Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:31][C:32]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]2[N:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])[CH3:33]>O1CCOCC1.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>[NH2:13][C:11]([C:9]1[CH:10]=[C:2]([C:47]2[CH:46]=[CH:45][C:44]([N:41]3[CH2:42][CH2:43][N:38]([C:36]([O:35][C:32]([CH3:34])([CH3:33])[CH3:31])=[O:37])[CH2:39][CH2:40]3)=[N:49][CH:48]=2)[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cn2)CC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cc23)CC1
Temperature: 160 °C
Yield: 89.7 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (100 mg, 0.241 mmol) in dioxane (1.0 mL) and H2O (0.8 mL) was added cesium carbonate (314 mg, 0.964 mmol), and [6-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)-3-pyridinyl]boronic acid (297 mg, 0.964 mmol). The reaction mixture was stirred before addition of tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol). The reaction was heated in a microwave at 160° C. for 20 min. Mixture was concentrated and taken up in EtOAc (10 mL) and H2O (5.0 mL). Compound was purified by Gilson Preparatory HPLC to give 129 mg of 1,1-dimethylethyl 4-(5-{7-(aminocarbonyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indol-5-yl}-2-pyridinyl)-1-piperazinecarboxylate and 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-7-carboxamide (44%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:34][C@@H:35]1[CH2:40][NH:39][CH2:38][C@H:37]([CH3:41])[NH:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:39]3[CH2:38][C@H:37]([CH3:41])[NH:36][C@H:35]([CH3:34])[CH2:40]3)=[O:32])[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1

Procedure:
5-[5-(3,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.24 mmol) was coupled with (2R,6S)-2,6-dimethyl-piperazine (34 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (1.2 eq.) to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[F:10][C:11]([F:19])([CH2:16][O:17][CH3:18])[C:12](OC)=[O:13]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:12](=[O:13])[C:11]([F:19])([F:10])[CH2:16][O:17][CH3:18])=[N:6][CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: COCC(F)(F)C(=O)OC
Solvent: Cc1ccccc1
Product: COCC(F)(F)C(=O)NNc1ccc(Br)cn1

Procedure:
(5-bromo-2-hydrazinylpyridine (1.83 g, 9.73 mmol) and methyl 2,2-difluoro-3-methoxypropanoate (1.00 g, 6.49 mmol) were refluxed in toluene (35 mL) overnight. The reaction mixture was concentrated and purified by chromatography (EtOAc: hexanes=1:4) to give N′-(5-bromopyridin-2-yl)-2,2-difluoro-3-methoxypropanehydrazide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][CH:6]=[CH:5]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[C:64]1([CH2:70][SH:71])[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>O1CCOCC1.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]>[CH2:70]([S:71][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][CH:6]=[CH:5]2)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: Clc1nccc2cc(Br)ccc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1nccc2cc(SCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A three-neck 2 L flask equipped with an overhead stirrer, a thermocouple and a nitrogen inlet was charged with 6-bromo-1-chloroisoquinoline (60.0 g, 247 mmol), xantphos (7.16 g, 12.4 mmol) and Pd2(dba)3 (5.66 g, 6.19 mmol) in that order. The flask was evacuated. To the reaction flask was charged sparged dioxane (540 mL) and DIPEA (64.8 mL, 371 mmol). The flask was purged with N2 and warmed to 63° C. upon which a solution of phenylmethanethiol (30.5 mL, 260 mmol) in 180 mL of sparged dioxane was charged to the reaction mixture dropwise over 1 hr. The reaction was completed according to LC/MS. The solids were filtered off. The filtrate was concentrated down to a low volume. 500 mL of isopropanol was added into a separate flask. The concentrated product solution was charged slowly to the flask containing isopropanol. The product crystallized out of the solution. The resulting slurry was stirred at RT for 2 hours. The slurry was cooled to 0° C., filtered, washed with 50% IPA/heptanes, and dried under a vacuum with nitrogen sweep. The product was obtained as yellow solids (44.3 g; 63% isolated yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.26-8.10 (m, 2H), 7.63-7.51 (m, 2H), 7.46-7.39 (m, 3H), 7.37-7.28 (m, 3H), 4.31 (s, 2H); m/z (ESI) 286.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].C1COCC1>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: COc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 65 °C

Procedure:
A mixture of tert-butyl 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (0.56 g, 1.6 mmol), ammonium acetate (1.0 g, 20 mmol) and 1.0 M sodium cyanoborohydride in THF (4.0 mL, 4.0 mmol) in methanol (4 mL)/acetonitrile (4 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane. The organic extracts were dried over MgSO4 and concentrated to give the crude product, which was used in the next step without further purifications. LCMS calculated for C18H27ClN2O3Na (M+Na)+: m/z=377.2. found: 377.1.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][C@@H:10]2[CH2:15][O:16][CH2:17][C@@H:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]2[CH2:15][O:16][CH2:17][C@@H:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CO[C@@H]2COC[C@H]2N1Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(CN2CCO[C@@H]3COC[C@H]32)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of trans-4-benzyltetrahydro-2H-furo[3,4-b][1,4]oxazin-3(4H)-one (3.1 g, 13.2 mmol) in THF (35 mL) at 0° C. was added BH3:THF (1.0 M in THF; 39.7 mL, 39.7 mmol). The reaction mixture was stirred at 0° C. for 16 hours. The reaction was quenched with aqueous 1 N NaOH solution, adjusting to pH 13, and extracted with EtOAc (100 mL). The organic extract was washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford trans-4-benzylhexahydro-2H-furo[3,4-b][1,4]oxazine. 1H NMR (400 MHz, CDCl3) δ 7.29-7.31 (m, 5H), 3.96 (t, J=7.2 Hz, 1H), 3.92 (ddd, J=11.6, 3.6, 1.2 Hz, 1H), 3.86 (m, 1H), 3.67-3.77 (m, 2H), 3.52-3.66 (m, 3H), 3.45 (dd, J=12.0, 9.0 Hz, 1H), 3.34 (d, J=13.2 Hz, 1H), 2.71 (ddd, J=12.0, 2.8, 1.2 Hz, 1H), 2.42 (ddd, J=15.6, 8.8, 6.8 Hz, 1H). MS APCl calc'd for C13H17NO2 [M+H]+ 220. found 220.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:25]=[C:16]4[C:17]5[CH:18]=[CH:19][CH:20]=[N:21][C:22]=5[CH:23]=[CH:24][N:15]4[N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1>CO.[OH-].[Na+].[Pd]>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:25]=[C:16]4[C:17]5[CH:18]=[CH:19][CH:20]=[N:21][C:22]=5[CH2:23][CH2:24][N:15]4[N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2nc(/C=C/c3nc4c5cccnc5ccn4n3)nn12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc2nc(CCc3nc4n(n3)CCc3ncccc3-4)nn12
Reaction time: 1 h

Procedure:
To a solution of (E)-2-(2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)vinyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridine (17 mg, 0.52 mmol) in MeOH (3 mL) and aqueous NaOH (1 N, 1 mL) was added 10% Pd/C (17 mg) under a nitrogen atmosphere. The reaction vessel was degassed for three times, followed by treatment with H2 for 1 h at room temperature. The mixture was then submitted for prep-HPLC purification to give a free base of the title compound as a white solid. The solid was triturated with a solution of HCl (gas) in EtOAc (2 mL) to afford the di-HCl salt of the title compound as a yellow solid (7.83 mg, yield 37%). ESI MS: m/z 332 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[C:7]([CH3:12])[N:6]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[NH2:11][C:9]1[CH:8]=[C:7]([CH3:12])[N:6]=[C:5]([O:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[C:22]2[CH:21]=[CH:20][C:19]([C:33]3[CH:38]=[N:37][C:36]([NH2:39])=[N:35][CH:34]=3)=[C:18]([F:17])[CH:23]=2)[N:10]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Cc1cc(N)nc(Oc2ccccc2Br)n1
Product: Cc1cc(N)nc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 2-(2-bromophenoxy)-6-methylpyrimidin-4-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H17FN6O, 388.15; m/z found, 389.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=1.2, 2H), 7.53 (t, J=8.2, 1H), 7.49-7.44 (m, 1H), 7.41-7.36 (m, 1H), 7.34 (s, 1H), 7.33-7.30 (m, 1H), 7.29-7.25 (m, 1H), 7.12 (d, J=8.0, 1H), 6.85 (s, 2H), 6.82 (s, 2H), 5.94 (s, 1H), 2.04 (s, 3H).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])=[CH:22][C:21]3=[O:33])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl.O>CC(O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:22][C:21]2=[O:33])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (1.00 g, 1.99 mmol) in 2-propanol (4 mL) was added 2N hydrochloric acid (4.00 mL, 8.00 mmol). The mixture was stirred for 2 h at 25° C. Water (4 mL) was added and the mixture was thoroughly extracted with methyl t-butyl ether (30 mL). The organic layer was separated and washed with 1N sodium hydroxide (20 mL) and then brine (20 mL). Concentration of the organic layer provided a white foam. The foam was chopped up with a spatula to afford (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (890 mg, 96.7%) as an off-white solid: LR-ES-MS m/z calculated for C22H27ClN4O5 [M]+ 462, [M+H]+ observed 463.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(Cl)Cl>[CH3:30][NH:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([O:21][C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)=[N:24][CH:25]=1
Reactant: Oc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Reactant: CNC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1ccc(Oc2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)nc1
Temperature: 100 °C

Procedure:
A mixture of (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-ol (Example 47, 20 mg, 0.066 mmol), 6-chloro-N-methylnicotinamide (Example 71A, 11 mg, 0.066 mmol) and K2CO3 (27 mg, 0.20 mmol) in N,N-dimethylformamide (0.25 mL) was heated to 100° C. for 1 hour, cooled, diluted with CH2Cl2, filtered, and concentrated. The residue was purified by HPLC as described in Example 66. The product was further purified by chromatography on silica gel eluting with a gradient of 2 to 10% (9:1 methanol:ammonium hydroxide) in CH2Cl2 to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.44-1.53 (m, 2H), 1.59-1.67 (m, 4H), 1.94-2.10 (m, 1H), 2.24-2.34 (m, 1H), 2.39-2.57 (m, 4H), 2.95-3.06 (m, 1H), 3.01 (d, J=4.7 Hz, 3H), 3.43 (t, J=9.3 Hz, 1H), 3.48-3.60 (m, 1H), 3.70-3.89 (m, 2H), 6.09-6.18 (m, 1H), 6.92 (dd, J=8.5, 0.7 Hz, 1H), 7.07 (dd, J=8.5, 2.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 8.12 (dd, J=8.6, 2.5 Hz, 1H), 8.53 (dd, J=2.7, 0.7 Hz, 1H); MS (DCI/NH3) m/z 438 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:18][N:19]([C:21](=[O:23])[CH3:22])[NH2:20].C(O)(C)C.CCOCC>CCOCC>[CH3:18][N:19]([C:21](=[O:23])[CH3:22])[NH:20][C:16]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([N:2]([CH3:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:14][CH:13]=1)=[S:17]
Reactant: CCOC(=O)CN(C)c1ccc(N=C=S)cc1
Reactant: CC(=O)N(C)N
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOC(=O)CN(C)c1ccc(NC(=S)NN(C)C(C)=O)cc1

Procedure:
A solution of 1.25 g (5.0 mmol) of ethyl N-methyl-N-(4-isothiocyanatophenyl)glycinate and 0.44 g (5.0 mmol) of 1-methyl-1-acetylhydrazine in 40 ml of 1/1 isoproply alcohol/ether was left uncovered so the ether could evaporate over a 24 hr period. The product was collected and washed with isopropyl alcohol to give 1.32 g (3.9 mmol, 78%), mp 162° dec?. Anal. C15H22N4O3S (338): Calcd.: C,53.24; H,6.55; N,16.56; S,9.48. Found: C,53.12; H, 6.45; N,17.05; S,8.90. MS(FD) m/z 338. 1H NMR(DMSO-d6)δ: 9.76,s,2H,NH; 7.11,d,2H,ArH; 6.58,d,2H,ArH; 4.15,s,2H,CH2--N; 4.05,q,2H,CH2--O; 2.93,s,3H,CH3--N; 1.92,s,3H,CH3CO; 1.14,t,3H,CH3--C.
Reaction SMILES: C1C2C(=CC=C(S(N(CC(O)=O)C3C=CC(C)=CC=3)(=O)=O)C=2)CCN1.C(NCC)C.[CH2:31]([N:33]([CH2:60][CH3:61])[C:34](=[O:59])[CH2:35][N:36]([S:44]([C:47]1[CH:56]=[C:55]2[C:50]([CH2:51][CH2:52][N:53](C=O)[CH2:54]2)=[CH:49][CH:48]=1)(=[O:46])=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)[CH3:32]>C(O)=O>[CH2:60]([N:33]([CH2:31][CH3:32])[C:34](=[O:59])[CH2:35][N:36]([S:44]([C:47]1[CH:56]=[C:55]2[C:50]([CH2:51][CH2:52][NH:53][CH2:54]2)=[CH:49][CH:48]=1)(=[O:46])=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)[CH3:61]
Reactant: CCN(CC)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc2c(c1)CN(C=O)CC2
Agent: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc3c(c2)CNCC3)cc1
Solvent: CCNCC
Solvent: O=CO
Product: CCN(CC)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc2c(c1)CNCC2

Procedure:
prepared by reaction of [(1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-p-tolyl-amino]-acetic acid with diethylamine; due to the presence of formic acid in the eluent of the HPLC chromatography the product contained considerable amounts of N,N-diethyl-2-[(2-formyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-p-tolyl-amino]-acetamide (LC-MS: rt=0.91 min, 444 (M+1, ES+))
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=2)[S:5][C:6]=1[C:7]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:10]=[CH:9][N:8]=1.[Cl-].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][Zn+])=[CH:34][CH:33]=1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][C:2]2[N:3]=[C:4]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=3)[S:5][C:6]=2[C:7]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:10]=[CH:9][N:8]=2)=[CH:34][CH:33]=1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: CC(=O)Nc1cc(-c2nc(Br)c(-c3ncnn3COCC[Si](C)(C)C)s2)ccn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2nc(Cc3ccc(Cl)cc3)c(-c3ncnn3COCC[Si](C)(C)C)s2)ccn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a solution of N-{4-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-5-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.292 g, 0.589 mmol) in tetrahydrofuran (4.1 mL) was added 4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 2.36 mL, 1.18 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.0226 g, 0.0442 mmol) under argon. The solution was stirred at 60° C. for 2 hours. The reaction was incomplete by LCMS, so additional 4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 2 mL, 1 mmole) was added, then the reaction was stirred at 60° C. for an additional 2 hours. The reaction was allowed to cool to room temperature then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (0.112 g, 35%). LCMS: (FA) ES+ , 542. 1H NMR (400 MHz, d4-methanol) δ: 8.73-8.69 (m, 1H), 8.42-8.38 (m, 1H), 8.14 (s, 1 H), 7.58-7.55 (m, 1H), 7.27-7.20 (m, 4H), 5.52 (s, 2H), 4.32 (s, 2H), 3.68-3.61 (m, 2H), 2.20 (s, 3H), 0.90-0.84 (m, 2H), 0.040 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[CH:7][N:6]=1)=[O:4].[BH4-].[Na+].C(O)(=O)C.Cl>CN(C)C=O.CO.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N=Cc2ccc(Cl)c(Cl)c2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NCc2ccc(Cl)c(Cl)c2)cn1
Temperature: 0 °C

Procedure:
The solution of 13.7 g of 5-(3,4-dichlorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester in 35 ml of hot dimethylformamide is added all at once to the solution of 3.25 g of sodium borohydride in 150 ml of methanol while stirring at -20°. The mixture warms to 10° and the temperature is lowered by application of a bath to 0°. After one hour the reaction mixture is warmed to 35° for 10 minutes, cooled again to 0° and 1.5 ml of acetic acid and the solution of 6 ml 12 N hydrochloric acid in 45 ml of ice water is added. A solid separates, more ice and water are added to complete crystallization. The solid is collected, washed with cold water and recrystallized from methanol, to yield the 5-(3,4-dichlorobenzylamino)-pyridine-2-carboxylic acid methyl ester melting at 158°-161°.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([CH2:6][CH2:7][S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.[BH4-].[Na+]>C(O)C>[OH:20][CH:1]1[C:2]2[C:3](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:4](=[O:15])[N:5]1[CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1CCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2C(O)N1CCSc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
To a solution of 5.69 g (20.0 mmol) of 4-(2-phthalimidoethylthio)pyridine in 150 ml of ethanol, 2.27 g (60 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10), after which subsequent recrystallization from ethyl acetate gave 3.63 g of the desired compound (63.4% yield, colorless crystals), mp. 111.5°-112.5° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C:10]1([C:41]1[CH:49]=[C:48]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[C:47]([Br:59])=[C:46]2[C:42]=1[CH2:43][CH2:44][CH2:45]2)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:24]([O:23][C@H:13]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]([C:41]2[CH:49]=[C:48]([CH2:50][C:51]3[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=3)[C:47]([Br:59])=[C:46]3[C:42]=2[CH2:43][CH2:44][CH2:45]3)[O:11][C@@H:12]1[CH2:31][O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(Cc2cc(C3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Br)CCC3)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Br)CCC3)cc1
Temperature: -30 °C
Yield: 42.1 %

Procedure:
To a solution of the intermediate 16 (6.96 g, 8.13 mmol) in CH2Cl2 (40.1 mL) were added triethylsilane (3.24 mL, 16.2 mmol) and boron trifluoride diethyl etherate (2.55 mL, 16.2 mmol) at −60° C. under nitrogen atmosphere. The mixture was warmed up to −30° C. for 3 h. To the mixture was added saturated K2CO3 solution (50 mL) slowly and the mixture was extracted with EtOAc (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the desired intermediate 17 (2.87 g, 3.42 mmol, 42%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1.O>C(Cl)Cl>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:9](=[CH:8][C:7]=1[O:6][CH3:5])[CH:10]=[C:11]([C:19](=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:12]=[CH:13]2
Reactant: COc1cc2ccccc2cc1OC
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2ccc(C(=O)CCC(=O)O)cc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminium chloride (9.5 g) was added to a solution of 2,3-dimethoxynaphthalene (10 g) and succinic anhydride 7.1 g in methylene chloride (140 ml). The mixture was stirred at room temperature overnight and then treated with water and filtered. The resulting solid was taken into 1 M sodium hydroxide, washed once with methylene chloride, acidified and filtered. Yield: 8.3 g, melting point 215-229° C.