Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.[Si]([O:15][CH2:16][CH2:17][N:18]([CH2:77][CH3:78])[CH2:19][CH2:20][C@@H:21]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41](=[O:69])[C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][CH:51]([C@H:54]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=4[C:62]4[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=4)[OH:55])[CH2:50][CH2:49]3)=[CH:44][CH:43]=2)(=[O:39])=[O:38])=[CH:33][C:32]=1[S:70]([C:73]([F:76])([F:75])[F:74])(=[O:72])=[O:71])[CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(C(C)(C)C)(C)C>C(Cl)Cl>[Cl:68][C:65]1[CH:66]=[CH:67][C:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[C@H:54]([OH:55])[CH:51]2[CH2:50][CH2:49][N:48]([C:45]3[CH:46]=[CH:47][C:42]([C:41]([NH:40][S:37]([C:34]4[CH:35]=[CH:36][C:31]([NH:30][C@H:21]([CH2:20][CH2:19][N:18]([CH2:77][CH3:78])[CH2:17][CH2:16][OH:15])[CH2:22][S:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[C:32]([S:70]([C:73]([F:74])([F:75])[F:76])(=[O:71])=[O:72])[CH:33]=4)(=[O:38])=[O:39])=[O:69])=[CH:43][CH:44]=3)[CH2:53][CH2:52]2)=[CH:63][CH:64]=1
Reactant: CCN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCN(CCO)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A solution of HCl in dioxane (4M, 11.18 ml, 44.70 mmol) was added slowly to a light yellow solution of N-(4-((R)-4-((2-(tert-butyldimethylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzamide (INTERMEDIATE 66, 2.4 g, 2.24 mmol) in DCM (11.2 ml) at 0° C. Once the addition was complete, the ice bath was removed. The resulting solution was allowed to warm to r.t. and stirred for 1 hour before being concentrated under reduced pressure to half volume and diluted with ethyl acetate. The resulting mixture was washed with sodium bicarbonate (saturated, aqueous) and sodium chloride (saturated, aqueous) before being dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, silica gel, 0→20% methanol in ethyl acetate for 30 min) to provide the title compound (1.64 g, yield: 76%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[S:44]1[CH:48]=[CH:47][C:46]([CH2:49][C:50](O)=[O:51])=[CH:45]1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:50](=[O:51])[CH2:49][C:46]3[CH:47]=[CH:48][S:44][CH:45]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1ccsc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccsc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3-thiopheneacetic acid (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-thiophen-3-yl-acetamide (0.7 g, 80%) as a white solid: mp 163-165° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.39 min. (99%); 1H NMR (DMSO-d6) δ 2.02-2.09 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.55 (s, 2H), 4.71 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.04-7.06 (m, 1H), 7.28-7.29 (m, 1H), 7.45-7.48 (m, 1H), 7.61-7.67 (m, 1H), 7.76-7.83 (m, 2H), 8.60 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ21.95, 30.90, 36.88, 37.83, 48.83, 121.87, 122.35, 125.76, 127.11, 128.67, 131.51, 133.18, 134.67, 135.82, 139.17, 166.91, 167.44, 169.78, 170.23, 172.73; Anal. Calcd. for C20H17N3O5S: C, 58.39; H, 4.16; N, 10.21; S, 7.79. Found: C, 58.37; H, 3.98; N, 10.05; S, 7.83.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[N:25]=[CH:24][NH:23][N:22]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:33])[NH:12][C:11]([C:21]2[N:25]=[CH:24][NH:23][N:22]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 45.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.82 g, 2 mmol) was reacted with NBS (0.39 g, 2.2 mmol) in chloroform (40 mL) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.44 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19]C)=[CH:16][CH:17]=2)[N:12]([CH3:21])[C:11]=1[CH3:22])=[O:9].B(Br)(Br)Br>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]([CH3:21])[C:11]=1[CH3:22])=[O:9]
Reactant: COc1ccc2c(C(=O)Nc3ccccn3)c(C)n(C)c2c1
Agent: BrB(Br)Br
Product: Cc1c(C(=O)Nc2ccccn2)c2ccc(O)cc2n1C

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indol-3-carboxylic acid pyridin-2-ylamide 69a by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (300 MHz, CD3OD) δ8.29 (1H, m), 8.24 (1H, d, J=8.3 Hz), 7.82 (1H, m), 7.64 (1H, d, J=8.7 Hz), 7.12 (1H, m), 6.82 (1H, d, J=2.2 Hz), 6.76 (1H, dd, J=2.2, 8.7 Hz), 3.66 (3H, s), 2.69 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 282, found 282.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:13])=[O:12])[CH:9]=2)[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:3]1.[S:42]1[CH:46]=[CH:45][N:44]=[C:43]1[NH2:47].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(Cl)Cl.CO.C(O)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([NH:47][C:43]3[S:42][CH:46]=[CH:45][N:44]=3)(=[O:12])=[O:13])[CH:9]=2)[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:3]1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A vial was charged with perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonate (Intermediate E) (32.98 mg, 0.055 mmol), thiazol-2-amine (7.14 mg, 0.071 mmol), and THF (0.4 mL) to give a clear solution. Lithium bis(trimethylsilyl)amide (1M in THF) (137 μl, 0.137 mmol) was added dropwise over 5 min, and the resulting solution was stirred overnight. In the morning, acetic acid (0.03 mL) was added, resulting in a viscous mixture. The mixture was diluted with DCM/MeOH, transferred to a flask, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0 to 5% MeOH/DCM) to give 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-1H-indole-6-sulfonamide (20.6 mg, 0.040 mmol, 72.6% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=7.96-7.83 (m, 3 H), 7.78-7.71 (m, 1 H), 7.60-7.43 (m, 2 H), 7.40 (d, J=1.9 Hz, 1 H), 7.21 (s, 1 H), 7.12 (s, 1 H), 6.79 (d, J=4.6 Hz, 1 H), 6.36 (s, 1 H), 3.80 (s, 3 H), 3.22 (s, 3 H). m/z (ESI) 518.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1C=[CH:8][C:7]([O:10]C)=[CH:6][C:3]=1C#N.[C:12]([OH:15])(=[O:14])[CH3:13]>Br.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:6][C:7]([OH:10])=[CH:8][C:13]=1[C:12]([OH:15])=[O:14]
Reactant: COc1ccc(F)c(C#N)c1
Reactant: CC(=O)O
Agent: Br
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(O)ccc1F

Procedure:
2-Fluoro-5-methoxybenzonitrile (3d, purchased from Alfa Aesar) (5 g, 33 mmol) was dissolved in hydrobromic acid (50 mL) and glacial acetic acid (30 mL), refluxed for 28 hours at 140° C., and then the reaction mixture was diluted with 100 mL ethyl acetate. The reaction mixture was then washed with 50 mL water and saturated sodium chloride solution successively for three times. The organic layers were combined and concentrated to give a crude product of 2-fluoro-5-hydroxybenzoic acid (3e), 2.88 g white solid (yield 56%). 1H NMR (600 MHz, DMSO-d6) δ 7.19-7.17 (m, 1H), 7.08-7.04 (m, 1H), 6.95-6.92 (m, 1H); ESI-MS m/z: calculated for 156.02. found 154.91 [M−H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=1[CH2:11][C:12]([N:14]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)[CH2:15][CH3:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=1[CH2:11][CH2:12][N:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=1)[CH2:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(CC)C(=O)Cc2ccccc2OCc2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N(CC)CCc2ccccc2OCc2ccccc2)cc1
Yield: 23 %

Procedure:
Ethyl 4-[N-(2-benzyloxybenzylcarbonyl)-N-ethylamino]benzoate (8.1 g) was dissolved in THF (20 ml) and IM borane tetrahydrofuran complex added. The reaction mixture was heated at reflux for 1 hour and cooled. 2N Hydrochloric acid (20 ml) was added. The volume of the reaction mixture was reduced to half the original by evaporation. Water (100 ml) was added and made basic (pH 8) by the addition of solid potassium carbonate and the mixture extracted with diethyl ether (3×30 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was purified by MPLC, eluting with 1:1 dichloromethane/hexane, to give ethyl 4-[N-(2-(2-benzyloxyphenyl)ethyl)-N-ethylamino]benzoate (1.8 g) m.p. 76° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.Br[C:26]1[N:34]2[C:29]([CH:30]=[N:31][C:32]([S:35][CH3:36])=[N:33]2)=[CH:28][CH:27]=1.[OH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:36][S:35][C:32]1[N:31]=[CH:30][C:29]2=[CH:28][CH:27]=[C:26]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[OH:37])[N:34]2[N:33]=1
Reactant: OB(O)c1ccccc1O
Reactant: CSc1ncc2ccc(Br)n2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc2ccc(-c3ccccc3O)n2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
Palladium Acetate (0.365 g, 0.00162 mol) and Triphenylphosphine (0.442 g, 0.00168 mol) were dissolved in Tetrahydrofuran (20 mL, 0.3 mol) and the mixture was stirred at room temperature for 10 minutes. 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (1.943 g, 0.007959 mol) was added and the reaction was stirred for another 10 minutes. 2-hydroxyphenyl boronic acid (3.09 g, 0.022 mol) was added followed by saturated sodium carbonate solution (7.6 mL) and Ethanol (20 mL, 0.4 mol;). The reaction mixture was heated at 80° C. for 2 days. Brine was poured into the reaction mixture and organics were extracted three times into ethyl acetate. Combined organic layers were dried over sodium sulfate, filtered, concentrated and purified by normal phase silica gel chromatography eluting with ethyl acetate/heptane to yield a yellow solid, 2-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenol (1.92 g, 94%). LCMS: m/z=258.02 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.97 (s, 1H), 7.87 (m, 1H), 7.22 (d, 1H, J=4.7 Hz), 7.12 (m, 1H), 7.05 (d, 1H, J=4.7 Hz), 7.01 (d, 1H, J=7.8 Hz), 6.93 (m, 1H), 2.47 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[F:10][CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][F:10])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: OCCF
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCCF)ccc1Br
Reaction time: 8 h

Procedure:
A solution of 4-bromo-3-methyl-phenol (3.74 g, 20 mmol), 2-fluoro-ethanol (2.29 mL, 22 mmol), and triphenylphosphine (5.77 g, 22 mmol) in dry THF (15 mL) was cooled to 0° C. under stirring. Diethyl azodicarboxylate (40% in toluene, 10 mL, 22 mmol) was added and the reaction mixture was allowed to come to RT overnight. After 18 h at RT the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase was extracted with more EtOAc. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by chromatography eluting with DCM/petroleum ether 1:6 to afford the title compound as colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17](Cl)=[O:18]>C(OCC)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12])=[O:18]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1O)c1ccc(Cl)c(Cl)c1

Procedure:
2-Amino-4-chloro-5-nitrophenol (34.0g, 0. 18 mole) was slurried in ethyl acetate (250 ml). 3,4-Dichlorobenzoyl chloride (38.g, 0.18 mole) was added and the reaction mixture refluxed for 2 h. After cooling, the beige precipitate was filtered then slurried in hot ethyl acetate (200 ml). Filtration gave the product as a beige solid, 50.5 g, (77%), mp.263-265° C.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]=[N:4][C:5]1[S:6][CH:7]=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11].[N+:14]([O-])([OH:16])=[O:15]>>[CH3:1][N:2]([CH3:13])[CH:3]=[N:4][C:5]1[S:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11]
Reactant: O=[N+]([O-])O
Reactant: CN(C)C=Nc1scc(Cl)c1C#N
Product: CN(C)C=Nc1sc([N+](=O)[O-])c(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
21.3 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-thien-2-yl)-formamidine are introduced into 100 parts of 100% strength nitric acid, while cooling with ice. The mixture is stirred for 1 hour at room temperature, after which the product is precipitated by pouring the mixture onto ice water, and the precipitate formed is filtered off under suction, washed with water and dried to give 18.8 parts (73% of theory) of N,N-dimethyl-N'-(4-chloro-3-cyano-5-nitrothien-2-yl)-formamidine. Decomposition temperature: 254° C. (from glacial acetic acid).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:14][C:15]1[S:16][C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=1>>[C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([NH:14][C:15]1[S:16][C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=1)=[O:12])(=[O:3])[CH3:1]
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Product: CC(=O)Oc1ccccc1C(=O)Nc1nnc(C(F)(F)F)s1
Yield: 51.1 %

Procedure:
Using O-acetylsalicyloyl chloride and 2-amino-5-(trifluoromethyl)-1,3,4-thiadiazole as the raw materials, the same operation as the Example 2(1) gave the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30](B(O)O)=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>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.CN(C=O)C>[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:2]3[CH:3]=[C:4]4[N:10]([O:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH:9]=[CH:8][C:5]4=[N:6][CH:7]=3)=[CH:31][CH:32]=2)[CH:27]=[CH:26]1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: Brc1cnc2ccn(Oc3ccccc3)c2c1
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: [K+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(-c3cnc4ccn(Oc5ccccc5)c4c3)ccc21

Procedure:
6-bromo-1-phenoxy-1H-pyrrolo[3,2-b]pyridine (56 mg, 0.205 mmol, 1.0 eq), Pd(PPh3)4 (13 mg), 2.0 M K2CO3 (1.0 ml), DMF (1.2 ml), and (1-methyl-1H-indol-5-yl)boronic acid (1.5 eq, 0.315 mmol) were refluxed under N2 overnight. The crude products were purified with preparation HPLC to give the product in 50%.
Reaction SMILES: C([S:4][C@H:5]1[CH2:9][C@@H:8]([CH2:10][C:11]2[S:15][C:14]3=[CH:16][N:17]=[C:18]([CH3:19])[N:13]3[CH:12]=2)[N:7]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:6]1)(=O)C.C1(OP(O[C:43]2[C@H:44]([CH3:60])[C@@H:45]3[C@@H:55]([C@H:56]([OH:58])[CH3:57])[C:54](=[O:59])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][CH:52]=[CH2:53])=[O:49])(OC2C=CC=CC=2)=O)C=CC=CC=1>>[CH2:23]([O:22][C:20]([N:7]1[C@H:8]([CH2:10][C:11]2[S:15][C:14]3=[CH:16][N:17]=[C:18]([CH3:19])[N:13]3[CH:12]=2)[CH2:9][C@H:5]([S:4][C:43]2[C@H:44]([CH3:60])[C@@H:45]3[C@@H:55]([C@H:56]([OH:58])[CH3:57])[C:54](=[O:59])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][CH:52]=[CH2:53])=[O:49])[CH2:6]1)=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cc1cn2c(C)ncc2s1
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4c(C)ncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 53.5 %

Procedure:
The procedure of Example 23-a) is repeated to prepare 653.0 mg of a mercaptan compound as a yellow oil from 766.4 mg of (3S,5S)-3-acetylthio-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine described in Synthesis Example 11. Allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (560.2 mg) is prepared as a colorless amorphous material from this mercaptan and 891.6 mg of allyl(1R,5R,6S)-2-(diphenylphosphono)oxy-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate.
Reaction SMILES: [CH:1]([N:14]=[C:15]=[S:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][NH2:18]>CCOCC>[CH:1]([NH:14][C:15]([NH:18][CH3:17])=[S:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: S=C=NC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CNC(=S)NC(c1ccccc1)c1ccccc1

Procedure:
A solution of 13.50 g (0.06 Mole) of benzhydrylisothiocyanate in ether is saturated with anhydrous methylamine in an ice bath. The crystals are filtered to yield the product, N-benzhydryl-N'-methylthiourea; mp 152°-154° C, which is sufficiently pure for the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[C:4]([CH3:14])[CH:3]=1.[O-:15][CH2:16][CH3:17].[Na+]>>[CH2:16]([O:15][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[C:4]([CH3:14])[CH:3]=1)[CH3:17]
Reactant: CC[O-]
Reactant: CCOC(=O)Nc1nnc(Cl)cc1C
Agent: [Na+]
Product: CCOC(=O)Nc1nnc(OCC)cc1C
Temperature: 110 °C
Yield: 69.3 %

Procedure:
A 20 mL microwavable vial was charged with ethyl (6-chloro-4-methylpyridazin-3-yl)carbamate (550 mg, 2.55 mmol) and sodium ethoxide (3.11 mL, 17.85 mmol), then stirred and heated at 110° C. for 12 h. The reaction mixture was then concentrated and partitioned between ammonium chloride and DCM. The layers were separated and the aqueous layers were washed with DCM (2×). The combined organic layers were washed with water, brine, and eluted through a phase separator. The organic layers were concentrated to afford ethyl (6-ethoxy-4-methylpyridazin-3-yl)carbamate (398 mg, 65.8% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:9][C:5]1[N:4]=[C:3]([CH2:2][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=3)[CH:19]=[CH:18]2)[CH:8]=[CH:7][CH:6]=1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(CBr)n1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: Cc1cccc(Cn2ccc3ccc(CC(=O)O)cc32)n1

Procedure:
The titled compound (26 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2-(bromomethyl)-6-methylpyridine according to the method of the process (7) of Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCOCC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CCOCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.57 g (3.32 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoate (racemate) in 25 ml of dichloromethane and 5.12 ml (66.4 mmol) of TFA were reacted according to General Method 6A. Yield: 1.60 g (quant.)
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][C:23]=1[O:30][CH3:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45](O)=[O:46])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45](=[O:46])[NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:23]([O:30][CH3:31])[CH:24]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: COc1cc(CN)ccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.5 g) was added to a mixture of 4-benzyloxy-3-methoxy benzylamine hydrochloride (14.0 g), 1-(t-butoxycarbonyl)-piperidine-4-carboxylic acid (11.5 g), triethylamine (14.0 ml) and methylene chloride (300 ml). After stirring the reaction mixture at room temperature for 20 hours, the mixture was washed with saturated ammonium chloride aqueous solution and then saturated brine, the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane/ethyl acetate=100/0 to 0/100 gradient) to obtain 16.3 g of t-butyl-4-(4-benzyloxy-3-methoxybenzylcarbamoyl)-piperidine-1-carboxylate.