Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[O:19]1[CH2:23][CH2:22][C:21](=O)[CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[O:19]1[CH2:23][CH2:22][CH:21]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:4][CH2:3]2)[CH2:20]1
Reactant: O=C1CCOC1
Reactant: N[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(N[C@H]1CC[C@H](NC2CCOC2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of benzyl trans-4-aminocyclohexylcarbamate (396 mg, 1.595 mmol) in CH2Cl2 (9 ml) was added dihydrofuran-3(2H)-one (151 mg, 1.754 mmol) followed by acetic acid (150 μL, 2.62 mmol) and sodium triacetoxyborohydride (439 mg, 2.073 mmol) under Argon. Stirred at 25° C. for 16 h, then concentrated in vacuo. The resulting residue was partitioned between EtOAc and 1M NaOH. The organics were combined, then washed with 1M NaOH (×2), water (×2), saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure to give racemic benzyl trans-4-(tetrahydrofuran-3-yl-amino)cyclohexylcarbamate (495 mg). The resulting residue was used in next step without further purification.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.N1C=CN=C1.[C:13]([Si:17](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)([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[Si:17]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1C=CCCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1C=CCCC1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 5.0 g of 2-cyclohexen-1-ol, 7.6 g of imidazole and 14.6 ml of tert-butylchlorodiphenylsilane in 100 ml of N,N-dimethylformamide was stirred at room temperature for 16 hrs. The mixture was then partitioned between 100 ml of saturated brine and 250 ml of ether. The layers were separated and the organic layer was washed with 100 ml of water and dried over magnesium sulfate and the solvent was evaporated in vacuo to give 3-(tert-butyldiphenylsilyloxy)cyclohexene as a viscous oil which was used without further purification. 1H NMR (CDCl3) δ 1.05 (s, 9H); 4.10 (m, 1H); 5.50 (br s, 2H); 7.20-7.70 (m, 10H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]([SH:13])[CH3:12]>>[CH:11]([S:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([CH3:12])[CH3:10]
Reactant: CC(C)S
Reactant: N#Cc1ccc(F)cc1
Product: CC(C)Sc1ccc(C#N)cc1

Procedure:
2 g of 4-fluorobenzonitrile was used in Procedure Q with 2-propanethiol to afford 4-(isopropylthio)benzonitrile. 900 mg of 4-(isopropythio)benzonitrile was reacted via Procedure T to give 4-(isopropylthio)benzoic acid. 730 mg of 4-(isopropylthio)benzoic acid was reacted via Procedure R to give 4-(isopropylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(isopropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonyl)benzamide. MS (Q1) 415.0 (M)
Reaction SMILES: [F-].[Cs+].[Br:3][C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1.[F:11][C:12]([Si](C)(C)C)([F:14])[F:13]>COCCOC>[Br:3][C:4]1[S:8][C:7]([CH:9]([OH:10])[C:12]([F:14])([F:13])[F:11])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: OC(c1ccc(Br)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
CsF (400 mg, 2.6 mmol) was added to a solution of 5-bromothiophene-2-carbaldehyde (5.0 g, 26.17 mmol) in dry 1,2-dimethoxyethane (20 mL), followed by trifluoromethyl trimethylsilane (4.6 mL, 31.4 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 3 h, quenched with 1.5N HCl, and stirred for an additional 30 min. The crude product was extracted with CH2Cl2. The combined extracts were dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 5-10% EtOAc in petroleum ether) to get 1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethanol (4 g, yield 59%). 1H NMR (400 MHz, CDCl3) δ 7.01 (m, 1H), 6.95 (m, 1H), 5.23-5.18 (q, J=5.9 Hz, 1H), 3.07 (br s, 1H). MS (ESI) m/z: Calculated for C6H4BrF3OS: 261.91. found: 260.7 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([NH:12]C(OCC1C=CC=CC=1)=O)(=[O:11])=[O:10])[CH2:5][CH2:6][CH3:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([NH2:12])(=[O:10])=[O:11])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(NS(=O)(=O)NC(=O)OCc1ccccc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCC(NS(N)(=O)=O)C(=O)OC
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 2-(N-carbobenzyloxyaminosulfonyl) aminopentanoic acid methyl ester (33 g) in methanol (250 ml) under nitrogen was cooled to 0° C. and 1.4 g of 10% Pd/C was added. The mixture was placed into a Parr Apparatus and hydrogenated for 2 hours. The catalyst was removed on a pad of CELITE® and the filtrate was concentrated in vacuo and purified by flash silica gel chromatography (50% ethyl acetate in hexane) to afford 13.5 g (76%) of 2-(aminosulfonylamino)pentanoic acid methyl ester (Formula VII: R=CH3 ; R1 =H; R2 =propyl; R3 =H) as a solid, m.p. 63°-64° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[C:12](C)C=C(C)N=2)[CH:7]=1.O=C1NC=C(C2C=C(C)C=C(C)N=2)C=[C:19]1[C:20]([NH2:22])=O>>[NH2:1][C:2]1[C:3](=[O:16])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:22]=[CH:20][CH:19]=2)[CH:7]=1
Reactant: Cc1cc(C)nc(-c2c[nH]c(=O)c(C(N)=O)c2)c1
Reactant: Cc1cc(C)nc(-c2c[nH]c(=O)c(N)c2)c1
Product: Nc1cc(-c2ccncc2)c[nH]c1=O

Procedure:
F-7. 3-Amino-5-(4,6-dimethyl-2-pyridinyl)-2(1H)-pyridinone using 1,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinamide.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[C:12](Cl)=[O:13])=[CH:3]1.Cl.C([O:20][C:21](=[NH:34])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[N:25]([CH3:33])[CH:24]=1)(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:33][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[C:23]([C:22]2[C:21](=[O:34])[NH:20][C:12](=[O:13])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:24]1
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccccc21
Reactant: Cc1ccc2c(CC(=N)OC(C)C)cn(C)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)cn(C)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of the known (1-methyl-1H-indol-3-yl)-oxo-acetyl chloride (183 mg, 0.83 mm) and 2-(1,6-dimethyl-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride (233 mg, 0.83 mm) in CH2Cl2 (6 mL) which had been cooled to 0° C., was added Et3N (0.46 mL, 3.3 mm). The reaction was allowed to warm to room temperature overnight, then diluted with CH2Cl2 (20 mL), and extracted with H2O(15 mL) and 0.5N HCl(15 mL). The organic fraction was dried over MgSO4, filtered and evaporated, and the residue combined with toluene (3 mL). After cooling to 0° C., para-toluene sulfonic acid (pTsOH) (174 mg, 0.91 mm) was added, and the mixture was stirred at room temperature for 3 hours. The red solids which precipitated were collected and partitioned between CH2Cl2 (50 mL) and H2O(25 mL). The organic fraction was washed with saturated NaHCO3 (25 mL) solution, then dried over MgSO4, filtered and evaporated. The residue was washed with cold CH2Cl2 to yield 3-(1,6-dimethyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3yl)-pyrrole-2,5-dione; mp=264°-266° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Si:12]([O:19][CH2:20][CH2:21][CH2:22][OH:23])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].CCOCC>ClCCl>[Si:12]([O:19][CH2:20][CH2:21][CH:22]=[O:23])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCC=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.5 %

Procedure:
To a suspension of pyridinium chlorochromate (8.50 g, 39.4 mmol) in dichloromethane (53 ml), stirred at room temperature under dry nitrogen, was added 3-(t-butyldimethylsilyloxy)propan-1-ol (5.00 g, 26.3 mmol). After 1.5 hr, dry ether (50 ml) was added and the supernatant liquid decanted from a black gum. The residual gum was washed with ether (3×50 ml) and the combined organic portions passed through a column of Florisil. The resulting brown solution was evaporated then the residue taken up in dichloromethane and passed through fresh Florisil to give a yellow solution from which the solvent was removed to leave a brown liquid (2.75 g). This material was shown by 1Hnmr analysis to be approximately 40% pure and was used without further purification; δH (CDCl3) 0.10 (6H, s, CH3), 0.93 (9H, s, C(CH3)3), 0.63 (2H, dt, J 2 HZ and 6 Hz respectively, CH2), 4.03 (2H, t, J 6 Hz, CH2O ), 9.97 (1H, d, J 2 Hz, CHO).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH:5]=[O:6].[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5][OH:6]
Reactant: CN(C)S(=O)(=O)c1ccc(C=O)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
To a solution of OBS02001 (6.0 g, 19.47 mmol) in anhydrous THF (50 mL) was added sodium borohydride (0.81 g, 21.42 mmol). The mixture was stirred at room temperature for 4 h, quenched with water (CARE!!) and filtered through a Celite pad. The filtrate was concentrated in vacuo and re-dissolved in DCM (200 mL). The organic layer was washed with brine (2×200 mL), dried (Na2SO4) and filtered. Concentration in vacuo of the filtrates gave OBS02002 as a pale yellow oil (5.54 g, 92%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.47; 1H-NMR (270 MHz, CDCl3)=2.97 (6H, s), 3.14 (1H, bs, OH), 4.51 (2H, s), 7.19 (1H, dd, J=1.5, 8.1), 7.37 (1H, d, J=8.4), 7.52 (1H, d, J=1.8). 3-Bromo-4-(N,N-dimethylsulfamoyl)benzyl chloride (OBS02003)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[C:30]([NH:32][CH3:33])[C:29]([NH2:34])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.[CH3:44][O:45][C:46]([CH:48]1[CH2:50][CH:49]1[C:51](O)=O)=[O:47]>CN(C=O)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]2[N:34]=[C:51]([CH:49]3[CH2:50][CH:48]3[C:46]([O:45][CH3:44])=[O:47])[N:32]([CH3:33])[C:30]=2[CH:31]=1
Reactant: CNc1cc(Br)ccc1N
Reactant: COC(=O)C1CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CC1c1nc2ccc(Br)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
HATU (554 mg) was added to a solution of 5-bromo-N1-methylbenzene-1,2-diamine (279 mg), N,N-diisopropylethylamine (0.727 ml) and (1RS,2SR)-2-(methoxycarbonyl)cyclopropanecarboxylic acid (200 mg) in DMF (5 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (5 ml), and the mixture was stirred at 80° C. for 1 h. After concentration of the mixture, the residue was neutralized with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/EtOAc) to give the title compound (80 mg) as an off-white solid.
Reaction SMILES: [S:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14](F)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([O:10][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[CH:2][S:1][C:9]2=3)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: OC1CNCc2ccsc21
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(OC2CNCc3ccsc32)cc1Cl

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 13) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: CCOc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-ethoxybenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-ethoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])[CH:32]=O)[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:44][CH:43]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([C@@H:31]([CH3:32])[CH2:34][N:52]6[CH2:53][CH2:54][CH:49]([O:48][C:45]7[CH:46]=[CH:47][C:42]([Cl:41])=[CH:43][CH:44]=7)[CH2:50][CH2:51]6)[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C=O)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H]([C@@H](C)CN3CCC(Oc4ccc(Cl)cc4)CC3)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 33.6 %

Procedure:
To a solution of (1S,2R,4aS,5R,8R,8aR)-2-(acetyloxy)-8a-hydroxy-3,8-dimethyl-5-[1-methyl-2-oxoethyl]-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 141, 60 mg, 0.11 mmol) and 4-[(4-chlorophenyl)oxy]piperidine (Preparation 200, 25 mg, 0.1 mmol) was added dichloromethane (2 ml) and sodium triacetoxyborohydride (35 mg, 0.16 mmol), followed by triethylamine (0.02 ml, 0.17 mmol). The reaction mixture was stirred at room temperature for 17 h, before diluting with dichloromethane (5 ml) and saturated aqueous sodium hydrogen carbonate (3 ml). The reaction mixture was shaken vigorously and the layers were separated using a hydrophobic filter cartridge. The filtrate was concentrated under a stream of nitrogen and purified to give the title compound (26 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[C:9]2[NH:10][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:12][C:8]=2[CH:7]=[CH:6]1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>ClC(Cl)C>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([C:6]2[S:5][C:9]3[NH:10][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:12][C:8]=3[CH:7]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc2ccsc2[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc2cc(C(=O)c3ccc(Cl)cc3)sc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
Under a N2 atmosphere and at 0° C., to a 40-mL scintillation vial fitted with a magnetic stir bar was added solid aluminum chloride (0.7 g 5.28 mmol) and a solution of ethyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (0.61 g, 3.14 mmol, 0.9 equiv) in solution in 10 mL dichloroethane (DCE). 4-Chlorobenzoyl chloride (0.92 g, 5.28 mmol) was then added at 0° C. and stirring was continued for 2 h as the reaction was allowed to warm to rt. The reaction was cooled and was added to an ice-filled beaker. The aqueous mixture was extracted ×3 with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resulting residue was purified via ISCO Companion (0-30% gradient EtOAc/heptane over 30 min) to give ethyl 2-(4-chlorobenzoyl)-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.34 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.13 Hz, 3H) 4.43 (q, J=7.13 Hz, 2H) 7.17 (d, J=1.81 Hz, 1H) 7.50 (d, J=8.44 Hz, 2H) 7.59 (s, 1H) 7.77-7.86 (m, 2H) 10.03 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:23])([F:14])[F:24])=[CH:21][N:20]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccc(C(F)(F)F)cn1
Product: O=C(Nc1ccc(C(F)(F)F)cn1)c1ccc(F)c([N+](=O)[O-])c1
Yield: 100 %

Procedure:
The product from Example 172a was reacted with 5-trifluoromethyl-pyridin-2-ylamine (239 mg, 1.474 mmol) according to the procedure from Example 172b to provide the title compound (485 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.O.[NH2:33][NH2:34]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:34][N:33]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]4)=[CH:14][CH:13]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(C(=O)CC(=O)c3ccc(Cl)cc3)cc2)C1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(-c3cc(-c4ccc(Cl)cc4)[nH]n3)cc2)C1
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of tert-butyl 2-(4-(3-(4-chlorophenyl)-3-oxopropanoyl)phenyl)morpholine-4-carboxylate (210 mg, 0.473 mmol) and hydrazine hydrate (35.5 mg, 0.70 mmol) in ethanol (3.5 ml) was heated to reflux with stirring overnight. The clear yellow solution was evaporated under reduced pressure, water was added and ethyl acetate. The organic layer was separated, the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (10 g silica gel, 10 to 50% ethyl acetate in heptane) to yield a white solid (208 mg, 89%). MS (ISP neg): 438.3 ([{35Cl}M−H]+), 440.4 ([{37Cl}M−H]+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]4[CH2:17][CH:16]5[C:18]6([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]6)[CH:13]([CH2:14][CH2:15]5)[CH2:12][C:11]=4[CH:30]=3)=[N:4][CH:3]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Product: COc1ccc(-c2cnc(-c3ccc4c(c3)CC3CCC(C4)C34CN(CC(F)(F)F)S(=O)(=O)N4)s2)cc1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 4-methoxybenzeneboronic acid by the method described for Example 36 Step 3. MS (ES+) 550 ([MH]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=1.[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[S:31](Cl)(=[O:33])=[O:32]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:19][CH:20]=2)[S:31]([C:27]2[S:26][CH:30]=[CH:29][N:28]=2)(=[O:33])=[O:32])[CH:7]=1
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(C(C)(C)C)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(C(C)(C)C)cc2)S(=O)(=O)c2nccs2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 1 from 3-{3-[(4-tert-butyl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 12s, and thiazole-2-sulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, 1H), 7.56 (d, 1H), 7.23 (d, 2H), 7.14 (m, 1H), 7.04 (m, 3H), 6.98 (m, 2H), 4.47 (s, 2H), 4.41 (s, 2H), 3.67 (s, 3H), 2.84 (t, 2H), 2.54 (t, 2H), 1.27 (s, 9H); MS 487 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](B3OC(C)(C)C(C)(C)O3)[CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[N:41]=[C:42](Cl)[S:43][CH:44]=2)=[O:39])[CH3:36])[CH:26]=[C:27]([F:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:34][C:27]1[CH:26]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[N:41]=[C:42]([C:6]3[CH:7]=[C:8]([CH:10]4[CH2:11][CH2:12]4)[CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=3)[S:43][CH:44]=2)=[O:39])[CH3:36])[CH:24]=[C:23]([F:22])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC(NC(=O)c1csc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC1(C)OB(c2cc(C3CC3)cc(C3CC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1csc(-c2cc(C3CC3)cc(C3CC3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 16.3 %

Procedure:
2-(3,5-Dicyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (74 mg, 0.26 mmol) and 2-chloro-thiazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (110 mg, 0.26 mmol) was reacted using Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cs2CO3 (254 mg, 0.78 mmol) as described above to give the title compound (22 mg, 16%) after purification by flash chromatography on silica gel (% EtOAc′ in hexane=30%˜70%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCCCO1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(2-bromoethyl)tetrahydro-2H-pyran.