Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[C:29]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](O)=[O:36])(=O)[CH3:30].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCCl>[CH3:28][C:4]1[C:3]([N:2]2[C:35](=[O:36])[C:34]3[C:33](=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:32]=[C:29]2[CH3:30])=[CH:27][N:6]2[C:5]=1[C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=1)=[C:9]([C:25]#[N:26])[CH:8]=[N:7]2
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-n2c(C)nc3ccccc3c2=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (10.4 mg, 0.027 mmol), 2-acetylamino benzoic acid (7 mg, 0.04 mmol), PyBOP (21 mg, 0.04 mmol) and DIEA (8.6 mg, 0.067 mmol) in 1.2-dichloroethane (0.5 ml) were stirred at RT for 16 hrs. The reaction mixture was concentrated and purified by silica gel flash chromatography to isolate 375 as a yellow film (5.8 mg, 42%). [M+H]+=498.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]([CH3:19])([CH3:18])[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1([C:11]([CH3:18])([CH3:19])[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9][N:8]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCN(CC(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a stirred mixture of 3-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (444 mg, 1.54 mmol), triethylamine (214 μl, 1.54 mmol) and cesium carbonate (251 mg, 0.77 mmol) in acetonitrile (5 ml) was added tert-butyl bromoacetate (351 μl, 2.38 mmol) slowly. The mixture was stirred for 1 hour, filtered and concentrated. The residue was diluted with ethyl acetate, washed with water and dried over MgSO4. Solvent was removed under reduced pressure to give a crude product that was purified by column chromatography on silica gel. Elution with a solution of ethyl acetate in hexanes (1:4) provided 580 mg (94%) of the title compound.
Reaction SMILES: [N+]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[N+](C1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1[N+]([O-])=O)([O-])=O.[N+](C1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1)([O-])=O>>[CH:11]1[C:10]2[C:9](=[O:19])[C:8]3[C:17](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:16](=[O:18])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Agent: O=C1c2ccccc2C(=O)c2cc([N+](=O)[O-])ccc21
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
By 1-nitroanthraquinone containing dinitroanthraquinone there is here understood a 1-nitroanthraquinone essentially contaminated with 2-nitroanthraquinone and 1,5-, 1,6-, 1,7- and 1,8-dinitroanthraquinone, such as is obtained on nitration of anthraquinone.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:28][CH2:29][CH3:30])[C:17](=[O:27])[C:18]2[CH:26]=[CH:25][CH:24]=[C:20]([C:21]([OH:23])=[O:22])[CH:19]=2)=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC.[OH-].[Na+].C(Cl)Cl.CO>C1(C)C(C)=CC=CC=1>[CH2:28]([N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]2[NH:46][N:45]=[N:44][N:2]=2)=[CH:14][CH:13]=1)[C:17](=[O:27])[C:18]1[CH:26]=[CH:25][CH:24]=[C:20]([C:21]([OH:23])=[O:22])[CH:19]=1)[CH2:29][CH3:30]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)c1cccc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)c1cccc(C(=O)O)c1

Procedure:
A solution of 2.76 g of N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-isophthalic acid monoamide and 8.68 g of tributyltin azide in 75 ml of xylene is heated under reflux for 2 hours. When cool, the mixture is stirred with 50 ml of 2N sodium hydroxide solution at room temperature for 1 hour, and is then acidified and extracted with 100 ml and twice with 50 ml of CH2Cl2. After customary treatment, the combined dichloromethane phases yield a crude product that, after chromatography on silica gel 60 (40-63 μm) using CH2Cl2 /CH3OH (9:1) as eluant, yields N-propyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-isophthalic acid monoamide that has an Rf value of 0.10 [CH2Cl2 /CH3OH (4:1)]. ##STR10##
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[C:5]([CH3:17])=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH4+].[OH-].Cl>C(Cl)Cl.O.CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:25][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:6]2[C:5]([CH3:17])=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1nc(C)c2c(Cl)c3ccccc3nc21
Reactant: NCc1ccccc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCn1nc(C)c2c(NCc3ccccc3)c3ccccc3nc21
Temperature: 80 °C
Yield: 66.2 %

Procedure:
A mixture of 1-ethyl-3-methyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and benzylamine (0.98 ml, 9 mmol) is heated at 80° C. overnight. The reaction mixture is poured into water (100 ml), then NH4OH (0.5 ml) is added. The mixture is extracted with CH2Cl2 (200 ml) and the CH2Cl2 is concentrated to about 20 ml, and then this solution is purified by column chromatography on silica gel, followed by high pressure liquid chromatography eluting with 20% ethyl acetate/hexane to afford the product as the free base. The free base is dissolved in CH2Cl2 (20 ml) and treated with ethereal HCl. The mixture is evaporated and the residue is crystallized from ether to afford 0.9 g of 1-ethyl-3-methyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine.HCl, as an off white solid, m.p. 228°-231° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[OH:18].[CH2:19]1N2CN3CN(C2)CN1C3.O.Cl>C(O)(=O)C.O>[C:10]([C:9]1[C:4]([CH2:3][NH:2][CH3:19])=[C:5]([OH:18])[CH:6]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CC(C)(C)c1cc(O)c(CN)c(C(C)(C)C)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CNCc1c(O)cc(C(C)(C)C)cc1C(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 1.25 g (4.60 mmol) of the product of Example 19 (as the hydrochloride salt) in 10 mL of acetic acid-water (11:3) was added 0.75 g (5.35 mmol) of hexamethylenetetramine. The mixture was refluxed for 3 h then treated with 6 mL of water and 3 mL of conc. hydrochloric acid. Heating was continued for 10 min at which point the reaction mixture was cooled and concentrated in vacuo to remove the acetic acid. The residue was partitioned between EtOAc and water, and the aqueous layer was separated and extracted. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The product was purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)=O)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[F:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][C@@H:9]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1cccc(F)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To benzyl N-(tert-butoxycarbonyl)-3-fluoro-L-phenylalaninate (659 mg) was added a 4 M solution of hydrogen chloride in dioxane (8.82 mL), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain benzyl 3-fluoro-L-phenylalaninate hydrochloride (505 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.CCOC(C)=O>[N:13]([CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1cccc2cccnc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cccc2cccnc12
Reaction time: 4.5 h

Procedure:
To a solution of 1.0119 g (4.56 mmol) 20 in 25 mL of DMF was added 0.3557 g (5.47 mmol) sodium azide. After 4.5 h at room temperature, the reaction mixture was diluted with 80 mL EtOAc and washed with 40 mL brine. The aqueous layer was extracted with 20 mL EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (60×220 mm silica gel, linear gradient 5-20% (EtOAc:hexane) provided 21. 1H NMR (CDCl3, 400 MHz) δ 8.965 (dd, 1H, J=1.74, 4.21 Hz, ArH); 8.185 (dd, 1H, J=1.74, 8.32 Hz, ArH); 7.823 (dd, 1H, J=1.12, 8.32 Hz, ArH); 7.743 (d, 1H, J=6.95 Hz, ArH); 7.555 (dd, 1H, J=7.18, 8.10 Hz, ArH); 7.455 (dd, 1H, J=4.21, 8.23 Hz, ArH); 5.065 (s, 2H, ArCH2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]3[C:19]([C:20]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[O:21])=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=1)[N:6]=[CH:5]2.FC(F)(F)C(O)=O>ClCCl>[OH:25][CH2:24][C:23]([NH:22][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[CH:5]=[N:6]3)[N:12]=2)[NH:17][CH:18]=1)=[O:21])([CH3:27])[CH3:26]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(F)ccc43)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(-n3ncc4cc(F)ccc43)nc12
Reaction time: 15 h
Yield: 0.1 %

Procedure:
To a stirred solution of 2-(5-fluoro-1H-indazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 100 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo and a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane (25 mL) added. After 1 h the mixture was concentrated in vacuo and purified by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) to give 2-(5-fluoro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (25 mg, 68%). MS (M−H)−=367; 1H NMR (DMSO-d6) δ: 9.04 (s, 1H), 8.70 (dd, J=9.3, 4.6 Hz, 1H), 8.52 (d, J=0.8 Hz, 1H), 8.41 (s, 1H), 7.76 (dd, J=8.9, 2.3 Hz, 1H), 7.63 (s, 1H), 7.49 (d, J=2.6 Hz, 1H), 3.57-3.62 (m, 2H), 1.44 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>>[CH3:33][N:34]([CH3:38])[C:35]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32])=[O:36]
Reactant: CN(C)C(=O)Cl
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and dimethylcarbamyl chloride employing methods similar to those described in Step 2 of Example 373 and was obtained as a lyophile: ES+ MS: 514 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][O:12]C(=O)C)[C:9]=1[Cl:10])=[O:4].[OH-].[Na+]>O1CCOCC1.O>[C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][OH:12])[C:9]=1[Cl:10])([OH:4])=[O:2]
Reactant: COC(=O)c1scc(COC(C)=O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1scc(CO)c1Cl
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of 2-methoxycarbonyl-3-chloro4-(acetoxymethyl)thiophene (83 g, 0.33 mol) in 1,4-dioxane (350 mL) was added a solution of sodium hydroxide (26.5 g, 0.66 mol) in water (200 mL) and the mixture stirred at ambient temperature. After 1 hour the dioxane was removed in vacuo and the aqueous solution washed with ethyl acetate (2×100 mL). The aqueous layer was brought to pH 2 by addition of concentrated HCl, then extracted with n-butanol (4×200 mL). The combined extracts were concentrated and the resulting solid dried in vacuo to afford 63 g (90% yield) of 2-carboxy-3-chloro-4-(hydroxymethyl)thiophene as a tan powder; NMR (DMSO-d6) 7.7 (s, 1), 4.4 (s, 2) ppm.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[ClH:13].Cl.[CH3:15][O:16][C:17]1[CH:31]=[CH:30][C:20]([C:21](=[O:29])[CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:1].[ClH:13].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21](=[O:29])[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:2][C:3]([NH:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:4])[CH2:25][CH2:24]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(C(=O)CN2CCNCC2)cc1
Reactant: O=C(CCl)NCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CN2CCN(CC(=O)NCc3ccccc3)CC2)cc1

Procedure:
A mixture of chloroacetylbenzylamine (3.06 mmol), N-(4-methoxyphenacyl) piperazine dihydrochloride (3 mmol, prepared by using the general preparation 1) and K2CO3 (10.5 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-28), 0.86 g (74%), M+ 381.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[BH4-].[Na+].CCOC(C)=O.O>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(O)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 3-chloro-4-hydroxybenzaldehyde (4.697 g, 30.0 mmol) and to trimethoxyborate (0.5 mL) in THF (20 mL) and EtOH (20 mL) was added NaBH4 (2.0 g, 52.87 mmol) in small portions over a period of 8 hours. The mixture was stirred overnight and EtOAc (100 mL) and water (50 mL) were added. The organic layer was separated and washed with 2M KHSO4 (30 mL) and brine (30 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO2, CHCl3/acetone (0.3:1)] followed by recrystallistion from EtOAc/hexane to give CAB06028 (3.82 g, 80%) as fine colorless needles: Mp. 126-127° C.; 1H NMR (400 MHz, DMSO-d6) δ 4.36 (d, J=6.5 Hz, 2H), 5.11 (t, J=6.5 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 7.06 (dd, J=82, 2.0 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 9.99 (s, 1H); 13C NMR (100.6 MHz, DMSO-d6) δ 62.1, 116.3, 119.2, 126.4, 128.1, 134.5, 151.7; LRMS (ES−): m/z 156.9 (100%, [M−H]).
Reaction SMILES: [Cl:1][C:2]([C:4]1([C:10]([O:12]C)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[CH2:3].[OH-].[K+].C(O)(C)C>O>[Cl:1][C:2]([C:4]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[CH2:3]
Reactant: C=C(Cl)C1(C(=O)OC)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: C=C(Cl)C1(C(=O)O)CCCCC1

Procedure:
13 g of methyl 1-(1'-chlorovinyl)-cyclohexylcarboxylate were refluxed with 4 g of potassium hydroxide, 20 cm3 of isopropanol and 10 cm3 of water for 6 hours. A solid was obtained by evaporating off the alcohol and this solid was dissolved in water. The basic aqueous solution was washed with ether and then acidified with dilute hydrochloric acid. The expected 1-(1'-chlorovinyl)-1-cyclohexyl-carboxylic acid was extracted with ether. After evaporating off the solvent, the product was purified by recrystallisation from pentane and colourless crystals were obtained.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([CH3:16])=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>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>[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28]([C:12]3[CH:13]=[CH:14][C:9]([C:8]4[O:7][N:6]=[C:5]([CH3:16])[C:4]=4[CH2:1][CH:2]=[CH2:3])=[CH:10][CH:11]=3)=[CH:27][CH:26]=2)[CH2:23][CH2:24]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=CCc1c(C)noc1-c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CCc1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 4-allyl-5-(4-bromo-phenyl)-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:3]=1/[CH:4]=[CH:5]/[C:6]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14](=[O:22])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[CH3:28][O:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:3](/[CH:4]=[CH:5]/[C:6]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[C:2]=1[NH:1][S:30]([CH3:29])(=[O:32])=[O:31]
Reactant: COc1cccc(/C=C/c2nc3ccccc3c(=O)n2-c2ccccc2)c1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cccc(/C=C/c2nc3ccccc3c(=O)n2-c2ccccc2)c1NS(C)(=O)=O
Yield: 83.9 %

Procedure:
A solution of 14 (123 mg, 0.333 mmol) and MsCl (260 μL, 3.33 mmol) in pyridine (20 mL) was heated to ˜70° C. under N2 for 2 days. The mixture was concentrated in vacuo, and the residue was dissolved in CHCl3, washed with 10% citric acid, dried and concentrated in vacuo. The crude product was purified by flash chromatography eluting with EtOAc/DCM (5-20%) to give pure 15 as a white solid (125 mg, 84%). MS (APCI): m/z 448 (100%, [M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(C)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1ccc(C)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-methoxy-5-methylaniline (40 mg, 0.290 mmol) similar to Example 58 and isolated as a yellow solid (41 mg, 59%). 1H NMR (CDCl3): 9.66 (d, J=1.8 Hz, 1H), 8.74–8.70 (m, 2H), 7.98 (s, 1H), 7.55 (s, 1H), 7.44–7.40 (m, 1H), 6.99–6.95 (m, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 3.89 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9][CH2:8][C:7]=2[N:20]=1>Br>[CH3:13][CH:12]1[CH2:11][NH:10][CH2:9][CH2:8][C:7]2[N:20]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]1=2
Reactant: COc1ccc2c(n1)CCN(C(=O)C(F)(F)F)CC2C
Agent: Br
Product: CC1CNCCc2nc(O)ccc21

Procedure:
2-Methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (1.99 g, 6.90 mmol) in 48% aq. HBr (15 ml) was heated at reflux for 18 h. Evaporation of aq. HBr rendered 1.78 g (99%) of hydrobromide salt of 5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (D2O) δ 7.78 (d, 1H), 6.66 (d, 1H), 3.55-3.10 (m, 7H), 1.36 (d, 3H) ppm.
Reaction SMILES: N1CCCC1.B.O1CCCC1.C([Li])CCC.[CH2:17]([CH:19]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:20](N(C(C)C(O)C1C=CC=CC=1)C)=[O:21])[CH3:18]>>[CH2:17]([C@@H:19]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:20][OH:21])[CH3:18]
Reactant: CCC(C(=O)N(C)C(C)C(O)c1ccccc1)c1ccccc1
Agent: B
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CC[C@H](CO)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A dry 200 mL Schlenk flask equipped with a magnetic stirrer was cooled to 0° C. and charged with pyrrolidine (1.61 mL, 19.27 mmol, 3.0 equiv) and borane.tetrahydrofuran (1.0M in tetrahydrofuran, 19.27 mL, 19.27 mmol, 3.0 equiv). The mixture was warmed to 23° C. and stirred for 1 hour, before being recooled to 0° C. n-Butyllithium (1.71M in hexanes, 11.27 mL, 19.27 mmol, 3.0 equiv) was added, and the reaction was stirred at 0° C. for 30 minutes. The ice bath was removed, and [1S-[1R*(R*), 2R*]]-α-ethyl-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl benzeneacetamide (1.99 g, 7.21 mmol, 1.0 equiv) was added neat, and the reaction was stirred at 23° C. overnight. The reaction was quenched with aqueous hydrochloric acid, diluted with 1N HCl (300 mL), and extracted with ether (4×60 mL). The ether extracts were washed with 1:1 brine/1N HCl (2×15 mL), and then concentrated. The residue was stirred in 1N NaOH (100 mL) for 30 minutes at 23° C., and extracted with ether (4×25 mL). These ether extracts were washed with 1:1 brine/1N NaOH (2×20 mL),, dried over sodium sulfate, and concentrated. Flash chromatography (40% ether/petroleum ether) of the residue afforded the desired alcohol (819 mg, 85% yield) as a colorless oil: 1H NMR (300 MHz, C6D6) δ7.0-7.2 (m, 5H), 3.48 (m, 2H), 2.44 (m, 1H), 1.58-1.65 (m, 1H), 1.36-1.45 (m, 1H), 0.91 (t, 1H, J=5.3 Hz), 0.72 (t, 3H, J=7.4 Hz); 13C NMR (75.5 MHz, CDCl3) δ: 142.2, 128.6, 128.1, 126.6, 67.3, 50.4, 24.9, 11.9; FTIR (neat film) cm-1: 3354 (br, s), 3028 (m), 2961 (s), 2930 (s), 2874 (s), 1602 (w), 1494 (s), 1454 (s), 1379 (m), 1038 (S), 760 (S), 700 (S).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.C(C(NC1C=C[C:22]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])=CC=1)(C)C)#N>>[C:11]([CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]2([C:28]#[N:29])[CH2:22][CH2:25][CH2:26]2)=[CH:7][CH:6]=1)#[N:12]
Reactant: N#CCCCc1ccc(N)cc1
Reactant: CC(C)(C#N)Nc1ccc(CCCC#N)cc1
Product: N#CCCCc1ccc(NC2(C#N)CCC2)cc1

Procedure:
Compound 85 was prepared from compound 83 in a manner similar to synthesis of 84.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1)[NH2:25]>>[NH2:25][C:24]1[CH:26]=[CH:27][C:28]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[C:22]([F:21])[CH:23]=1
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3F)ccn2c1=O
Yield: 69.8 %

Procedure:
Methyl 8-(4-amino-2-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (122 mg, 0.51 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (87 mg, 64%). ESI-MS m/z: 367 (M+H)+.