to give N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]formamide (19.18 g). The NMR spectrum of this compound indicates the existence of its rotamer.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH:13]([CH3:17])[C:14]([OH:16])=[O:15])([O-:3])=[O:2].CO.[CH3:20][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1>[CH3:20][O:15][C:14](=[O:16])[CH:13]([C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:17]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 90 %

Procedure:
A 250 ml three-necked conical flask equipped with a nitrogen inlet and a stirrer was purged with nitrogen, and was added with 2,4-dinitrophenylpropanoic acid (2.40 g, 0.01 mole), methanol (20 ml) and toluene (83 ml). Stirring was conducted at room temperature until 2,4-dinitrophenylpropanoic acid was dissolved. Trimethylsilyldiazomethane (8.3 ml) was then added, and reaction was conducted for 3 hours at room temperature. Solvent was removed by distilling under a reduced pressure and by drying at 70° C. to obtain 2,4-dinitrophenylpropanoic acid methyl ester (2.29 g, yield: 90%).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1)[OH:5].O[C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1COCC1>[CH3:37][C:26]1[CH:25]=[C:24]([O:5][CH:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=3)[N:7]=2)[CH2:3][CH:2]([CH3:22])[CH3:1])[CH:36]=[CH:35][C:27]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: CC(C)CC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OC(CC(C)C)c2cccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Temperature: 0 °C
Yield: 47.1 %

Procedure:
A solution of 3-methyl-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-butanol (180 mg, 0.58 mmol) in dry THF (12 mL) under nitrogen was treated with ethyl (4-hydroxy-2-methylphenoxy)acetate (122 mg, 0.58 mmol) and cooled to 0° C. This was treated portion-wise with ADDP (0.3 g, 1.2 mmol), then drop-wise with nBu3P (0.29 mL, 1.2 mmol). The resulting pale yellow suspension allowed to warm to rt slowly over 16 hours. The solvent was removed under vacuum and the residue partitioned between EtOAc (60 mL) and water (60 mL) and the layers separated. The aqueous was re-extracted with EtOAc (60 mL) and the combined organic layer dried (Na2SO4) and reduced. Purification by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 99:1 to 49:1) gave the title compound as a colourless oil (137 mg).
Reaction SMILES: [NH:1]1[C:11]2[C:12]3[C:3]([CH2:4][NH:5][C:6](=[O:13])[C:7]=3[CH:8]=[CH:9][CH:10]=2)=[CH:2]1.F[B-](F)(F)F.[CH2:19]([O+](CC)CC)[CH3:20]>C(Cl)Cl>[CH2:19]([O:13][C:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[NH:1][CH:2]=[C:3]([C:12]=23)[CH2:4][N:5]=1)[CH3:20]
Reactant: CC[O+](CC)CC
Reactant: O=C1NCc2c[nH]c3cccc1c23
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC1=NCc2c[nH]c3cccc1c23
Reaction time: 24 h

Procedure:
3,4-Dihydropyrrolo[4,3,2-de]isoquinolin-5(lH)-one (8.6 g), described in Example 4, is added in one portion to a solution of 12 g of triethyloxonium fluoroborate [H.-L. Pan and T. L. Fletcher, J. Org. Chem., 27, 3639 (1962)] in 500 ml dry methylene chloride. The suspension is stirred for 24 hours. The solid is collected and washed with a little methylene chloride and then ether to give 5-ethoxy-1,3-dihydropyrrolo[4,3,2-de]isoquinoline hydrofluoroborate, mp 233° - 234°C, νmaxnujol 3380, 3280, 1645, 1605, 1594, 1540 and 1512 cm-1.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]1[C:8]([P:24]([O:29]CC)(=[O:28])[O:25]CC)([P:16]([O:21]CC)(=[O:20])[O:17]CC)[CH:9]=[C:10]2[C:15]=1[NH:14][CH2:13][CH:12]=[CH:11]2)(=O)C.Cl>>[SH:4][CH2:5][CH2:6][C:7]1[C:8]([P:24]([OH:29])(=[O:25])[OH:28])([P:16]([OH:21])(=[O:17])[OH:20])[CH:9]=[C:10]2[C:15]=1[NH:14][CH2:13][CH:12]=[CH:11]2
Reactant: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=CCNC2=C1CCSC(C)=O
Agent: Cl
Product: O=P(O)(O)C1(P(=O)(O)O)C=C2C=CCNC2=C1CCS

Procedure:
Dihydro-7-(2-acetylthioethyl)-1-pyrindine-6,6-bisphosphonic acid, tetraethyl ester (4.0 mmol) is added to 6N HCl (35 ml) and heated at reflux under nitrogen for 18 hours. The reaction mixture is then cooled and concentrated under reduced pressure. The product is obtained by recrystallizing from water and isopropanol.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([N+:24]([O-])=O)[CH:18]=2)[CH2:12]1)=[O:9])=[O:5].C(OCC)(=O)C>[C].[Pd].CO>[NH2:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[CH2:16][N:13]1[CH2:14][CH2:15][C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][NH:6][C:4](=[O:5])[C:3]2[CH:27]=[C:28]([C:31]([F:34])([F:32])[F:33])[CH:29]=[CH:30][C:2]=2[NH2:1])[CH2:12]1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)ccc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine (32.6 mg) with 10% palladium carbon (8 mg), ethyl acetate (2.7 mL) and methanol (0.3 mL) was stirred at room temperature under a hydrogen atmosphere for 15 hours. The palladium carbon was removed by filtration, and the filtrate was concentrated and purified by solid-phase extraction (Bond Elut™ SI, 20% methanol/ethyl acetate) to thereby provide (R)-1-(3-amino-4-chlorobenzyl)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Comp d. No. 2132) (10.5 mg, 34%). The purity was determined by RPLC/MS (84%). ESI/MS m/e 470.2 (M++H, C21H23F3N5O2).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[N:29]1([CH2:36][CH2:37][C:38]2[S:42][C:41]([C:43]([O-])=O)=[CH:40][CH:39]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[Li+]>>[N:29]1([CH2:36][CH2:37][C:38]2[S:42][C:41]([CH2:43][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:40][CH:39]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C([O-])c1ccc(CCN2CCCCCC2)s1
Agent: [Li+]
Product: CCN(Cc1ccc(CCN2CCCCCC2)s1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 71.1 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and lithium 5-(2-azepan-1-ylethyl)thiophene-2-carboxylate (60 mg) according to an analogous synthetic method to Example 152 and purified by LC-MS, the title compound (29 mg) was obtained.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][C:9]2[CH:12]=[N:13][N:14]([C:15]3[N:20]=[C:19]([N:21]4[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]4)[CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:7]=1)CCC.Br[C:44]1[N:45]=[C:46]([CH3:51])[C:47]([NH2:50])=[N:48][CH:49]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CN(C)C(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:50][C:47]1[N:48]=[CH:49][C:44]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)=[N:45][C:46]=1[CH3:51]
Reactant: Cc1nc(Br)cnc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(cn1)cnn2-c1cccc(N2CCCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: Cc1nc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)cnc1N
Temperature: 150 °C
Yield: 39.2 %

Procedure:
A mixture of tert-butyl 4-[6-(6-tributylstannylpyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]-1,4-diazepane-1-carboxylate (0.5852 mmol; 400 mg), 5-bromo-3-methyl-pyrazin-2-amine (1.170 mmol; 220.1 mg), tricyclohexylphosphine (0.1405 mmol; 39.39 mg) and tris(dibenzylideneacetone)dipalladium (0) (0.05852 mmol; 53.59 mg) in N,N-Dimethylacetamide (30 mL) was purged with Argon for 1 min. The reaction mixture was sealed in a Biotage microwave tube and heated under microwave at 150° C. for 45 min. The mixture was partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on silica eluted with 10% MeOH in DCM to afford tert-butyl 4-[6-[6-(5-amino-6-methyl-pyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-1,4-diazepane-1-carboxylate (115.0 mg, 39%).
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:31](=[O:32])[N:6]2[CH:7]([C:15]([O:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:8]([CH:11]=[C:12]([Br:14])[Br:13])=[CH:9][S:10][C@H:5]12)=[O:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(OCC)(=O)C>[CH:1]([NH:3][CH:4]1[C:31](=[O:32])[N:6]2[C:7]([C:15]([O:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:16])=[C:8]([CH:11]=[C:12]([Br:13])[Br:14])[CH2:9][S:10](=[O:41])[C@H:5]12)=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C=C(Br)Br)=CS[C@H]12
Solvent: CCOC(C)=O
Product: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Br)Br)CS(=O)[C@H]12
Yield: 44 %

Procedure:
To a solution of benzhydryl 7-formamido-3-(2,2-dibromovinyl)-2-cephem-4-carboxylate (4.2 g) in ethyl acetate (42 ml) was added a solution of m-chloroperbenzoic acid (1.72 g) in ethyl acetate at -20° to -10° C. and the resultant mixture was stirred at -10° C. for 45 minutes. The precipitates were collected by filtration to give benzhydryl 7-formamido-3-(2,2-dibromovinyl)-3-cephem-4-carboxylate-1-oxide (1.9 g).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:40])[N:24]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:25][CH2:26][CH2:27][N:28]2[N:32]=[N:31][CH:30]=[N:29]2)[CH:20]=[C:19]([Cl:41])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[Cl:41][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[CH2:25][CH2:26][CH2:27][N:28]1[N:32]=[N:31][CH:30]=[N:29]1)=[O:40]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCn2ncnn2)c2cccc(F)c2)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCn1ncnn1)c1cccc(F)c1
Yield: 72.1 %

Procedure:
A solution of {2-[3-chloro-5-(3-fluorophenyl-(3-tetrazol-2-yl-propyl)-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.07 g) in trifluoroacetic acid (0.75 ml) and dichloromethane (0.75 ml) was stirred at room temperature for 1 h then concentrated under vacuum. The residue was purified by flash chromatography, eluting with dichloromethane/methanol/ammonia (90:10:1) to give the title compound as a white foam (0.042 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:22])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O.C1(B(O)O)C=CC=CC=1.[NH2:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:37]=1>>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][C:36]1[N:37]=[C:33]([NH:32][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([O:5][C@@H:4]([CH3:22])[CH2:3][O:2][CH3:1])[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[S:34][CH:35]=1)[CH3:43]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COC[C@H](C)Oc1cc(Oc2ccccc2)cc(C(=O)O)c1
Agent: OB(O)c1ccccc1
Product: CCOC(=O)Cc1csc(NC(=O)c2cc(Oc3ccccc3)cc(O[C@@H](C)COC)c2)n1

Procedure:
{2-[3-phenoxy-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoylamino]-thiazol-4-yl}-acetic acid ethyl ester was prepared from 3-{(1S)-2-methoxy-(methylethyl)oxy}-5-phenyloxy-benzoic acid (prepared in analogy to the method described in general synthetic descriptions, using phenylboronic acid in step D) and ethyl 2-aminothiazol-4-ylacetate following synthetic description A.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)OC(C)(C)C)=[C:5]([NH:17][C:18](=[O:27])/[CH:19]=[CH:20]/[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH:4]=1>O1CCOCC1.C(OCC)C>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([F:2])=[CH:4][C:5]=1[NH:17][C:18](=[O:27])/[CH:19]=[CH:20]/[C:21]1[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=1
Reactant: Cn1cc(/C=C/C(=O)Nc2cc(F)ccc2NC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cn1cc(/C=C/C(=O)Nc2cc(F)ccc2N)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
Protecting group removal was effected by addition of a 4M solution of HCl in dioxane (2.5 mL) to a solution of (E)-tert-butyl (4-fluoro-2-(3-(1-methyl-1H-pyrazol-4-yl)acrylamido)phenyl)carbamate (0.10 g, 0.28 mmol) in dioxane (2.5 mL). The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with diethyl ether (20 mL) and the hydrochloride salt of (E)-N-(2-amino-5-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)acrylamide precipitated was filtered. It was suspended in a saturated sodium bicarbonate solution and the mixture was stirred. The solid was filtered and washed with water then dried under vacuum to give the pure product (58 mg) as an off-white solid. ES+(M+H)+261.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][S:13][C:14](=[N:17]C#N)SC>>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][S:4][CH2:3][CH2:2][NH:1][C:14](=[NH:17])[S:13][CH3:12]
Reactant: CSC(=NC#N)SC
Reactant: NCCSCc1ccccn1
Product: CSC(=N)NCCSCc1ccccn1

Procedure:
The reaction of 2-((2-aminoethyl)thiomethyl)pyridine with dimethylcyanodithioimidocarbonate by a method similar to that described in Example (3d) afforded N-cyano-N'-[(2-(2-pyridylmethylthio)ethyl]-S-methylisothiourea, m.p. 85 - 88°. (from isopropyl alcohol-ether)
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)[CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:1]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CNCC3)nc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CN(Cc2ccccc2)CC3)nc1
Yield: 25.7 %

Procedure:
Combine 6-(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide (94 mg, 0.35 mmol), benzaldehyde (37 μL, 0.37 mmol), sodium triacetoxyborohydride (96 mg, 0.46 mmol), acetic acid (21 μL, 0.37 mmol), and 1,2-dichloroethane (5 mL) then stir at room temperature for 18 hours. Dilute the reaction with saturated aqueous sodium bicarbonate solution and extract with 5% methanol in dichloromethane (3×25 mL). Dry the combined 5% methanol in dichloromethane extracts with sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 100 mg of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform to yield 6-(2-benzyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide 2039910 (30 mg, 0.09 mmol): m/z=360.12 (M+1); 1H NMR (CDCl3, 300.00 MHz): 8.50 (d, 1H); 8.09-8.05 (m, 1H); 7.34-7.20 (m, 5H); 7.09 (d, 1H); 6.87-6.82 (m, 2H); 6.71 (d, 1H); 5.80 (s, 2H); 3.63-3.57 (m, 4H); 2.87-2.69 (m, 4H), HPLC=96% @ 2.98 m (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nm).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH2:10]Br>C1COCC1.[Cu]I>[CH2:10]([C:9]1[CH:8]=[C:7]([O:6][CH3:5])[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=1)[CH:1]=[CH2:2]
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: C=C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CCc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a suspension of 308 mg (1.62 mmol, 25 mol %) of copper (I) iodide in 30 mL of THF was added dropwise vinylmagnesium bromide as a 1 M solution in THF at −50° C. After stirring for 10 min, a solution of 1.5 g (6.49 mmol) of 3,5-dimethoxybenzyl bromide in 8 mL of THF was added, and the resulting solution was stirred at −30° C. for 1 h and then was warmed to room temperature. The reaction mixture was quenched by the slow addition of 20 mL of water. After stirring for 5 min, the layers were separated and the aqueous layer was extracted twice with 20-mL portions of ethyl acetate. The combined organic fractions were dried (Na2SO4), filtered through a plug of silica gel (eluted with ethyl acetate) and concentrated in vacuo to afford 1.2 g (100%) of product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=O)=[N:8][C:7]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1)=[CH:6]2.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:15])=[N:8][C:7]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1)=[CH:6]2
Reactant: C1COCCN1
Reactant: COc1ccc2c(C(=O)O)nc(Nc3cc(C)[nH]n3)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: COc1ccc2c(C(=O)N3CCOCC3)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-1-carboxylic acid (100 mg) (example 9A), morpholine (70 mg), 1-hydroxybenzotriazole (HOBt) (130 mg), NMP (100 mg), N,N-dimethylformamide (DMF) (2 ml), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDCI) (180 mg) was stirred at room temperature overnight. The reaction mixture was purified by preparative LC-MS to give 20 mg of [6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-morpholin-4-yl-methanone. LC-MS: m/e 368(MH+).
Reaction SMILES: BrC1C=CC([N+]([O-])=O)=C(F)C=1.C(O)C.CNC.Br[C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([N:25]([CH3:27])[CH3:26])[CH:24]=1.[C:31]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[CH3:26][N:25]([CH3:27])[C:23]1[CH:24]=[C:19]([N:42]2[CH2:43][CH2:44][N:39]([C:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:38])[CH2:40][CH2:41]2)[CH:20]=[CH:21][C:22]=1[N+:28]([O-:30])=[O:29]
Reactant: CN(C)c1cc(Br)ccc1[N+](=O)[O-]
Reactant: O=C(c1ccccc1)N1CCNCC1
Agent: [Pd]
Agent: CNC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCO
Product: CN(C)c1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 21.2 %

Procedure:
A solution of 4-bromo-2-fluoro-1-nitrobenzene (1.0 g, 4.5 mmol) and 2.0 M dimethylamine ethanol solution (6.9 ml, 13.6 mmol) in 20 ml NMP was stirred at room temperature for 16 hours. The solution was added 200 ml water. The solids (1.03 g, 90%) were filtered dried under high vacuum. A solution of 5-bromo-N,N-dimethyl-2-nitrobenzenamine (0.2 g, 0.8 mmol), benzoyl piperazine (0.19 g, 1.0 mml), Tris(dibenzylideneacetone)dipalladium (9 mg), BINAP (38 mg) and cesium carbonate (0.24 g, 1.2 mmol) in 20 ml NMP was stirred at 100° C. under argon atmosphere for 16 hours. The reaction was cooled to room temperature before filtration. (4-(3-(dimethylamino)-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (0.06 g, 20%) was obtained after flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.93 (s, 6H), 3.40-3.57 (m, 8H), 6.26 (d, J=2.6 Hz, 1H), 6.35 (dd, J=2.6, 9.6 Hz, 1H), 7.48 (m, 5H), 7.98 (d, J=9.6 Hz, 1H).