Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7].C1(C2C=CC=CC=2)C=CC(S([Cl:19])(=O)=O)=CC=1>>[Cl:19][C:5]1[S:1][C:2]([S:6]([NH2:9])(=[O:8])=[O:7])=[CH:3][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NS(=O)(=O)c1cccs1
Product: NS(=O)(=O)c1ccc(Cl)s1

Procedure:
5.2.4 5-chlorothiophene-2-sulfonamide was prepared according to the procedure for thiophene-2-sulfonamide YG1-030 except using 4-biphenylsulfonyl chloride, which afforded the title compound 932.5 mg (94.4%) as a white solid, m.p.: 110-112° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])=[N:6][CH:7]=1.[CH2:14](N(CC)CC)[CH3:15].C(#N)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[CH:14]([C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])=[N:6][CH:7]=1)=[CH2:15]
Reactant: CCN(CC)CC
Reactant: CC(C)C(=O)Nc1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCOCC
Product: C=Cc1cnc(NC(=O)C(C)C)nc1
Temperature: 80 °C

Procedure:
A glass-lined pressure vessel was charged with 4.85 g of 5-bromo-2-(isobutyramido)pyrimidine, 5.0 ml of triethylamine, 15 ml of acetonitrile, 245 mg of tris(O-tolyl)phosphine, and 55 mg of palladium acetate. The vessel was placed under an ethylene atmosphere at 200 psi and heated at 80° C. for 18 hours in a rocking autoclave. The vessel was cooled and then vented. The residue was treated with 50 ml of ether and the resulting mixture filtered. The solid was further washed with ether (2×25 ml). The organic filtrate was concentrated and then chromatographed on silica gel. Elution with methylene chloride:methanol (95:5) afforded 2.99 g of product, mp 110°-112° C.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][C:8]2[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=2)[N:12]=1)=[O:28]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(F)cc3Cl)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=410.03.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[NH:18][C:19](=[O:24])[CH2:20][N:21]([CH3:23])[CH3:22].C(N(CC)CC)C.[C:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])#[CH:33]>ClCCl.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.[Cu]I>[CH3:22][N:21]([CH3:23])[CH2:20][C:19]([NH:18][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:33]#[C:32][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:3]=2)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=1)=[O:24]
Reactant: C#C[Si](C)(C)C
Reactant: CN(C)CC(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(Br)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(C#C[Si](C)(C)C)cc12
Temperature: 60 °C

Procedure:
To a mixture of Example 282C (2.56 g, 6.44 mmol), bis(triphenylphosphine)palladium(II) chloride (0.225 g, 0.321 mmol), and copper(I) iodide (0.073 g, 0.383 mmol) was added triethylamine (20 mL, 144 mmol) followed by ethynyltrimethylsilane (0.760 g, 7.73 mmol). The reaction mixture was heated at about 60° C. for about 3 hours. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate in dichloromethane (10%) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (s, 1H), 8.08 (s, 1H), 8.04 (d, 1H, J=9.0), 7.62 (d, 1H, J=8.8), 3.21 (s, 2H), 2.30 (s, 6H), 1.61 (s, 9H), 0.23 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:5]([CH3:20])=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1.[CH2:21]([O:23][C:24]([C:26]([CH3:40])([O:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1)[C:32]([OH:34])=O)[CH3:27])=[O:25])[CH3:22].OC1C=C(C=C(OC)C=1)C=O.C(CC(Br)(C)C([O-])=O)C.Cl([O-])=O.[Na+]>>[CH2:21]([O:23][C:24](=[O:25])[C:26]([O:28][C:29]1[CH:30]=[C:31]([C:32](=[O:34])[N:2]([CH3:1])[CH2:3][C:4]2[C:5]([CH3:20])=[N:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1)([CH3:27])[CH3:40])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)O)c1
Reactant: CNCc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: COc1cc(O)cc(C=O)c1
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1

Procedure:
A] In analogy to the procedures described in example 26B] and 26C], methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-amine (example 123D]) was reacted with 3-(1-ethoxycarbonyl-1-methyl-ethoxy)-5-methoxy-benzoic acid (prepared from 3-hydroxy-5-methoxy-benzaldehyde [Journal of Organic Chemistry (1985), 50(13), 2236–40], by reaction with ethyl-bromoisobutyrate followed by oxidation with sodium chlorite in analogy to the procedures described in examples 52A] and 59A]) to give 2-(3-methoxy-5-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-carbamoyl}-phenoxy)-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[CH2:14][CH2:15][CH2:16][OH:17].[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:14][CH2:15][CH2:16][OH:17])[CH:6]=[CH:5]2
Reactant: OCCCBr
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCCCOc1ccc2cc(Br)ccc2c1
Yield: 40 %

Procedure:
mixture of 6-bromo-2-naphthol (10.0 g), 3-bromopropanol (9.4 g) and potassium hydroxide (3.0 g) in 50 ml of ethanol was refluxed for 16 h. The mixture was washed with diethyl ether and water. The combined organic layers were dried, filtered, and concentrated. The crude product was crystallized from ethanol to give 6-bromo-2-(3-hydroxypropyloxy)-naphthalene in 40% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[C@@H:7]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:11]([CH2:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=3[Cl:32])=[CH:16][CH:15]=1)[CH2:10][N:9]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:8]2)=[O:5])C.[OH-].[Na+]>CCO>[C:44]([O:43][C:41]([N:9]1[CH2:8][C@H:7]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:11]([CH:12]=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]4[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=4[Cl:32])=[CH:18][CH:19]=3)[CH:6]2[C:4]([OH:5])=[O:3])[CH2:10]1)=[O:42])([CH3:45])([CH3:46])[CH3:47]
Reactant: CCOC(=O)C1=C(c2ccc(CCCOc3c(F)ccc(F)c3Cl)cc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H]2C=C(c3ccc(CCCOc4c(F)ccc(F)c4Cl)cc3)C(C(=O)O)[C@@H](C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
In a 250 mL round-bottom flask equipped with a magnetic stirrer is dissolved compound A1 (4.72 g, 6.97 mmol) in EtOH (100 mL). To this is then added aq. 1M NaOH (50 mL), and the resulting colorless sol. is heated to 80° C. for 14 h. The resulting pale pink sol. is allowed to cool to rt, and carefully acidified to a pH of 1.5. The volatiles are removed in vacuo and the resulting residue is partitioned between EtOAc (300 mL) and water (300 mL). The aq. phase is separated and back-extracted with EtOAc (3×300 mL). The combined org. extracts are then washed with brine (500 mL), decolorized with activated charcoal and dried over MgSO4. Filtration through a bed of Celite and concentration of the colorless filtrate in vacuo affords a white froth. Separation of (rac.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester [1.01 g, 22%; Rf=0.55 (1:1 Hex:EtOAc+1% AcOH)] and the title compound (2.77 g, 61%) can be achieved by way of FC (SiO2, 2:1 hexane:EtOAc+1% AcOH). Residual AcOH can be removed quantitatively by first azeotroping with heptane and then toluene. Rf=0.50 (1:1 Hex:EtOAc+1% AcOH); ES−=646.8.
Reaction SMILES: O[NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)=[NH:4]>C(O)(=O)C.[Pd]>[C:13]([OH:15])(=[O:14])[CH3:12].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:9][CH:10]=1)(=[NH:2])[NH2:4]
Reactant: N=C(NO)c1ccc(CC(C(=O)O)c2cccc(C(F)(F)F)c2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc(CC(C(=O)O)c2cccc(C(F)(F)F)c2)cc1
Reaction time: 48 h
Yield: 130.7 %

Procedure:
3-[4-(N-Hydroxycarbamimidoyl)-phenyl]-2-(3-trifluoromethyl-phenyl)-propionic acid (680 mg, 1.93 mmol) was hydrogenated in acetic acid (50 ml) using palladium/charcoal (10%) as the catalyst. After two days, the catalyst was filtered off and the solvent evaporated in vacuo to give 500 mg of the desired product (65%). MS m/z: 337.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:15]([OH:19])[C:16]([OH:18])=O)=[O:12])=[CH:5]2.[NH:27]1[CH2:31][CH:30]=[CH:29][CH2:28]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:15]([OH:19])[C:16]([N:27]1[CH2:31][CH:30]=[CH:29][CH2:28]1)=[O:18])=[O:12])=[CH:5]2
Reactant: C1=CCNC1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)N1CC=CC1)c1cc2cc(Cl)ccc2[nH]1
Temperature: 20 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
A 5.00 g (0.0134 mmol) sample of (αR,βS)-β-[[(5-chloro-1H-indol-2-yl)carbonyl]amino]-α-hydroxy-benzenebutanoic acid (Ia) (prepared according to the methods disclosed in the aforementioned U.S. Pat. Nos. 6,107,329, 6,277,877, and 6,297,269) and 3-pyrroline (1.11 g, 0.015 mmol) (Aldrich Chemical Co., Milwaukee, Wis.) were slurried in 100 ml of tetrahydrofuran at a temperature of between 20° and 25° C. The mixture was treated with 0.6 g (0.33 equiv.) of 1-hydroxybenzotriazole hydrate (HOBT) and the mixture was cooled to between 0° and 5° C. N,N-diisopropylethylamine (2.08 ml, 2.1 equiv.) was added to the mixture over 15 minutes at 0° to 5° C. The mixture was then treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (2.78 g, 1.1 equiv.) at −10° to −6° C. The reaction was allowed to warm to about 20° C. and was stirred at ambient temperature for about 24 hours. The reaction mixture was treated with water (50 ml) and ethyl acetate (50 ml) to give a two-phase mixture. The layers were settled and the organic layer was separated and concentrated to furnish a solid by distillation under partial vacuum. A total of 5.1 g (92.7% yield) of the pure title product was isolated.
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15](F)([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.O[C@@]1([C@]2(C)[C@H]([C@H]3C(=CC2)[C@]2(C)C(=CC(=O)C=C2)CC3)CC1=C)C(=O)C>>[O:26]1[C@@H:16]2[C@:15]31[C@H:5]([C@H:4]1[C@:18]([CH3:25])([CH2:17]2)[C@@:19]([OH:24])([C:20](=[O:21])[CH2:22][OH:23])[C@H:2]([CH3:1])[CH2:3]1)[CH2:6][CH2:7][C:8]1[C@:14]3([CH3:28])[CH:13]=[CH:12][C:10](=[O:11])[CH:9]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@]1(O)C(C)=O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(O)C(=O)CO

Procedure:
Dexamethasone (9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione) can also be prepared from 17β-hydroxy-16-methylenepregna-1,4,9(11)-triene-3,20-dione by first transforming it to 17α,21-dihydroxy-16-methylenepregna-1,4,9(11)-triene-3,20-dione 21-acetate as described above and next transforming it to 17α,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione 21-acetate by the process of U.S. Pat. No. 3,130,209. 17α,21-Dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione 21-acetate is then epoxidized by means well known to those skilled in the art, see for example U.S. Pat. No. 3,980,778, Examples 2 and 7 to produce 9β,11β-epoxy-17α,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione which is transformed to dexamethasone 21-acetate by the process of U.S. Pat. No. 3,007,932, Example 2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.CS(O[CH:16]1[CH2:19][N:18]([C:20]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[O:21])[CH2:17]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[CH3:10][C:4]1[CH:3]=[C:2]([O:1][CH:16]2[CH2:17][N:18]([C:20]([C:22]3[O:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:25][N:26]=3)=[O:21])[CH2:19]2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reactant: Cc1cc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1C=O
Temperature: 90 °C
Reaction time: 20 h
Yield: 71.9 %

Procedure:
To a solution of 4-hydroxy-2-methylbenzaldehyde (0.11 g, 0.79 mmol) and 1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yl methanesulfonate (0.20 g, 0.62 mmol, Intermediate IB above) in DMF (10 mL) under nitrogen was added Cs2CO3 (0.24 g, 0.74 mmol). The mixture was stirred at 90° C. for 20 h, cooled to RT and then diluted with DCM. The solids were filtered off and the filtrate was evaporated. The product was purified on two occasions by preparative HPLC (Kromasil, C8) eluting with a gradient of acetonitrile and a mixture of acetic acid and water (0.2%). The pure fractions were combined and concentrated. The aqueous residues were extracted with DCM and the organic solutions were evaporated. There was obtained 162 mg (72%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3): δ 2.66 (s, 3H), 4.34 (d, 1H), 4.69 (dd, 1H), 4.76 (d, 1H), 5.17 (m, 2H), 6.64 (d, 1H), 6.72 (dd, 1H), 7.53 (t, 2H), 7.59 (t, 1H), 7.78 (d, 1H), 8.15 (d, 1H), 10.14 (s, 1H), MS (APCI+) m/z 364 [M+H]+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:36](C)=O.[Na+]>C(Cl)Cl>[CH3:36][N:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@H]3CCNC3)ccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC[C@H](NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)C1
Yield: 88.2 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid ((S)-1-methyl-pyrrolidin-3-yl)amide (35 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (S)-pyrrolidin-3-ylamide dihydrochloride (45 mg), 37% formaldehyde (500 uL), and Na(OAc)3BH (32 mg) in DCM (500 uL). LC/MS: m/z 440.7.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][OH:20])([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:21])[CH:3]=1.[C:22]([C:26]1[C:27]2[CH:45]=[CH:44][CH:43]=[CH:42][C:28]=2[S:29][C:30]=1[S:31]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:22]([C:26]1[C:27]2[CH:45]=[CH:44][CH:43]=[CH:42][C:28]=2[S:29][C:30]=1[S:31][C:3]1[C:4](=[O:21])[O:5][C:6]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][OH:20])([CH:8]([CH3:9])[CH3:10])[CH2:7][C:2]=1[OH:1])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)C1(CCc2ccccc2CO)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2sc3ccccc3c2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C1(CCc2ccccc2CO)CC(O)=C(Sc2sc3ccccc3c2C(C)(C)C)C(=O)O1

Procedure:
The title compound was prepared according to General Method 16a using 4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-34; 0.20 g, 0.73 mmol), toluene-4-thiosulfonic acid S-(3-tert-butyl-benzo[b]thiophen-2-yl)ester (Example BB-8; 0.302 g, 0.803 mmol), potassium carbonate (0.11 g, 0.80 mmol), and DMF (2.0 mL). The product was purified via column chromatography (eluting with EtOAc) to the title compound, mp 92-94° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH:10]1[CH:11]=[CH:12][C:13]2[NH:18][CH:17]=[C:16]([CH2:19][CH2:20][OH:21])[C:14]=2[CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]1([CH3:5])[C:17]2[NH:18][C:13]3[C:14]([C:16]=2[CH2:19][CH2:20][O:21]1)=[CH:15][CH:10]=[CH:11][CH:12]=3)[CH3:9]
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CC1(C)OCCc2c1[nH]c1ccccc21
Reaction time: 0.17 h

Procedure:
Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of the starting material of formula II, tryptophol (10.0 g., 0.06 moles). in 200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonic acid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate (Molecular Sieves No. 4) are added. The mixture is subjected to reflux for thirty minutes, 600 mg. more of p-toluenesulfonic acid is added and refluxing continued for 21/2 hours. The molecular sieves are collected and the benzene solution washed successively with 5% sodium bicarbonate and water, dried over sodium sulfate, and evaporated under reduced pressure to dryness affording an oil. The oil is subjected to chromatography on silica gel. Elution with 5% ether in benzene yields the ester, 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid ethyl ester, as an oil, δmaxCHCl3 1715 cm-1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[C-:36]#[N:37].[Na+].O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([OH:35])([C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[C:6]4[CH:5]=[CH:4][C:3]([CH2:2][C:36]#[N:37])=[CH:8][CH:7]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(CC#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (described in Example B14) (0.000694 mol) and NaCN (0.00139 mol) in DMSO (3.5 ml) was stirred at room temperature for 2 hours, poured out into H2O, basified with K2CO3 (10%) and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 95/5/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.08 g (23%) of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzeneacetonitrile, as a white foam.
Reaction SMILES: CN(OC)[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)=[O:4].C1(C)C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOCC.C(OCC)(=O)C>[CH2:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([CH:3]=[O:4])[CH2:6][CH2:7]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Methyl-N-methoxy 1-benzyloxycarbonylpiperidin-4-carboxamide (79.9 g, 261 mmol) was azeotroped with toluene (2×200 mL) to remove any water and dissolved in THF (700 mL). The solution was cooled to −60° C., before dropwise addition of a solution of lithium aluminum hydride in TBF (1 M, 100 mL, 100 mmol). The temperature of the reaction mixture was allowed to rise slowly to −30° C. over approx. 1 h. The mixture was transferred by cannula into a rapidly stirred mixture of ethyl acetate (200 mL) and 10% aqueous citric acid (500 mL), cooled to 0° C. After addition was complete, ether (500 mL) was added and the phases separated. The organic layer was washed with 1M HCl, water, saturated sodium bicarbonate solution and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated in vacuo to afford the crude product, used without further purification (59 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][NH2:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]1([CH2:18][C@H:19]([CH2:23][N:24]([CH:32]=[O:33])[O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:20](O)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[N:5]=[C:6]([NH:9][NH:10][C:20](=[O:21])[C@H:19]([CH2:18][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:23][N:24]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:32]=[O:33])[C:7]=1[F:8]
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: CSc1nc(Cl)c(F)c(NN)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CSc1nc(Cl)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of 4-chloro-5-fluoro-6-hydrazino-2-(methylthio)pyrimidine (9.70 g, 46.5 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (19.9 g, 46.5 mmol), HOAt (6.96 g, 51.2 mmol), EDCI (9.82 g, 51.2 mmol) and N-methyl morpholine (25.6 mL, 232.5 mmol) in DMF (300 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate/hexanes (3:2, 1 L) and washed with water (3×500 mL), and the organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by Gilson RP-HPLC (35-95% acetonitrile/water, 8 min gradient time) to afford [(2R)-3-{2-[6-chloro-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a red glass (12.89 g, 56.0%). LCMS: (M+H)+: 490.4.