Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20]C)[CH:16]=3)[CH:11]2[CH3:24])=[CH:6][CH:5]=1.Cl.CCOCC>Br.CO.C(O)(C)C>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([OH:20])[CH:16]=3)[CH:11]2[CH3:24])=[CH:25][CH:26]=1
Reactant: COc1cc2c(cc1OC)C(C)N(CCc1ccc(N)cc1)CC2
Agent: Br
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CO
Product: COc1cc2c(cc1O)CCN(CCc1ccc(N)cc1)C2C
Temperature: 0 °C

Procedure:
N-(4-Aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline dihydrochloride (20.0 g, 0.05 m) was suspended in 49% HBr (50 ml) maintained under nitrogen and heated to 120° for 1.5 hr. The mixture was cooled and then poured into 500 cc of ice/water and the solution basified to pH 11 and extracted with ether (3×250 ml). The aqueous phase was buffered to pH 8 by adding glacial acetic acid and dilute NaOH as needed, then extracted with chloroform (4×300 ml). The chloroform extracts were dried over MgSO4 and evaporated to an oil, 8.5 g. This crude product was purified by HPLC on silica gel eluting with ammonia saturated 5% CH3OH/CHCl3. Pure fractions were combined and evaporated to give a yellow oil, 5.5 g. This was dissolved in methanol (20 ml) and isopropanol (10 ml), acidified with HCl gas and the stirred solution treated with ether (100 ml). The solid precipitate was collected by filtration, washed with 10% isopropanol/ether and vacuum dried to give N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6-hydroxy-7-methoxy-1-methylisoquinoline dihydrochloride as a white solid, m.p. 201°-205°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:16][CH:15]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O>O>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CC1(c2ccc(NC(c3ccccc3)c3ccccc3)cc2)CCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)CC1(c2ccc(N)cc2)CCc2ccccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
[1-(4-(Benzhydryl-amino)-phenyl)-indan-1-yl]-acetic acid methyl ester [(0.15 g, Reference Example 19(b)] was treated with a mixture of trifluoroacetic acid (9 mL) and water (1 mL). The resulting deep red solution was stirred at 50° C., under argon, for 2 hours and then evaporated. The residue was chased with toluene (25 mL) and then placed under vacuum to give the title compound (0.19 g) as a red gum. LC-MS: RT=2.54 minutes, MS(ES+): 282(M+H)+. This material was used immediately for the preparation of Reference Example 9(b).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C(OC(=O)C)C.C1(C)C=CC=CC=1>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[C:22]([F:23])([F:25])[F:24])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate 1.04 g, (5.6 mmol), 2-bromo-5-fluoro benzotrifluoride (1.21 g, 5.0 mmol), tris(dibenzylidineacetone)dipalladium (0) (45.8 mg, 0.05 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (93.4 mg, 0.15 mmol) and sodium tert-butoxide (600 mg, 6.25 mmol) were charged to a microwave vial. Toluene (10.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 30 minutes. Reaction was complete as determined by TLC. The reaction was repeated four times. Reaction mixtures were combined, diluted with ethylacetate, washed with water, saturated brine then dried over MgSO4 and concentrated. The crude product was purified via flash column chromatography to yield tert-butyl-4-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate in quantitative yield (6.8 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]3[CH:11]=[C:12]([O:23][CH3:24])/[C:13](=[CH:15]/[C:16]4[NH:17][C:18]([CH3:22])=[CH:19][C:20]=4[CH3:21])/[N:14]=3)[N:5](C(OC(C)(C)C)=O)[C:4]=2[CH:3]=1>C(O)=O>[Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]3[CH:11]=[C:12]([O:23][CH3:24])/[C:13](=[CH:15]/[C:16]4[NH:17][C:18]([CH3:22])=[CH:19][C:20]=4[CH3:21])/[N:14]=3)[NH:5][C:4]=2[CH:3]=1
Reactant: COC1=CC(c2cc3sc(Cl)cc3n2C(=O)OC(C)(C)C)=N/C1=C\c1[nH]c(C)cc1C
Solvent: O=CO
Product: COC1=CC(c2cc3sc(Cl)cc3[nH]2)=N/C1=C\c1[nH]c(C)cc1C
Yield: 64 %

Procedure:
A solution of (Z)-tert-butyl 2-chloro-5-(2-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-3-methoxy-2H-pyrrol-5-yl)-4H-thieno[3,2-b]pyrrole-4-carboxylate (10 mg) in 2 mL of 88% aqueous formic acid solution was sonicated in an ultrasonic bath for 1 h and then concentrated in vacuo. The residue was purified by Combiflash on a silica gel column eluted with a gradient up to 70% EtOAc/hexanes to give 5 mg of the title compound as a dark solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:9]=2[N:10]=1>[Fe].C(O)(=O)C>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2cc([N+](=O)[O-])ccc2o1
Agent: [Fe]
Solvent: CC(=O)O
Product: CN(C)CCN(C)c1nc2cc(N)ccc2o1
Reaction time: 3 h

Procedure:
The title compound was prepared according to the procedure described in General Method B using N,N,N′-Trimethyl-N′-(5-nitro-benzooxazol-2-yl)-ethane-1,2-diamine (4.131 g, 15.63 mmol), acetic acid (50 mL), and Fe (8.72 g, 78.15 mmol), stirring for 3 h: (3.57 g, 98%). mass spectrum (m/e): 265.3 (M+1).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:16](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=1)[CH2:4][CH3:5].N1C=CC=CC=1.[S:38](Cl)([C:41]1[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=1)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:16](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:17][CH2:18][O:19][S:38]([C:41]2[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=2)(=[O:40])=[O:39])=[CH:11][CH:10]=1)[CH2:4][CH3:5]
Reactant: CCN(CC)CCOc1ccc(/C(=C(/CCO)c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)CCOc1ccc(/C(=C(/CCOS(=O)(=O)c2ccc(C)cc2)c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Cis- or trans- N,N-diethylhydroxytamoxifen (II) (100 mg, 0.27 mmol) was dissolved in methylene chloride (2 ml) and cooled to 0° C. Pyridine (150 μl) and tosyl chloride (55 mg, 0.27 mmol) were added. After 2 hours, the reaction mixture was diluted with methylene chloride and washed with water. The methylene chloride layer was evaporated and chromatographed on a 18C column using 85:15:1 acetonitrile/water/triethylamine as eluant to yield cis (51 mg, 34%, oil) or trans tosyl analog (30 mg, 20%, oil): m/z 569(60, M+), 397(20, +OSO2PhCH3). Values for aliphatic protons are presented in Table 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([O:11][CH2:13][CH:15]2[CH2:16][O:17]2)=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Br)cc(F)c1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Br)cc(F)c1OCC1CO1
Temperature: 60 °C
Yield: 85.4 %

Procedure:
A mixture of 1-(5-bromo-3-fluoro-2-hydroxyphenyl)ethanone (3.7 g, 15.8 mmol), epibromohydrin (2.6 ml, 31.7 mmol) and K2CO3 (3.3 g, 23.8 mmol) in DMF (20 ml) was heated at 60° C. for 1 h 50 min. The solution was brought to ambient temperature and water and EtOAc was added. The water phase was extracted with EtOAc. The combined organic phases were washed with LiCl (5%), HCl (1 N) and brine and were dried (Na2SO4) and evaporated to dryness. Purification on flash column chromatography (isooctane/EtOAc) gave the title compound (3.9 g). MS m/z (rel. intensity, 70 eV) 289 (M+, 13), 288 (M+, 14), 218 (91), 217 (bp), 81 (39), 57 (95).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH2:6].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[N:22]=[CH:21][N:20]=1>>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][S:29]([C:25]1[CH:24]=[C:23]2[C:28]([C:19]([C:10]3[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:16])[F:17])=[CH:14][C:9]=3[O:8][CH3:7])=[N:20][CH:21]=[N:22]2)=[CH:27][CH:26]=1)(=[O:31])=[O:30]
Reactant: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)Cl)ccc12
Reactant: NC1=NCCS1
Product: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)NC3=NCCS3)ccc12

Procedure:
The title compound was prepared in a manner analogous to example 512 except 4,5-dihydrothiazol-2-amine (Pfaltz & Bauer) was used instead of 2-aminothiazole and 4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline-7-sulfonyl chloride was used instead of 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)quinazoline-7-sulfonyl chloride. (M+H)+=469.0.
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH3:11][C:12]1([CH3:25])[CH2:23][C:22]2[CH:21]=[C:20]3[N:15]([CH2:16][CH2:17][NH:18][C:19]3=[O:24])[C:14]=2[CH2:13]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]3[C:20](=[CH:21][C:22]4[CH2:23][C:12]([CH3:11])([CH3:25])[CH2:13][C:14]=43)[C:19]2=[O:24])[C:3]=1[CH:4]=[O:5]
Reactant: CC1(C)Cc2cc3n(c2C1)CCNC3=O
Reactant: O=Cc1c(Cl)ccnc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Temperature: 90 °C
Yield: 23.6 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 2-bromo-4-chloronicotinaldehyde 103a (3.0 g, 13.6 mmol), 4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one 107e (1.84 g, 9.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (826 mg, 0.9 mmol), XantPhos (1.04 mg, 1.8 mmol), Cs2CO3 (5.8 g, 18.0 mmol), and 1,4-dioxane (40 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was recrystallized from ethyl acetate to afford 108a as a yellow solid (730 mg, purity: 99%; yield: 31.7%). MS: [M+H] 344.0.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([Cl:37])[CH:36]=1)[C:31](Cl)=[O:32]>O1CCOCC1>[CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:31](=[O:32])[C:30]3[CH:29]=[C:28]([Cl:27])[CH:36]=[C:35]([Cl:37])[CH:34]=3)[CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1
Reactant: Cc1nc2cccnc2n(-c2cccc(N)c2)c1=O
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nc2cccnc2n(-c2cccc(NC(=O)c3cc(Cl)cc(Cl)c3)c2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
To a solution of 2-methyl-4-(3-aminophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (7.4 g) and triethylamine (5.72 ml) in dioxane was added 3,5-dichlorobenzoyl chloride (6.14 g) in dropwise. The mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched by water and extracted with ethyl acetate (100 ml). The crude product was purified by chromatography to obtain 2-methyl-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (4.4 g).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:26]1([C:29]([N:22]2[CH2:23][CH2:24][C@H:20]([O:19][C:17]3[CH:18]=[C:13]([C:9]4[CH:8]=[C:7]5[C:12](=[CH:11][CH:10]=4)[N:3]([CH3:2])[C:4](=[O:25])[CH2:5][CH2:6]5)[CH:14]=[N:15][CH:16]=3)[CH2:21]2)=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CC1
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCNC4)c3)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCN(C(=O)C5CC5)C4)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of 1-methyl-6-[5-((S)-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 60, 0.05 g, 0.139 mmol) in dry DCM (1.5 mL) was added cyclopropanecarbonyl chloride (0.015 g, 0.139 mmol) followed by TEA (0.035 g, 0.347 mmol) and the reaction mixture was stirred at room temperature for 1 h. Then, the reaction mixture was diluted with EtOAc, poured into sat. NaHCO3 solution (10 mL) and extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.032 g, 59%) as a colorless foam. MS: 392.2 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8]C(OC(C)(C)C)=O)[C:5](O)=[O:6])[CH3:3].CN1CCOCC1.[NH2:23][C@H:24]([C:29]([N:31]1[CH2:45][CH2:44][CH2:43][C@H:32]1[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CCOC(C)=O>[NH2:8][C@H:4]([C:5]([NH:23][C@H:24]([C:29]([N:31]1[CH2:45][CH2:44][CH2:43][C@H:32]1[C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:6])[CH:2]([CH3:3])[CH3:1]
Reactant: CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a flask containing Boc-Valine-OH (652 mg, 3 mmol) in DCM (6 ml) at 0° C. was added NMM (0.35 ml, 3.15 mmol). After stirring for 15 min, A5 (1.065 g, 3 mmol), HOBt (405 mg, 3.0 mmol) and DCC (650 mg, 3.15 mmol) were added in portions, The reaction mixture was allowed to warm to 23° C. and stirred for 14 h. The suspension was diluted with DCM (25 ml) and washed successively with aq KHSO4 (2×10 ml, 10%), aq NaHCO3 (2×10 ml, sat) and brine (10 ml) dried over Na2SO4 filtered and concentrated under reduced pressure. The residue was purified by flash LC (silica, gradient hex-EtOAc 2:1 to 1:1) to give SVPLA4 (1.48 g, 93%) as a white solid. Rf==0.57 (hex-EtOAc 1:2).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](Cl)(=[O:13])[C:10]([Cl:12])=[O:11]>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:9](=[O:13])[C:10]([Cl:12])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNc1ccccc1
Solvent: Cc1ccccc1
Product: CN(C(=O)C(=O)Cl)c1ccccc1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
N-methylaniline (1.0 g) was dissolved in toluene (10 mL). Under cooling with ice, oxalyl chloride (4.07 mL) was added thereto, and the temperature of the mixture was lowered to room temperature, followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, to thereby give the title compound (1.06 g, 86.8%) as a brown oil. The compound was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[C:12](C(OCC)=O)([C:18]([O:20]CC)=[O:19])[C:8]2[S:9][CH:10]=[CH:11][C:7]1=2)=[O:5])C.[OH-].[K+].Cl>CO>[S:15]1[CH2:16][CH2:17][C:13]2[C:12]([C:18]([OH:20])=[O:19])=[C:8]3[C:7](=[C:6]([C:4]([OH:5])=[O:3])[C:14]1=2)[CH:11]=[CH:10][S:9]3
Reactant: CCOC(=O)C1(C(=O)OCC)c2ccsc2C(C(=O)OCC)(C(=O)OCC)c2ccsc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c2c(c(C(=O)O)c3sccc13)CCS2

Procedure:
Benzo[1,2-b;4,5-b′]dithiophene-4,4,8,8-tetracarboxylic acid tetraethyl ester (2 g) was suspended in methanol (60 g) and KOH (7.5 g) under inert atmosphere and heated to reflux for 5 hours. The reaction mixture was acidified with 2M HCl (62.5 g) and the yellow precipitate filtered off, washed with water and dried in vacuum to yield 2,3-dihydro-benzo[1,2-b;4,5-b′]dithiophene-4,8-dicarboxylic acid in quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:13]=2)=[N:6][CH:7]=1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][C:2]1[C:3]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2([C:31]([NH2:33])=[O:32])[CH2:29][CH2:30]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:36])[CH2:16][CH2:15]3)[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C3CCNCC3)c2)nc1CCc1ccccc1C1(C(N)=O)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(Nc2cnn(C3CCN(C)CC3)c2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
To a solution of 1-(2-(2-(5-methyl-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A44 (0.064 g, 0.14 mmol) in MeOH (12 mL) was added formaldehyde solution (37% in water, 32 μL, 0.43 mmol) and sodium triacetoxyborohydride (0.122 g, 0.575 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 4 hours before concentrating under reduced pressure. The mixture was diluted with sat. aq. NaHCO3 (20 mL) and the aqueous phase was extracted with EtOAc (3×25 mL). The combined organics were washed with brine, and dried (MgSO4) before the solvent was removed in vacuo to give the title compound 48 as a white solid (0.035 g, 53%). LCMS-D: rt 2.89 min; m/z 460 [M+H]+.
Reaction SMILES: [C:1](=[O:16])([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[O:2][CH2:3]Cl.[I-:17].[Na+]>CC(C)=O>[C:1](=[O:16])([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[O:2][CH2:3][I:17]
Reactant: [I-]
Reactant: COCCOCCOCCOC(=O)OCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: COCCOCCOCCOC(=O)OCI
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
Chloromethyl 2-(2-(2-methoxyethoxy)-ethoxy)-ethyl carbonate (9 g) was added to a solution of sodium iodide (21.07 g) in acetone (45 ml). After stirring at 40° C. for 2.5 hours the reaction mixture was cooled in ice, filtered and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous sodium bicarbonate and sodium thiosulfate, dried over magnesium sulfate, filtered and evaporated in vacuo. Purification on silica gel with petroleum ether/ethyl acetate (1:1) as eluent gave the title compound as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(F)c(Cl)c2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N45-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(3-chloro-4-fluorophenyl)-boronic acid (CAN 144432-85-9) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 424.0483 (M-H)−.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([N:24]3[CH:30]4[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]4)[CH2:26][CH2:25]3)=[N:21][C:20]=2[CH:33]=1.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[OH-].[Na+]>ClCCCl>[CH2:34]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([N:24]3[CH:30]4[CH2:29][CH2:28][N:27]([CH2:32][CH2:31]4)[CH2:26][CH2:25]3)=[N:21][C:20]=2[CH:33]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccc2oc(N3CCN4CCC3CC4)nc2c1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: c1ccc(CNc2ccc3oc(N4CCN5CCC4CC5)nc3c2)cc1
Yield: 53.1 %

Procedure:
Sodium triacetoxyborohydride (118 mg, 0.56 mmol) was added to a solution of 4-(5-amino-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (52 mg, 0.20 mmol, prepared as in Example 39) and benzaldehyde (21 μL, 0.204 mmol) in 1,2-dichloroethane. The resulting mixture was allowed to stir at RT for a period of 3 h. at which time 2 mL of 1 N NaOH solution was added. The aqueous layer was extracted with CHCl3 (3×) and the combined organic layers were washed with water and brine and then dried (Na2SO4), filtered and concentrated. The crude residue was purified by chromatography (Biotage, 25M) eluting with 6% MeOH in CHCl3 containing 1 mL of NH4OH per L of eluent to give 37 mg of the title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 7.37-7.29 (m, 3H), 7.25-7.22 (m, 2H), 7.00 (d, 1H, J=8.7 Hz), 6.64 (d, 1H, J=2.1 Hz), 6.27 (dd, 1H, J=8.7, 2.1 Hz), 4.47-4.45 (m, 1H), 4.30 (s, 2H), 3.87 (t, 2H, J=5.8 Hz), 3.16-3.09 (m, 4H), 3.01-2.96 (m, 2H), 2.15-2.08 (m, 2H), 1.81-1.73 (m, 2H): 13C NMR (CDCl3, 100 MHz) δ 146.0, 145.1, 142.0, 139.8, 128.8, 127.7, 127.3, 108.8, 106.0, 100.6, 57.3, 50.1, 49.4, 46.5, 44.1, 27.0; MS (Cl) m/z 349.2 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:29])[C@@H:19]([CH:20]=[N:21][O:22][CH2:23][CH:24]=[CH2:25])[C@H:18]1[C:26]([OH:28])=[O:27].C(N(CC)CC)C.[O-][Si]([O-])=O.[Mg+2]>C(OCC)(=O)C.CCOCC.C(Cl)Cl>[CH3:16][C:17]1([CH3:29])[C@@H:19]([CH:20]=[N:21][O:22][CH2:23][CH:24]=[CH2:25])[C@H:18]1[C:26]([O:28][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)=[O:27]
Reactant: C=CCON=C[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=CCON=C[C@H]1[C@@H](C(=O)OCc2cccc(Oc3ccccc3)c2)C1(C)C
Yield: 46.9 %

Procedure:
A solution of 3.7 g of 3-phenoxybenzyl bromide and 2.8 g of (1R,cis)-2,2-dimethyl-3-((allyloxyimino)methyl)cyclopropanecarboxylic acid (prepared by a method similar to that shown in Embodiment I) and 1.4 g of triethylamine in 30 ml of ethyl acetate was refluxed for 21/2 hours. The reaction mixture was diluted with ether and washed with water. The ether phase was dried over magnesium sulfate, filtered and stripped to give an oil. This oil in methylene chloride was passed through a florisil column to give 2.5 g of the desired product as an oil [α]D25 +22.9° (CHCl; c=0.012 g/cc).