Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@@H:9](OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C@H:24]1[CH2:30][S:29][CH:28]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH2:27][N:26]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:25]1=[O:44].C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([O:12][C:10]([C@@H:9]([NH:23][C@H:24]1[CH2:30][S:29][CH:28]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH2:27][N:26]([CH2:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C:25]1=[O:44])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:11])[CH3:14]
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccs2)SC[C@H](N)C1=O
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC(c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
A solution of 4.0 g of ethyl 4-phenyl-2-(R)-trifluoromethanesulfonyloxybutyrate in 15 ml of methylene chloride was added dropwise to a solution of 4.0 g of t-butyl α-[6(R)-amino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above] and 1.62 ml of triethylamine in 50 ml of methylene chloride. The reaction mixture was stirred for 2 hours at room temperature, after which it was washed with water and dried over anhydrous magnesium sulfate; the solvent was then evaporated off under reduced pressure. The residue was purified by silica gel column chromatography, using a 20:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 5.5 g of the title compound in the form of a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[F-:12].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 82 %

Procedure:
A suspension of 1,500 parts of 3,4-dichloronitrobenzene, 680 parts of potassium fluoride and 25 parts of 18-crown-6 in 1,420 parts of dimethylformamide is refluxed for 9 hours, the temperature being 165° C. The mixture is worked up by the method described in Example 1. 1,124 parts (82% of theory) of 3-chloro-4-fluoronitrobenzene of melting point 41°-42° C. are obtained.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4]Br.[Mg].[CH3:18][O:19][C:20]1[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH3:30])[C:21]=1[CH2:31][CH2:32][C@:33]1([CH3:36])[O:35][CH2:34]1.[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:18][O:19][C:20]1[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH3:30])[C:21]=1[CH2:31][CH2:32][C@:33]([CH3:36])([OH:35])[CH2:34][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCBr
Reactant: COc1c(C)c(C)c(OC)c(CC[C@@]2(C)CO2)c1C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)c1C
Reaction time: 8 h

Procedure:
5.8 mmol of (3R,7R)-3,7,11-trimethyldodecyl bromide are heated at reflux for 1/4 hour in 20 ml of ethyl acetate with activated magnesium. Then, there are added at 0° C. 1 g of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-epoxybutane and 0.9 g of copper(I)-2-propylacetylide [or 1.2 g of copper(I) bromide/dimethyl sulphide complex]. The temperature of the reaction mixture is subsequently left to rise to room temperature and the mixture is stirred overnight. 10 ml of ammonium chloride are then added and the mixture is extracted with ethyl ether. The extract is dried and concentrated, and the residue is distilled in a bulb-tube (b.p.0.01 =140° C.). There are obtained 1.28 g (72%) [or 1.41 g (79%)] of (3R,7R,11R)-1-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-3,7,11,15-tetramethylhexadecan-3-ol as a colourless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(O[CH2:32][C@H:33]1[O:35][CH2:34]1)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:3]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:32][C@@H:33]2[CH2:34][O:35]2)=[CH:16][N:15]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=C(Nc1ccc(O)cn1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC[C@@H]2CO2)cn1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
Under nitrogen, to a suspension of sodium hydride (60% in oil, 189 mg) in N,N-dimethylformamide (20 ml) was dropwise added 2-benzyloxycarbonylamino-5-hydroxypyridine (1.1 g) in N,N-dimethylformamide (12 ml) at 5° C., and the mixture was stirred at room temperature for 1 hour. To this one was added (2S)-(+)-1-tosyloxy-2,3-epoxypropane (1.1 g) at 5° C., and the mixture was stirred at room temperature for 7 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:ethyl acetate=9:1) to give 2-benzyloxycarbonylamino-5-[(2S)-oxiranylmethoxy]pyridine (780 mg).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:31][C:32]4[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)=[N:17][CH:18]=[C:19]([CH:21]([N:23]4[CH2:26][CH:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:24]4)[CH3:22])[CH:20]=3)[N:12]=[C:11]([CH3:40])[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O.[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]>>[F:63][C:62]([F:65])([F:64])[C:60]([OH:66])=[O:61].[CH3:39][O:38][C:35]1[N:34]=[CH:33][C:32]([NH:31][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:40])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH:21]([N:23]3[CH2:24][CH:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:26]3)[CH3:22])=[CH:18][N:17]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CC(S(C)(=O)=O)C4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(C)N3CC(S(C)(=O)=O)C3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Yield: 76 %

Procedure:
An orange solution of N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(3-(methylsulfonyl)azetidin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (70.0 mg, 0.098 mmol) and trifluoromethanesulfonic acid (0.030 mL, 0.338 mmol) in TFA (1.5 mL) was stirred at 75° C. for 18 h. The resulting mixture was subsequently cooled to 25° C. and concentrated in vacuo. The residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (Phenomenex Luna 5 gm C18 30×150 mm, 35 mL/min, 5 to 100% CH3CN/H2O (plus 0.1% TFA, both solvents) to provide 4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(3-(methylsulfonyl)azetidin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine 2,2,2-trifluoroacetate (43.6 mg, 0.075 mmol, 76% yield) as an orange solid. 1H NMR (400 MHz, d4-MeOH) δ 9.10 (d, J=2.5 Hz, 1H), 8.70 (d, J=2.7 Hz, 1H), 8.40 (d, J=2.5 Hz, 1H), 8.19 (dd, J=9.0, 2.7 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 4.65 (q, J=6.7 Hz, 1H), 4.54-4.61 (m, 1H), 4.38-4.53 (m, 4H), 4.02 (s, 3H), 3.05 (s, 3H), 2.66 (s, 3H), 2.52 (s, 3H), 1.67 (d, J=6.8 Hz, 3H). 19F NMR (376 MHz, d4-MeOH) δ −79.11 (s, 3F). m/z (ESI, +ve) 471.3 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C:10]1([CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:12][CH2:11]1)[NH:9][CH2:8][C:7]2=[O:32].[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([O-:35])=[O:34]>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C:10]1([CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)[CH2:12][CH2:11]1)[N:9]([CH2:40][C:39]1[CH:42]=[CH:43][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=1)[CH2:8][C:7]2=[O:32]
Reactant: COc1cc2c(cc1OC)C1(CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)NCC2=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C1(CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)N(Cc1ccc([N+](=O)[O-])cc1)CC2=O

Procedure:
A mixture of 6,7-dimethoxy-1'-[2-(4-nitrophenyl)ethyl]-spiro[1,2,3,4-tetrahydro-isoquinoline- 1,4'-piperidin]-4-one hydrochloride (0.33 g) sodium bicarbonate (0.1 g) and p-nitrobenzylbromide (0.25 g) in ethanol were refluxed for 18 hours. The reaction was concentrated and chromotographed on silica (methylene chloride/methanol, 90:10) to give 60 mg upon concentration and crystallization of the dihydrochloride salt from isopropanol. mp 174°-177° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH3:23])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[S:14]1[CH:15]=[C:11]([CH2:10][C@@H:9]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[CH3:23])=[O:17])[NH2:8])[N:12]=[CH:13]1
Reactant: C[C@@H]1CCCN1C(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CCCN1C(=O)[C@@H](N)Cc1cscn1
Reaction time: 0.75 h
Yield: 62 %

Procedure:
Compound (3) (33.77 g, 99.48 mmol) and p-toluenesulfonic acid hydrate (37.85 g, 199 mmol) were dissolved in ethyl acetate (101 ml) and the solution was cooled with ice. To the mixture, 4 mol/L solution of hydrogen chloride-ethyl acetate (125 ml) was added, and the mixture was stirred for 2 hours 45 minutes. After the mixture was concentrated under reduced pressure, methanol was added to the residue. The mixture was concentrated. Methanol-toluene (1:1) was added to the residue and concentrated under reduced pressure to give crystalline residue. The residue was washed with acetone and filtered to give compound (4) as crystals (36 g, 62%). After the mother liquor was concentrated under reduced pressure, methanol and toluene were added to the residue and concentrated. Obtained crystalline residue was washed with acetone to give compound (4) (10.67 g, 18.4%).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[CH:17]=[C:16]([CH2:18][CH3:19])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N#N.[F:22]F>FC(F)(F)C(O)=O>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([NH:11][C:12]2[C:17]([F:22])=[C:16]([CH2:18][CH3:19])[N:15]=[CH:14][N:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FF
Reactant: CCc1cc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)ncn1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1F
Yield: 41 %

Procedure:
A solution of 2.62 g of 4-(cis-4-tert-butylcyclohexylamino)-6-ethyl pyrimidine in 40 ml of trifluoroacetic acid was charged into a reactor for direct fluorination. A stream of a mixture of F2/N2 (1:10 by volume) was passed through the mixture at 15° C. After 0.015 mol of fluorine was passed through, the reaction was flushed with nitrogen in order to remove unconsumed fluorine. The solvent was removed in vacuo and the residue was treated with 50 ml of 2N sodium hydroxide, extracted with diethyl ether, washed with water and dried over MgSO4. After ether evaporation, the product was isolated in 41% yield by column chromatography, eluting with a mixture hexane/ethyl acetate 2:1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:13][CH2:12]1.[Li]CCCC.C([O:22][B:23]1OC(C)(C)C(C)(C)[O:24]1)(C)C>O1CCCC1>[CH:11]1([CH2:10][O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[B:23]([OH:24])[OH:22])[CH2:13][CH2:12]1
Reactant: Fc1ccc(OCC2CC2)c(Br)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(F)ccc1OCC1CC1
Temperature: -40 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a solution of Example 274a (0.1 g, 0.408 mmol) in tetrahydrofuran (2 mL) at −20° C. was added nBuLi (0.180 mL of a 2.5 M solution in hexanes, 0.449 mmol). The reaction mixture was stirred for 2 hours, then cooled to −40° C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.092 mL, 0.449 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes. The reaction mixture was quenched with 1M citric acid at 0° C. The mixture was stirred at ambient temperature for 1 hour and then extracted with ethyl acetate. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (silica gel, 10-33% ethyl acetate/hexanes gradient) to provide the title compound (23 mg, 20% yield).
Reaction SMILES: [C:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][CH:7]([C:12]1[N:16]=[C:15]([NH:17][C:18]3[N:23]=[CH:22][C:21]([S:24][CH2:25][C:26](OC)=[O:27])=[CH:20][C:19]=3[O:30][C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)[S:14][N:13]=1)[CH2:8]2)(=[O:3])[CH3:2].[Li+].[BH4-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:27][CH2:26][CH2:25][S:24][C:21]1[CH:20]=[C:19]([O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[C:18]([NH:17][C:15]2[S:14][N:13]=[C:12]([CH:7]3[CH2:6][CH:5]4[N:4]([C:1](=[O:3])[CH3:2])[CH:9]([CH2:10][CH2:11]4)[CH2:8]3)[N:16]=2)=[N:23][CH:22]=1
Reactant: COC(=O)CSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(C)=O)ns2)c(Oc2cccnc2C)c1
Agent: [Al+3]
Agent: [BH4-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)N1C2CCC1CC(c1nsc(Nc3ncc(SCCO)cc3Oc3cccnc3C)n1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
Methyl 2-(6-(3-(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)acetate (Prepared in Example 174, step d; 210 mg, 0.388 mmol) was dissolved in THF (4 mL) and LiBH4 (194 μL, 0.194 mmol) was added and stirred at ambient temperature for 30 minutes The reaction was cooled to 0° C. and LiAlH4 (194 μL, 0.194 mmol) was added and stirred for 20 minutes. The reaction was quenched with water and sodium sulfate, stirred for 10 minutes, filtered and concentrated. The residue was purified on silica gel (10% methanol in EtOAc) followed by reverse phase chromatography (5 to 95% ACN in water with 0.1% TFA) to afford 1-(3-(5-(5-(2-hydroxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone (52.5 mg, 0.102 mmol, 26.4% yield) as a solid after converting the salt to the free base. Mass spectrum (apci) m/z=513.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:17])=[CH:6][C:7]2[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=2[CH:16]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:26](I)[CH2:27][CH3:28]>C(C(C)=O)C>[CH2:1]([O:3][C:4]1[C:5]([O:17][CH2:26][CH2:27][CH3:28])=[CH:6][C:7]2[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=2[CH:16]=1)[CH3:2]
Reactant: CCOc1cc2cc(C(=O)OC)sc2cc1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1cc2sc(C(=O)OC)cc2cc1OCC

Procedure:
A solution of 0.42 g. of methyl 5-ethoxy-6-hydroxybenzothiophene-2-carboxylate, 0.25 g. of potassium carbonate, a catalytic amount of potassium iodide, and 0.31 g. of propyl iodide in methyl ethyl ketone was heated to reflux for 48 hours. The hot solution was filtered and the filtrate was evaporated in vacuo to provide the desired subtitle intermediate which was used in the subsequent reaction without purification.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:41]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:41]([S:51]([CH3:54])(=[O:52])=[O:53])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(-c2ccccc2)c(S(C)(=O)=O)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-2-(methylsulfonyl)biphenyl (Intermediate 203), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)=[CH:9][N:10](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39].C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[NH:26]1[C:27]2[C:23](=[CH:22][C:21]([C:8]3[C:6]4=[N:7][C:2]([C:34]5[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[CH:33]=5)=[CH:3][N:4]=[C:5]4[NH:10][CH:9]=3)=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3nc(Br)cnc32)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc5[nH]ccc5c4)c3n2)cc(OC)c1OC
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-7-(1H-indol-5-yl)-5-tosyl-5H-pyrrolo[3,2-b]pyrazine [Intermediate AV] (65 mg, 0.14 mmol) in CH3CN (1 mL) in a Personal Chemistry microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol), bis(triphenylphosphine)-palladium(II) dichloride (7.0 mg, 0.010 mmol), and 1 M Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The organic layer was separated, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL) and acetone (2 mL), and 2 M NaOH (1.5 mL) was added. The resulting mixture was stirred at 65° C. for 30 min, after which it was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue which was purified by preparatory HPLC to give the title compound as a yellow solid. HPLC retention time: 2.25 minutes; MS ESI (m/z) 401.2 (M+1)+, calc. 400.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20][C:21]1[CH:33]=[CH:32][C:24]2[C:25]([C:29]([OH:31])=[O:30])=[C:26]([CH3:28])[O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O.CC(O)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:20][C:21]3[CH:33]=[CH:32][C:24]4[C:25]([C:29]([OH:31])=[O:30])=[C:26]([CH3:28])[O:27][C:23]=4[CH:22]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc2cc(O)ccc2c1C(=O)O
Agent: Clc1ccnc2cc(OCc3ccccc3)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1oc2cc(Oc3ccnc4cc(OCc5ccccc5)ccc34)ccc2c1C(=O)O
Temperature: 130 °C
Yield: 189.9 %

Procedure:
7-(benzyloxy)-4-chloroquinoline 90-B was prepared (see general synthesis Scheme I) from the commercially available compound 90-A (from Aldrich). A mixture of 90-B (2.8 g, 10.4 mmol), 6-hydroxy-2-methyl-1-benzofuran-3-carboxylic acid 90-C (2 g, 10.4 mmol) and Cs2CO3 (10.1 g, 31.4 mmol) in DMSO (70 ml) was heated to 130° C. for 2 hours. The solution was poured into water, neutralized with AcOH and extracted with EtOAc. The concentrated residue was purified by silica gel chromatography using 2-5% MeOH in CH2Cl2 to give 6-{[7-(benzyloxy)quinolin-4-yl]oxy}-2-methyl-1-benzofuran-3-carboxylic acid 90-D (4.2 g, 94% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:21][CH2:20][C:19](=[O:22])[CH2:18][C:17]=4[CH:23]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:24][NH:25][C:26](=[O:29])[O:27][CH3:28].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:21][CH2:20][CH:19]([OH:22])[CH2:18][C:17]=4[CH:23]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:24][NH:25][C:26](=[O:29])[O:27][CH3:28]
Reactant: COC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)CC(=O)CO4)n2)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)CC(O)CO4)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of methyl N-[[2-chloro-5-[1-(3,4-dihydro-3-oxo-2H-1-benzopyran-6-yl)-1H-pyrazol-3-yl]phenyl]methyl]carbamate (i.e. the product of Example 10) (100 mg, 0.24 mmol) in methanol (10 mL) was added sodium borohydride (19 mg, 0.48 mmol) and the reaction mixture was stirred at ambient temperature for 1 hour. After TLC analysis (30% ethyl acetate/pet ether) showed completion of reaction, the solvent was concentrated under vacuum. The crude residue was cooled to 0° C. and acidified with 1N HCl. The aqueous mixture was extracted three times with ethyl acetate. The combined the organic phases were washed with water, brine and dried over Na2SO4. The solvent was concentrated under vacuum to give the title compound, a compound of the present invention, (60 mg, 60% yield) as a solid.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C:37](=[O:38])[N:14]2[C@@H:15]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[C@@:16]([Cl:20])([CH3:19])[CH2:17][S:18][C@H:13]12)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:12]1[C:37](=[O:38])[N:14]2[C@@H:15]([C:21]([O:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:22])[C@@:16]([Cl:20])([CH3:19])[CH2:17][S:18][C@H:13]12
Reactant: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)OCc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a solution of benzhydryl 7β-benzyloxycarbonylamino-3β-chloro-3-methylcepham-4α-carboxylate (110 mg) in ethanol (10 ml) is added previously reduced 5% palladium charcoal (50 mg), and the mixture is shaken under hydrogen gas. After 60 minutes, the reaction mixture is filtered, and the filtrate is evaporated. The residue is treated with a mixture of ether and petroleum ether to give solid benzhydryl 7β-amino-3β-chloro-3α-methylcepham-4α-carboxylate (52 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]([C:15]1[C:16]2[CH:17]=[CH:18][NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14].[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:29][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13]([C:15]2[C:16]3[CH:17]=[CH:18][NH:19][C:20]=3[CH:21]=[CH:22][CH:23]=2)=[O:14])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1ccccc1OCCCBr)c1cccc2[nH]ccc12
Reactant: NC1CCCC1
Product: O=C(Nc1ccccc1OCCCNC1CCCC1)c1cccc2[nH]ccc12

Procedure:
Using the procedure of Example 41, Step B, 4 g of the product of Step A of Example 41 and 2.11 ml of cyclopentylamine were reacted to obtain 3.3 g of N-[2-[3-(cyclopentylamino)propoxy]phenyl]-1H-indol-4-carboxamide and then 2.8 g of its hydrochloride melting at 244° C.