Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:5][CH:4]=1.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][CH2:13][O:12][C:6]1[C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:3]([CH2:2][CH:31]2[S:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])=[CH:4][CH:5]=1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)c2sccc12
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)c2sccc12

Procedure:
reacting 4-[2-(7-Bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole with 2,4-thiazolidinedione (commercially available) to give 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione,
Reaction SMILES: [H-].[Li+].[CH2:3]([N:5]1[C:10](=[O:11])[C:9]2=[N+:12]([O-:15])[O:13][N:14]=[C:8]2[NH:7][C:6]1=[O:16])[CH3:4].Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Cl)[CH:19]=1>CN(C=O)C>[CH2:3]([N:5]1[C:10](=[O:11])[C:9]2=[N+:12]([O-:15])[O:13][N:14]=[C:8]2[N:7]([CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[C:6]1=[O:16])[CH3:4]
Reactant: CCn1c(=O)[nH]c2no[n+]([O-])c2c1=O
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(no[n+]2[O-])n(Cc2cccnc2)c1=O
Temperature: 60 °C
Yield: 19.4 %

Procedure:
0.48 g (60 mmol) of lithium hydride is added in portions to a solution of 5.0 g (25 mmol) of 6-ethyl-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dione-1-oxide in 250 ml of DMF. The mixture is heated at 60° C. for 15 minutes, then 4.9 g (30 mmol) of 3-picolyl chloride hydrochloride are added and the mixture is heated at 80° C. for 3 hours. It is then largely concentrated, the residue is taken up with ethyl acetate and the mixture is extracted with 10% strength hydrochloric acid. The aqueous extract is neutralised and extracted with ethyl acetate. Relatively readily volatile impurities are removed by distillation in vacuo at 100° C./0.5 mm Hg and the residue is chromatographed. 1.4 g (20%) of 6-ethyl-4-(3-pyridylmethyl)-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dione-1-oxide are obtained as a highly viscous oil.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C@H:5]([C:12]1[C:21](=[O:22])[O:20][C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]=1[OH:23])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3].[CH3:24][C:25]([CH:27]([OH:47])[CH:28]([C:35]1[C:44](=[O:45])[O:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]=1[OH:46])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH3:1][C:2]([CH2:4][C@@H:5]([C:12]1[C:21](=[O:22])[O:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[OH:23])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3].[CH3:24][C:25]([CH:27]([OH:47])[CH:28]([C:35]1[C:44](=[O:45])[O:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]=1[OH:46])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26]
Reactant: CC(=O)C[C@@H](c1ccccc1)c1c(O)c2ccccc2oc1=O
Agent: CC(=O)C(O)C(c1ccccc1)c1c(O)c2ccccc2oc1=O
Product: CC(=O)C[C@H](c1ccccc1)c1c(O)c2ccccc2oc1=O

Procedure:
The microsomal incubations with R and S-warfarin clearly demonstrate the formation of all four 10-hydroxywarfarin isomers by human liver microsomes (FIG. 4). Incubations with R-warfarin (FIG. 7) produced two product peaks with the 10-hydroxywarfarin specific SRM as observed at 7.06 and 7.74 min at a ratio of 1:10 (25 μM reaction) or 1:18 (500 μM reaction). The presence of two peaks confirms the addition of a second chiral center of 10-hydroxywarfarin (FIG. 4). Similarly, two 10-hydroxywarfarin product peaks were observed for incubations with S-warfarin, eluting at 7.37 and 8.03 min at a 1.7:1 (25 μM reaction) or 1.6:1 (500 μM reaction) ratio. These two peaks further confirm the presence of a second chiral center on 10-hydroxywarfarin. For biomonitoring purposes we therefore assigned the 1st and 3rd peaks as 10-hydroxywarfarin metabolites derived from R-warfarin and the 2nd and 4th peaks as 10-hydroxywarfarin derived from S-warfarin. This appears to be the first report of separation and quantitation of all four 10-hydroxywarfarin isomers.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[N:14]=[N:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.[Li]CCCC.[Sn:28](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32]>C(OCC)C.O>[CH2:1]([O:8][CH2:9][N:10]1[N:14]=[N:13][C:12]([Sn:28]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:29][CH2:30][CH2:31][CH3:32])=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccc(COCn2ncnn2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(COCc2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-benzyloxymethyltetrazole (1 mmole) and TMEDA (2 mmole) in 3 mL diethyl ether at −78° C. was added n-BuLi in hexanes (1 mmole). This was let stir for 5 min at −78° C. and then it was added to a precooled (−78° C.) solution of (n-Bu)3SnCl (1 mmole) in 2 mL of diethyl ether. After stirring at −78° C. for 30 min it was diluted with water and diethyl ether. Extraction and chromatography provided 2-benzyloxymethyl-5-(tributylstannyl)tetrazole as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:10]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:40]=[N+:41]=[N-:42].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:42][N:41]=[N:40][N:17]=3)[CH2:15][C@@:9]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:10]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 137; 4 g, 7.4 mmol), sodium azide (1.4 g, 22 mmol) and ammonium chloride (1.2 g, 22 mmol) were stirred at 120° C. in N,N-dimethylformamide (15 ml) for 20 hours. On cooling to room temperature the mixture was poured into water (250 ml) and extracted (×2) with ethyl acetate. The combined organic extracts were washed (×3) with water then dried (MgSO4), filtered and concentrated. Residue was chromatographed on silica gel eluting with 1, 2 and 4% methanol/dichloromethane to give the title compound (2.7 g, 63%).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].O=[C:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.[BH4-].[Na+].[Cl-].[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.CO.C1(C)C=CC=CC=1>[C:2]([S:5]([NH:7][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:6])([CH3:4])([CH3:3])[CH3:1]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(NS(=O)C(C)(C)C)CC1
Temperature: 70 °C
Yield: 87.8 %

Procedure:
2-Methyl-2-propanesulfinamide (854 mg) and titanium (IV) ethoxide (3.0 mL) were added to a toluene solution (5 mL) containing ethyl 4-ketocyclohexanecarboxylate (1.0 g) at room temperature, followed by stirring under heating for 1 hr at 70° C. The reaction mixture was cooled to room temperature and admixed with sodium borohydride (854 mg) and then methanol (5.0 mL), followed by stirring for 30 min. The reaction mixture was admixed with an aqueous saturated sodium-chloride solution, and after the resultant insoluble matter was filtered out, the organic layer was concentrated under reduced pressure. The residue was separated and purified by silica-gel column chromatography (C-300, hexane:ethyl acetate=1:2) to give the title compound (1.42 g) composed mainly of the trans isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:8][S:9](O)(=[O:11])=[O:10].O=S(=O)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:9]([OH:11])(=[O:10])=[O:8])=[CH:4][N:3]=1
Reactant: Nc1ccccn1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Nc1ccc(S(=O)(=O)O)cn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
2-Aminopyridine (80 g, 0.85 mol) was added portionwise over 30 minutes to stirred oleum (320 g) and the resulting solution heated at 140° C. for 4 hours, then allowed to cool. The reaction mixture was poured onto stirred ice (200 g) and this mixture stirred at ice-salt bath temperature for a further 2 hours. The resulting suspension was filtered, then the collected solid washed successively with ice-water (200 ml) and cold industrial methylated spirit (IMS) (200 ml) and, finally, dried under suction to provide the title compound (111.3 g, 75%) as a solid. LRMS: m/z 175 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])[N:5]=[C:4]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[N:3]=1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1>CN(C=O)C>[Si:25]([O:13][CH2:12][C@H:11]([NH:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([Cl:1])[N:3]=[C:4]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[N:5]=1)[CH3:14])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc(Cl)c1C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Nc1nc(SCc2cccc(F)c2F)nc(Cl)c1C=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the subtitle product of step i) (5.60 g) in DMF was added tert-butyldimethylsilyl chloride (2.40 g) at −10° C. in portions. To this mixture was then added imidazole in portions. The mixture was then stirred at 0° C. for 2 h before being quenched with excess water. The mixture was then extracted with EtOAc (2×250 ml), the combined organics washed with water (3×300 ml) and brine (2×30 ml). The organic layer was dried (MgSO4) and solid was filtered. The filtrate was evaporated to dryness. The residue was purified by column chromatography (10% EtOAc/isohexane) to yield the subtitle compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH3:21])[O:20][CH2:19][CH2:18][O:17]3)=[CH:12][CH:11]=2)[CH:5]=[C:6](Br)[CH:7]=1.[CH2:22]([O:24][C:25]([N:27]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([N:27]1[CH2:31][CH2:30][C:29]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([S:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4([CH3:21])[O:20][CH2:19][CH2:18][O:17]4)=[CH:12][CH:11]=3)[CH:5]=2)([OH:32])[CH2:28]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)N1CCC(=O)C1
Reactant: CC1(c2ccc(Sc3cc(F)cc(Br)c3)cc2)OCCO1
Product: CCOC(=O)N1CCC(O)(c2cc(F)cc(Sc3ccc(C4(C)OCCO4)cc3)c2)C1
Yield: 50 %

Procedure:
Using an analogous procedure to that described in the fourth paragraph of the portion of Example 28 which is concerned with the preparation of starting materials, 5-fluoro-3-[4-(2-methyl-1,3-dioxolan-2-yl)phenylthio]bromobenzene was reacted with 1-ethoxycarbonylpyrrolidin-3-one to give 1-ethoxycarbonyl-3-{5-fluoro-3-[4-(2-methyl1,3-dioxolan-2-yl)phenylthio]phenyl}-3-hydroxypyrrolidine as a gum in 50% yield.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(N(C(C)C)CC)(C)C.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:43]=[C:42]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=[C:40]2[C:35]=1[CH2:36][N:37]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=1)[C:38](=[O:56])[N:39]2[C:48]1[C:53]([Cl:54])=[CH:52][CH:51]=[CH:50][C:49]=1[Cl:55]>C1COCC1>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:43]=[C:42]([S:44]([N:6]2[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH:2]([CH3:1])[CH2:7]2)(=[O:46])=[O:45])[CH:41]=[C:40]2[C:35]=1[CH2:36][N:37]([CH2:57][C:58]1[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=1)[C:38](=[O:56])[N:39]2[C:48]1[C:49]([Cl:55])=[CH:50][CH:51]=[CH:52][C:53]=1[Cl:54]
Reactant: CC1CNCCN1C(=O)OCc1ccccc1
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)Cl)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)N4CCN(C(=O)OCc5ccccc5)C(C)C4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Benzyl 2-methylpiperazine-1-carboxylate (34 mg, 0.144 mmol) and diisopropylethylamine (19 mg, 0.144 mmol) were added to a mixture of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-sulfonyl chloride (60 mg, 0.096 mmol) (COMPOUND CCC8) in 1 mL THF. The mixture was heated to 80° C. and stirred at this temperature for ca. 1 h. The reaction mixture was cooled to rt and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 50:50 hexanes-acetone to yield benzyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]sulfonyl}-2-methylpiperazine-1-carboxylate. Mass spectrum (ESI) 819.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH2:32][CH2:33][CH2:34][CH:35]=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1O[C@@H](CCCCO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@@H]1O[C@@H](CCCC=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a solution of 4-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)butan-1-ol (1.73 g, 3.53 mmol) in DCM (50 mL) was added Dess-Martin reagent (2.24 g, 5.29 mmol) and the resulting mixture stirred at room temperature for 3 hours. Mixture washed with sat. NaHCO3 (100 mL); dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography (Teledyne Isco: 80 g) eluent: gradient 0-80% EtOAc in Hexanes to give the title compound (1.24 g, 72%). 1H NMR (CDCl3) δ 9.77 (1H, s), 7.40-7.28 (15H, m), 4.80 (1H, d, J=12.0 Hz), 4.78 (1H, J=12.0 Hz), 4.71 (1H, d, J=12.0 Hz), 4.66 (2H, m), 4.54 (1H, d, J=11.8 Hz), 3.98 (1H, m), 3.92 (1H, m), 3.83-3.76 (3H, m), 2.43 (2H, m), 1.80-1.63 (2H, m), 1.62-1.48 (2H, m), 1.30 (3H, d, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4[S:33]([CH3:32])(=[O:35])=[O:34])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1S(C)(=O)=O
Yield: 58.3 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 22, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline (150 mg, 0.36 mmol), (prepared as described for the starting material in Example 12), was reacted with methanesulphonyl chloride (33 μl, 0.43 mmol). The product was purified by column chromatography, eluting with methanol/methylene chloride (2/98) to give 4[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[(2S)-1-(methylsulfonyl)pyrrolidin-2-yl]methoxy}quinazoline (105 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1.[F:21][C:22]([F:27])([F:26])[C@@H:23]([NH2:25])[CH3:24].O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:25][C@@H:23]([CH3:24])[C:22]([F:27])([F:26])[F:21])[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2Cl)c(F)c1
Reactant: C[C@H](N)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 5,7-dichloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]-pyrimidine (200 g, 0.627 mol) in anhydrous DMF (1000 mL) is added (S)-2,2,2-trifluoro-1-methyl-ethylamine (177 g, 1.57 mol). The solution is stirred from about 20° C. to about 30° C. for 24 h. The reaction mixture is added to cold water (3000 mL) slowly over 30 min. The mixture is stirred for 30 min at 10-20° C. The solid product is filtered and washed with water (2×500 mL). The crude product is dissolved into IPA (1000 mL) at 50° C. Water (2000 mL) is added to precipitate the product over 30 min. The mixture is cooled to 0° C. over 1 h and stirred for 1 h at this temperature. The solid is filtered and dried at 65° C./10 mmHg for 20 h to give a light yellow solid (204 g, 82%, 98% HPLC area purity and 99% ee).
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[S:12](Cl)([Cl:15])(=[O:14])=[O:13]>O1CCCC1.C(OCC)C>[O:3]1[CH:4]=[CH:5][C:6]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:2]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1ccco1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=S(=O)(Cl)c1ccoc1
Reaction time: 1 h

Procedure:
In flame dried glassware under a nitrogen atmosphere to a solution of 428 mg (2.909 mmol) of 3 bromofuran in anhydrous tetrahydrofuran at -78° C. was added 2.0 mL n-butyl lithium (3.2 mmol at 1.6 molar in hexane). After 45 minutes the resultant solution was added via cannula to a 20° C. solution of sulfuryl chloride in diethyl ether (5 mL plus a 2 mL rinse). After 1 h, the reaction was quenched with 0.5N hydrochloric acid and extraced into diethyl ether. The ethereal extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 158 mg of the title product. (1H) NMR (CDCl3) consistent with structure.
Reaction SMILES: C(OC([N:8]1[C:13]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[C:12](=[O:20])[N:11]([CH2:21][C:22]([OH:24])=O)[CH:10]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:9]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][C:57]1[CH:58]=[C:59]2[C:72](=[CH:73][CH:74]=1)[CH2:71][C@@:61]1([C:69]3[C:64](=[N:65][CH:66]=[CH:67][CH:68]=3)[NH:63][C:62]1=[O:70])[CH2:60]2>CN(C=O)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH:10]2[N:11]([CH2:21][C:22]([NH:56][C:57]3[CH:58]=[C:59]4[C:72](=[CH:73][CH:74]=3)[CH2:71][C@:61]3([C:69]5[C:64](=[N:65][CH:66]=[CH:67][CH:68]=5)[NH:63][C:62]3=[O:70])[CH2:60]4)=[O:24])[C:12](=[O:20])[C:13]3([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]3)[NH:8][CH2:9]2)=[CH:26][CH:27]=1
Reactant: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(F)cc2)N(CC(=O)O)C(=O)C12COCCOC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C2(COCCOC2)NCC1c1ccc(F)cc1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.26 g (0.6 mmol) 2-(1-(tert-butoxycarbonyl)-3-(4-fluorophenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecan-4-yl)ethanoic acid in 10 ml DMF were combined with 0.46 g (1.2 mmol) HATU and 0.20 ml (1.4 mmol) TEA and stirred for 10 min at RT. Then 0.17 g (0.66 mmol) (S)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one were added and the mixture was stirred overnight at RT. The reaction mixture was poured onto water. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([N:15]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C@H:17]1[O:29][CH3:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[CH2:8]([N:15]([C@H:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]1[O:29][CH3:30])[C:31](=[O:32])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CO[C@@H]1CNCC[C@@H]1N(Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (5 ml, 20 mmol) was added to a solution of tert-butyl cis(±)-4-{benzyl[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (259b) (about 1.44 mmol) in methanol (1 mL). The mixture was stirred for one hour and the solvent was evaporated under reduced pressure. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C[Si]([N:14]=[N+:15]=[N-:16])(C)C.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:14]=[N:15][NH:16][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc(Br)cc1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Brc1ccc(-c2c[nH]nn2)cc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
1-Bromo-4-ethynylbenzene (650 mg, 3.59 mmol) and trimethylsilyl azide (3.57 mL, 26.9 mmol) were combined in t-BuOH (5.0 mL) and water (3.0 mL) CuSO4.5H2O (90 mg, 0.36 mmol) in water (1.0 mL) and sodium ascorbate (285 mg, 1.44 mmol) in water (1.0 mL) were added, and the sealed reaction mixture was stirred at 100° C. for 48 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (dry load, 0-50% EtOAc/hexanes) afforded the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3([CH3:16])[C:7]([CH:8]=[C:9]([C:17]([O:19]C)=[O:18])[CH2:10][CH2:11]3)=[CH:6][CH2:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(=O)(=O)(O)O>CO.O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3([CH3:16])[C:7]([CH:8]=[C:9]([C:17]([OH:19])=[O:18])[CH2:10][CH2:11]3)=[CH:6][CH2:5][C:4]=2[CH:3]=1
Reactant: COC(=O)C1=CC2=CCc3cc(Cl)ccc3C2(C)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC12CCC(C(=O)O)=CC1=CCc1cc(Cl)ccc12
Temperature: 25 °C
Yield: 83.3 %

Procedure:
To a stirred solution of methyl (-)-2-chloro-4b-methyl-4b,5,6,10-tetrahydrophenanthrene-7-carboxylate (500 mg, 1.73 mmol.) in methanol (19 mL) and water (2 mL) was added potassium carbonate (300 mg). The solution was heated to reflux for 10 hours. The solution was allowed to cool to ambient temperature, was diluted with chloroform (100 mL) and was acidified with 1N sulfuric acid. The aqueous phase was further extracted with chloroform and the combined organic phases were dried over anhydrous magnesium sulfate. Removal of solvent under reduced pressure afforded crude acid as a yellow glass. The compound was purified by chromatography on silica (eluting with 25% ethyl acetate, 1% acetic acid in hexanes) to afford the title compound (396 mg) as a yellow crystalline solid.