Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28]OS(C)(=O)=O)[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Reactant: CS(=O)(=O)OCCc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCc1cccnc1
Yield: 63.2 %

Procedure:
Using General Procedure A: A solution of 3,3″-Dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-[2,2′;6′,2″]terpyridine (0.219 g, 0.82 mmol), methanesulfonic acid 2-pyridin-3-yl-ethyl ester (approx. 3 mmol), KI (15 mg), and DIPEA (0.25 mL, 1.44 mmol) in DMF (3 mL was heated at 80° C. for 17 hours. Purification of the crude material by column chromatography on silica gel (CH2Cl2—CH3OH—NH4OH, 94:4:2) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2—CH3OH—NH4OH, 50:1:1) provided 193 mg (63%) of COMPOUND 92 as a colorless oil. 1H NMR (CDCl3) δ 1.61-1.70 (m, 4H), 2.00-2.22 (m, 4H), 2.51 (s, 6H), 2.51-2.55 (m, 2H), 4.14-4.18 (m, 2H), 6.55-6.60 (m, 1H), 6.85 (dd, 1H, J=7.5, 4.8 Hz), 7.09-7.12 (m, 2H), 7.42 (d, 2H, J=6.9 Hz), 7.54-7.60 (m, 1H), 8.18 (dd, 1H, J=4.8, 1.5 Hz), 8.42-8.46 (m, 2H); 13C NMR (CDCl3) δ 17.59, 22.43, 24.32, 26.23, 28.85, 30.67, 47.26, 51.85, 63.52, 70.06, 121.05, 121.87, 131.24, 134.51, 137.16, 138.57, 145.34, 145.73, 148.78, 158.55; ES-MS m/z 373 (M+H). Anal. Calcd. for C24H28N4.0.3 H2O: C, 76.28; H, 7.63; N, 14.83. Found: C, 76.14; H, 7.78; N, 14.82.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH:10]N=C1CCCCC1=O.OS(O)(=O)=O.[C:24]([O-:27])(O)=O.[Na+]>CC#N>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]2[C:4]=1[C:2]1[CH2:3][CH2:4][CH2:5][C:24](=[O:27])[C:7]=1[NH:10]2
Reactant: O=C([O-])O
Reactant: O=C1CCCCC1=NNc1cc(Cl)c(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCCc2c1[nH]c1c(Cl)cc(Cl)c(Cl)c21
Temperature: 80 °C
Yield: 35 %

Procedure:
2-(2-(2,4,5-Trichlorophenyl)hydrazono)cyclohexanone (0.3 g, 0.98 mmol) was dissolved in MeCN (6 mL) and H2SO4 (0.1 mL, 1.8 M solution) was added. The reaction mixture was heated to 80° C. for 4 h and slowly cooled to room temperature. Saturated NaHCO3 was added to the reaction mixture until pH 5-6 was obtained and then extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to obtain the crude compound which was purified by silica gel chromatography [EtOAc-hexane (1:4) as eluant] to furnish the title compound as a brown solid (0.1 g, 35%). 1H NMR (200 MHz, DMSO-d6, δ in ppm) 12.55 (bs, 1H), 7.68 (s, 1H), 3.27 (t, J=5.6 Hz, 2H), 2.63 (t, J=6.0 Hz, 2H), 2.19 (m, 2H).
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C@@:13]1([C:21]2[S:22][CH:23]=[C:24]([Br:26])[CH:25]=2)[CH2:18][CH2:17][O:16][CH2:15][C@H:14]1[CH2:19]O)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.Cl>[Br:26][C:24]1[CH:25]=[C:21]([C@@:13]23[N:12]=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[S:11][CH2:19][C@@H:14]2[CH2:15][O:16][CH2:17][CH2:18]3)[S:22][CH:23]=1
Reactant: O=C(NC(=S)N[C@@]1(c2cc(Br)cs2)CCOC[C@H]1CO)c1ccccc1
Agent: Cl
Solvent: CO
Product: O=C(NC1=N[C@@]2(c3cc(Br)cs3)CCOC[C@H]2CS1)c1ccccc1
Reaction time: 2 h

Procedure:
(±)-1-Benzoyl-3-[(3R*,4S*)-4-(4-bromo-thiophen-2-yl)-3-hydroxymethyl-tetrahydro-pyran-4-yl]thiourea (233 mg) was dissolved in methanol (5 mL). Several drops of concentrated hydrochloric acid were added, followed by stirring for two hours. The reaction solution was returned to room temperature and the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][NH:11][C@@H:10]1[C@H:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=1[CH3:26])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:36](Cl)(Cl)=[O:37].C1(C)C=CC=CC=1>C(Cl)Cl>[O:8]([C@@H:9]1[C@@H:10]2[N:11]([C:36](=[O:37])[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=3[CH3:26])[C@@H:14]2[CH3:15])[CH2:12][CH2:13]1)[Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: Cc1c(N[C@H](C)[C@H]2NCC[C@@H]2O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N2C(=O)N3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@H]2C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of crude 80F (˜0.068 mmol) in CH2Cl2 (2 mL) was added i-Pr2NEt (36 μL, 0.20 mmol) followed by 20% phosgene in toluene (50 μL, 0.1 mmol)-dropwise. The reaction was stirred at rt for 4 days and no desired product was formed. The solvent was removed and the residue was dissolved in 1,2-dichloroethane (2 mL) and treated with i-Pr2NEt (108 μL) at 80° C. for 3 h. Reaction was concentrated and the residue was purified by preparative TLC (30% EtOAc/hexane) to provide the title compound 80G (11 mg): MS (ES) m/z 420.5 [M+H]+; HRMS calcd for C21H31N3O2C1Si 420.1874, found 420.1870.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[BrH:19].BrBr>C(O)(=O)C>[Br:19][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:11]
Reactant: Br
Reactant: CSc1ccc(CC(=O)c2ccc(C)cc2)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: CSc1ccc(C(Br)C(=O)c2ccc(C)cc2)cc1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
A 500 mL round-bottomed flask equipped with a pressure-equalizing addition funnel and provisions for magnetic stirring was charged with 2-(4-methylthiophenyl)-1-(4-methylphenyl)ethanone from Step 2 (10.0 g, 39.0 mmol), 33% HBr in acetic acid (70 mL) and glacial acetic acid (100 mL). Over approximately 20 minutes, a solution of bromine in acetic acid (1M, 39 mL) was added to the suspension, and the reaction was held at room temperature for one hour. Any undissolved solids were removed by filtration, and the reaction was concentrated in vacuo, to a residue. The residue was dissolved in methylene chloride (100 mL), washed with 5% Na2S2O5 (2×100 mL), dried over MgSO4, filtered, and concentrated in vacuo to a colorless oil. The oil was held under vacuum for 16 hours, yielding 2-bromo-2-(4-methylthiophenyl)-1-(4-methylphenyl)ethanone (8.38 g, 64%) as a dirty white solid: mp 97°-98° C. 1H NMR (CDCl3) 300 MHz 7.86 (d, J=8.46 Hz, 2H), 7.80(d, J=8.26 Hz, 2H), 7.33-7.16(m, 4H), 5.88(s, 1H), 2.43(s, 3H), 2.36(s, 3H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:6][CH:5]=1.Cl.[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH2:38])[CH3:34]>>[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH:38][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([S:16](=[O:17])(=[O:18])[NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:30])([F:1])[F:31])=[CH:29][CH:28]=2)=[CH:27][CH:26]=1)[CH3:34]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(OC(F)(F)F)cc2)cc1
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared from 4-[2-(4-trifluoromethoxy-phenoxy)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride according to the method described in Example 1.1/d.
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)[CH:2]=1.[NH2:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CN>C1COCC1>[NH2:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([NH:3][CH3:2])=[O:17]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(F)cc1N
Reaction time: 3 h
Yield: 55.3 %

Procedure:
Carbonyl-1,1′-diimidazole (1.26 g) was added to 2-amino-4-fluorobenzoic acid (1.0 g) in THF (16.3 mL). After stirring overnight a solution of methylamine in THF (2M, 4.9 mL) was added and the reaction stirred for 3 hours. The reaction was concentrated in vacuo and the residue dissolved in EtOAc (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The phases were separated and the organics were washed with water (2×100 mL) and then saturated aqueous brine (30 mL). The organics were dried (MgSO4, 15 g), filtered and concentrated in vacuo to give crude product (0.9 g). This material was purified by column chromatography (SiO2, 40 g, eluent 3% MeOH in DCM) to give 2-amino-4-fluoro-N-methylbenzamide (0.6 g). 1H NMR spectrum (270 MHz, DMSO): 2.69 (d, 3H), 6.28 (ddd, 1H), 6.42 (dd, 1H), 6.74 (bs, 2H), 7.48 (dd, 1H), 8.16 (q, 1H); Mass spectrum: ESI+ MH+ 169.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[C:54]([Cl:59])[CH:55]=[CH:56][CH:57]=2)[N:52]=[C:51]([C:60]2[CH:65]=[C:64]([CH3:66])[CH:63]=[CH:62][N:61]=2)[C:50]=1[CH3:67].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:59][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[C:53]=1[N:52]=[C:51]([C:60]1[CH:65]=[C:64]([CH3:66])[CH:63]=[CH:62][N:61]=1)[C:50]([CH3:67])=[C:49]2[NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)[CH:42]=1
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1ccnc(-c2nc3c(Cl)cccc3c(Cl)c2C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3c(Cl)cccc3c(Nc3cncc(N4CCOCC4)c3)c2C)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.021 g, 0.044 mmol), 5-morpholinopyridin-3-amine (0.060 g, 0.33 mmol), 4,8-dichloro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (0.084 g, 0.28 mmol) and Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.067 g, 0.70 mmol) in toluene (2.8 mL) at 100° C. for 1.6 h. The crude product was purified by column chromatography on alumina (0 to 50% EtOAc in hexanes). The desired product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution, the solvent was removed under reduced pressure to yield pure product 8-chloro-3-methyl-2-(4-methylpyridin-2-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (1H, s), 8.57 (1H, d, J=4.9 Hz), 8.02 (1H, dd, J=8.6, 1.2 Hz), 7.92 (1H, dd, J=7.5, 1.1 Hz), 7.82 (1H, d, J=2.5 Hz), 7.77 (1H, s), 7.53-7.57 (1H, m), 7.52 (1H, m), 7.34-7.36 (1H, m), 6.57 (1H, t, J=2.3 Hz), 3.68-3.72 (4H, m), 3.05-3.09 (4H, m), 2.47 (3H, s), 2.22 (3H, s). Mass Spectrum (ESI) m/e=446.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:4][C:5]([NH:8][C:9]2[C:22]([O:23][CH3:24])=[CH:21][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][OH:20])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.C(OC([NH:45][C@H:46]([C:50](O)=[O:51])[CH:47]([CH3:49])[CH3:48])=O)(C)(C)C>>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32](=[O:34])(=[O:33])[N:35]([CH3:36])[CH3:37])=[N:4][C:5]([NH:8][C:9]2[C:22]([O:23][CH3:24])=[CH:21][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][C:50](=[O:51])[C@@H:46]([NH2:45])[CH:47]([CH3:49])[CH3:48])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CCO)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CCOC(=O)[C@@H](N)C(C)C)CC2
Yield: 45 %

Procedure:
In an analogous manner to Example 1542, the product was prepared from [A] 2-{5-Chloro-2-[3-(2-hydroxy-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide and N-(tert-Butoxycarbonyl)-L-valine. The product was isolated as a pale yellow foam (65 mg, 45%). 1H-NMR (CDCl3, 400 MHz) δ 9.36 (s, 1H), 8.55 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.58 (t, 1H), 7.51 (s, 1H), 7.26 (m, 1H), 6.67 (s, 1 h), 4.32-4.28 (m, 2H), 3.89 (s, 3H), 3.33 (d, J=5 Hz, 1H), 2.87 (m, 2H), 2.84 (m, 2H), 2.82-2.70 (m, 13H), 2.10 (m, 1H), 1.01 (d, J=7 Hz, 3H), 0.95 (d, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28](Cl)=[O:29].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: Cc1cccc(C)c1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: Cc1cccc(C)c1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 28.1 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2,6-dimethylbenzoyl chloride (0.143 mmol), the title compound (12 mg, yield 18%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](I)[CH3:23]>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:22][CH3:23])=[O:7])[CH3:2]
Reactant: CCOc1ccc(C(=O)O)c(OCC)n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC)nc1OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of the compound prepared in Example 294 (1.75 g) and cesium carbonate (2.70 g) in N,N-dimethylformamide (21 mL) was stirred at room temperature for 2 hours. Ethyl iodide (0.663 mL) was added and stirring continued at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue partitioned between a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated in vacuo to a yellow oil and purified by column chromatography on silica gel (10-50% ethyl acetate in hexane) to obtain the title compound (1.6 g) having the following physical data.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]2[S:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].I[CH3:19]>C1COCC1.CO>[CH3:19][NH:3][C:4]1[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:6][C:7]2[CH:12]=[CH:11][S:10][C:8]=2[N:9]=1
Reactant: CCOC(=O)c1nc2ccsc2nc1N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2ccsc2nc1NC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a stirred suspension of neat NaH (0.82 g, 3.40 mmol) in 10 ml THF at -78° C. was canulated a cold (-78° C.) 20 ml THF solution of ethyl 3-aminothieno[2,3-b]pyrazine-2-carboxylate (0.690 g, 3.09 mmol). The reaction mixture was allowed to warm to rt, stir for 2 h and was then treated with iodomethane (0.460 g, 3.24 mmol). After stirring for 12 h at rt, the mixture was diluted with 5 ml MeOH and concentrated. Purification by column chromatography on silica gel eluting first with 10:1 then 5:1 hexanes:ethyl acetate gave the title compound (0.610 g, 84%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ1.40 (t, 3H), 3.60 (d, 3H), 4.36 (q, 2H), 7.48 (br s, 2H), 8.54 (d, 1H), 8.57 (d, 1H). MS (DCI/NH3) m/e 238 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH:37]([N:40]1[CH2:45][CH2:44][N:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1)([CH3:39])[CH3:38]>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13]([N:49]1[CH2:48][CH2:47][CH:46]([N:43]2[CH2:42][CH2:41][N:40]([CH:37]([CH3:39])[CH3:38])[CH2:45][CH2:44]2)[CH2:51][CH2:50]1)=[O:14])[CH3:2]
Reactant: CC(C)N1CCN(C2CCNCC2)CC1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C(C)C)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 210 mg (0.99 mmol) 1-isopropyl-4-piperidin-4-yl-piperazine.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[Cl:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:16]O>>[Cl:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1Cl

Procedure:
Thionyl chloride (3.8 g.) was added dropwise, over 10 minutes, to a solution of 2-chloropyridin-3-carboxylic acid HCl salt (1.0 g.) in methanol, stirred under an inert atmosphere and cooled in an ice/salt bath. The reaction was stirred for a further 5 days at ambient temperature. The methanol was evaporated away and the residue treated with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were dried and evaporated to dryness to give methyl 2-chloropyridin-3-carboxylate as a colourless liquid (0.9 g.)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([N+:15]([O-])=O)[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO.CCOC(C)=O.O>[NH2:15][C:7]1[C:6]([OH:18])=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(N)c(O)c(C(C)(C)C)c1

Procedure:
A solution of 2,4-di-tert-butyl-6-nitro-phenol (27 mg, 0.11 mmol) and SnCl2.2H2O (121 mg, 0.54 mmol) in EtOH (1.0 mL) was heated in microwave oven at 100° C. for 30 min. The mixture was diluted with EtOAc and water, basified with sat. NaHCO3 and filtered through Celite. The organic layer was separated and dried over Na2SO4. Solvent was removed by evaporation to provide 6-amino-2,4-di-tert-butyl-phenol (C-8), which was used without further purification. HPLC ret. time 2.74 min, 10-99% CH3CN, 5 min run; ESI-MS 222.5 m/z (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15]>N1CCCCC1.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.[Cu]I>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])=[CH:3][CH:4]=1
Reactant: C#CCCO
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: OCCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
The synthesis was performed following a procedure of Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel, Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes, Collect. Czech. Chem. Commun. (1999), 64(4), 649-672. To a degassed (argon) solution of 5.0 g (17.83 mmol) 1-iodo-4-trifluoromethyl-benzene in 65 ml piperidine was added 1.03 g (0.89 mmol) Pd(PPh3)4 and 0.17 g (0.89 mmol) CuI. The reaction mixture was stirred at 50° C. for 10 min, then 2.03 ml (26.75 mmol) of but-3-yn-1-ol were added dropwise within 1 h. During the addition of but-3-yn-1-ol the oil bath was slowly heated to 80° C. starting after 30 min. The reaction mixture was stirred at this temperature for 3 h and then extracted with chilled aqueous 10% KHSO4/Et2O (three times). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (n-heptane/EtOAc 9:1 to 4:1) yielded 3.58 g of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C=Cc2ccc(F)cc2)c(C(=O)OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCc2ccc(F)cc2)c(C(=O)OC)c1
Reaction time: 6 h
Yield: 96.3 %

Procedure:
A mixture of methyl 4-[2-(4-fluorophenyl)ethenyl]-3-methoxycarbonylbenzoate (56.75 g, 180.6 mmol), ethyl acetate (900 ml), 10% palladium on carbon (6 g) was stirred under an hydrogen atmosphere for 6 hours. The catalyst was filtered and replaced with fresh catalyst (6 g). The reaction was then stirred under an hydrogen atmosphere for 16 hours. The catalyst was filtered and the filtrate evaporated to dryness to give as a colourless gum, methyl 4-(4-fluorophenethyl)-3-methoxycarbonylbenzoate (55.00 g).
Reaction SMILES: S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Mg+2].[Cl:12][C:13]1[C:14]([C:20]([OH:22])=[O:21])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1.[C:23](O)([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:12][C:13]1[C:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Reactant: CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1nc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
Concentrated sulfuric acid (0.441 ml; 8.27 mmol) was dropped into a suspension (35 ml) of 3.86 g (32.2 mmol) of magnesium sulfate in dichloromethane and, after completion of the dropping, the mixture was stirred at room temperature for 20 minutes. After that, 750 mg (3.91 mmol) of 3,6-dichloro-2-pyridinecarboxylic acid and dichloromethane (10 ml) solution of 3.84 ml (40.2 mmol) of tert-butyl alcohol were added to the reaction solution at room temperature followed by stirring rapidly at room temperature for 15 hours. Under ice-cooling, an aqueous solution (40 ml) of 3.0 g of sodium carbonate was dropped thereinto followed by stirring until the reaction solution became a homogeneous solution. The reaction solution was extracted with chloroform and the organic layer was washed with a saturated aqueous saline solution, dried and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=97:3) to give 644 mg (yield: 66%) of tert-butyl 3,6-dichloro-2-pyridinecarboxylate as a white solid.