Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]([N:24]2[CH:28]=[N:27][N:26]=[CH:25]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17](Br)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].C(COC)OC.C([O-])([O-])=O.[Na+].[Na+]>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].CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]([N:24]2[CH:28]=[N:27][N:26]=[CH:25]2)[C:15]2[CH:16]=[C:17]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)cc2)n2cnnc2)cc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2cc(N(Cc3ccc(OCc4ccccc4)cc3)n3cnnc3)ccc2C#N)cc1
Reaction time: 5 h

Procedure:
A mixture of 4-((4-(benzyloxy)benzyl)(4H-1,2,4-triazol-4-yl)amino)-2-bromobenzonitrile (CAB05114, 0.460 g, 1.0 mmol), 4-cyanophenylboronic acid (0.184 g, 1.25 mmol), dimethoxyethane (20 mL) and 2M Na2CO3 (20 mL) was heated to reflux before Pd2(dba)3 (0.05 g) was added and heating was continued for 5 hours. After cooling to room temperature EtOAc (50 mL) was added to and the mixture was filtered (celite). The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO2, CHCl3/acetone (2:1)] to afford CAB06075 (4.03 g, 71%) as a white solid. Mp. 234-237-113° C.; 1H NMR (400 MHz, DMSO-d6) δ 5.02 (s, 4H), 6.72 (dd, J=8.6, 2.7 Hz, 1H), 6.91 (d, J=2.7 Hz, 1H), 6.95 (AA′BB′, 2H), 7.21 (AA′BB′, 2H), 7.30-7.45 (m, 5H), 7.75 (AA′BB′, 2H), 7.90 (d, J=8.6 Hz, 1H), 8.02 (AA′BB′, 2H), 8.75 (s, 2H); 13C NMR (100.6 MHz, DMSO-d6) δ 56.5, 69.2, 101.7, 111.7, 113.4, 113.7, 114.1, 114.8, 118.3, 118.4, 126.4, 127.8, 127.9, 128.4, 129.7, 130.0, 130.1, 132.7, 135.6, 136.9, 142.3, 143.3, 144.5, 145.9, 151.5, 158.2; LRMS (ES+): m/z 4833 (100%, [M+H]+); HRMS (ES+) calcd for C30H23N6O [M+H]+: 483.1928. found 483.1918.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[C:10]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([Br:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(N)cc1Br
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C)c(Br)c1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of 3-bromo-4-methylaniline (1.27 g, 6.82 mmol) in DCM (20 mL) at (0° C. is added acetic anhydride (0.676 mL, 7.16 mmol) dropwise. After 30 minutes, the mixture is partitioned between DCM and saturated sodium carbonate solution. The layer is separated and the aqueous layer is extracted with DCM. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound (1.55 g, 99%). The residue is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:20])[C:8]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][C:10](OC)([CH3:12])[CH:11]=1)[CH2:2][CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH2:1]([O:5][C:6]1[C:7](=[O:20])[C:8]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][C:10](=[CH2:12])[CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC1=CC(C)(OC)C=C(OCCCC)C1=O
Agent: [Al+3]
Agent: [Cl-]
Product: C=C1C=C(OCCCC)C(=O)C(OCCCC)=C1
Yield: 97.9 %

Procedure:
The procedure of Example 6 was repeated by using 250 mg of 2,6-dibutoxy-4-methoxy-4-methyl-2,5-cyclohexadienone and 20 mg of aluminum chloride, recovering 234 g of an oily crude product. The crude product was purified by silica gel column chromatography using a 20:1 benzene-ethyl acetate mixture, giving 217 mg of 2,6-dibutoxy-4-methylidene-2,5-cyclohexadienone in 87% of theoretical yield. The compound thus obtained was identified by NMR.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][C:3]1[C:4]([NH2:5])=[CH:6][CH:7]=[CH:8][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1
Reactant: Cc1c(N)cccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2cccc(N)c2C)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 93 %

Procedure:
To a solution of 3-bromo-2-methylaniline (15 g, 0.0806 mol) in 1,2-dimethoxyethane (330 ml) and water (165 ml) was added 4-methylphenylboronic acid (12.05 g, 0.0886 mol) and sodium carbonate (22.2 g, 0.2095 mol). The apparatus was flushed with nitrogen prior to the addition of tetrakis(triphenylphosphine) palladium (0) (1.86 g, 1.61 mmol). The resultant mixture was heated at 90° C. and stirred under nitrogen for 22 h, then allowed to cool to room temperature and the solvents removed in vacuo. The residue was partitioned between EtOAc (2×400 ml) and water (400 ml). The organic solution was dried (Na2SO4) and the solvent was removed in vacuo. Purification by Biotage™ chromatography (4×90 g Si column) eluted with 9:1 to 8:1 EtOAc:cyclohexane afforded the title compound as a yellow oil (14.78 g).
Reaction SMILES: [CH2:1]([CH:8]([C:25]([O-:27])=[O:26])[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28]CCCl>>[CH2:1]([CH:8]1[C:25](=[O:26])[O:27][C:10]([Cl:28])([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(Cc1ccccc1)C(=O)[O-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: ClCCCl
Product: O=C1OC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1Cc1ccccc1

Procedure:
In 18 ml of 1,2-dichloroethane was dissolved 475 mg of the Compound (73) obtained in Example 73. The solution was heated for 5 hours under reflux. The solvent was evaporated off, and the residue was subjected to a column chromatography using Florisil, followed by elution with hexaneethyl acetate (5:1) to give 370 mg of the subject Compound (74) as a pale yellow oily product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(Cl)cc1F
Product: O=C(O)Cc1ccccc1Nc1ccc(Cl)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-fluoro-4-chloroaniline to yield 2-[(2-fluoro-4-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N-:13]=[N+:14]=[N-:15].[Na+].O>CS(C)=O>[N:13]([CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[N+:14]=[N-:15]
Reactant: O=C(CCCCl)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCCC(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To a solution of 4-chloro-1-phenylbutan-1-one (26.4 mL, 164 mmol) in DMSO (200 mL) was added sodium azide (12.8 g, 197 mmol). The solution was warmed to 55° C. and stirred for 16 hours. The cooled mixture was then treated with water and extracted with ether. The combined organics were washed with water and brine, then dried over MgSO4 and concentrated to provide the product as an orange oil (30.7 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:11]12[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=1)NC(=O)O[C:12]2=[O:13]>C(O)(=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]2[NH:9][C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=3[C:12](=[O:13])[NH:10][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1ccc(N)c(N)c1C
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CC(=O)O
Product: Cc1ccc2c(c1C)NC(=O)c1ccccc1N2
Temperature: 85 °C

Procedure:
3,4-Dimethyl-1,2-phenylenediamine (0.1 mol) was dissolved in acetic acid (70%) and then isatoic anhydride (0.1 mol) was added to the solution. The resulting mixture was heated at 85° C. for 3 hrs. The mixture was poured into ice-cold water and 8,9-dimethyl-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one was isolated (97%) by neutralization and filtration.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[O:13]CC(C)(C)N=2)=[C:7]([CH:19]2[O:24]CCC[O:20]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.S(=O)(=O)(O)O>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[C:9]([F:11])[CH:10]=1)[C:12](=[O:13])[O:20][CH:19]2[OH:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)COC(c2c(F)cc(C(C)(C)C)cc2C2OCCCO2)=N1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(c1)C(O)OC2=O
Yield: 106.5 %

Procedure:
1.8 g (5.4 mmol) of 2-(4-tert-butyl-2-1,3-dioxinan-2-yl-6-fluoro-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole was weighed into a 200 mL round bottom flask fitted with a stir bar and reflux condenser. Added 75 mL of ethanol and stirred to obtain a clear solution. Added 50 mL of 50% aqueous sulfuric acid. Stirred at reflux for 18 h. Poured the reaction mixture into 400 mL water. Extracted the aqueous mixture with 2×200 mL CH2Cl2. Combined the organic extracts and washed with 200 mL brine. Dried over Na2SO4 and removed the solvent on rotavap. Dried under high vacuum to obtain 1.29 g of the title compound as on off-white solid. MS (ESI) 223 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)[CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 1 (2), but with 3-trifluoromethylphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a sticky oil (1.2 mg, 4%) having the following characteristics.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:17]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23](=O)[CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:17]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][CH2:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(S(=O)(=O)N2CCC(=O)Nc3ccccc32)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CCCNc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a suspension of lithium aluminum hydride (168 mg) in tetrahydrofuran (10 ml) was added dropwise a solution of 5-(3,4-dimethoxybenzenesulfonyl)-1,3,4,5-tetrahydro -1,5-benzodiazepin-2(2H)-one (800 mg) at 0° C. The mixture was refluxed for 2.5 hours, and then the reaction was quenched with methanol. To the resulting mixture was added dropwise 2N sodium hydroxide solution (5 ml), and the mixture was stirred at ambient temperature for 30 minutes. The suspension was filtered through a bed of celite, and then the filtrate was diluted with ethyl acetate. The organic layer was washed with brine. Drying, filtering and the removal or solvents afforded a crude product. The crude product was chromatographed on silica gel (1% methanol in chloroform) to give 1-(3,4-dimethoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (435 mg) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N+:13]1[CH:21]=[C:20]2[N:15](C(=O)[NH:17][CH2:18][CH2:19]2)[CH:14]=1.O.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.O1CCOCC1>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:29][CH:30]=1.[CH3:12][N:13]1[CH:21]=[C:20]([CH2:19][CH2:18][NH2:17])[N:15]=[CH:14]1
Reactant: C[n+]1cc2n(c1)C(=O)NCC2
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc(CCN)c1
Temperature: 90 °C

Procedure:
A mixture of 2-methyl-5-oxo-5,6,7,8-tetrahydroimidazo[1,5-c]pyrimidin-2-ium 4-methylbenzenesulfonate (625.1 g), 4-methylbenzenesulfonic acid hydrate (406.6 g), 1,4-dioxan (9.38 litres) and water (625 ml) was heated at reflux (ca. 90° C.) for 2.5 h. when the reaction was complete by nmr. The reaction mixture was concentrated by distillation at atmospheric pressure collecting 7.03 litres. The concentrate was allowed to cool to ca. 77° C., and IMS-G (1.56 litres) was added. The resulting bright solution was allowed to cool and was seeded with [2-(1-methyl-1H-imidazol-4-yl)ethyl]amine bis(4-methylbenzenesulfonate) (0.625 g) at ca. 54° C. The suspension was allowed to cool to ca. 22° C. and aged for 40 min. The solid was filtered off and washed successively with 1,4-dioxan-IMS (3:1, 1.25 litres), and then 1,4-dioxan (2×1.25 litres), pulled dry and dried in vacuo at ca. 50° C. to yield the title compound, 866.3 g.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(CC)CC>CS(C)=O.O>[N:19]1([C:2]2[C:3]([CH:8]3[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2N2CCCCC2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.99 %

Procedure:
To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (200 mg, 0.74 mmol, see Preparation 2) and piperidine (69.2 mg, 0.84 mmol) in DMSO (5 mL) was added Et3N (149.5 mg, 1.48 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give tert-butyl 3-(3-(piperidin-1-yl)pyrazin-2-yl)azetidine-1-carboxylate (74). (194 mg, 0.56 mmol, yield 75.99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1([CH2:37][C@@H:38]2[CH2:42][CH2:41][CH2:40][NH:39]2)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:39]4[CH2:40][CH2:41][CH2:42][C@H:38]4[CH2:37][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with (S)-2-(1-pyrrolidinylmethyl)pyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z=583.95 (M+H+); retention time=0.58 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([O:37][CH3:38])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:39]([NH2:43])[CH:40]([CH3:42])[CH3:41]>>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][CH2:39][CH:40]([CH3:42])[CH3:41])[N:7]=2)[C:20]=1[O:37][CH3:38])(=[O:28])=[O:27]
Reactant: CC(C)CN
Reactant: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(Cl)n1
Product: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(NCC(C)C)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzenesulfonamide (150 mg, 0.259 mmol) and isobutylamine (0.259 mL, 2.59 mmol) the title compound was obtained as a yellow solid (17.8 mg, 11% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.31 (s, 1H), 7.78 (d, J=5.3 Hz, 1H), 7.59-7.70 (m, 1H), 7.33 (dd, J=7.9, 1.5 Hz, 1H), 7.20 (t, J=9.1 Hz, 2H), 6.97-7.15 (m, 3H), 5.53 (d, J=5.3 Hz, 1H), 3.66 (t, J=4.7 Hz, 4H), 3.40 (t, J=4.6 Hz, 4H), 3.20 (s, 3H), 2.99 (t, J=6.3 Hz, 2H), 1.64-1.85 (m, 1H), 0.83 (d, J=6.6 Hz, 6H). MS (ESI): 617.2 [M+H]+.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.[C:24]1([P:30](Cl)(Cl)=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCCCCC.CCOCC.C1CCCCC1>[C:24]1([P:30]2(=[O:31])[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[CH2:16][N:15]2[CH3:14])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: CNCc1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CN1Cc2ccc(Cl)cc2P1(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 13.2 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (7.87 g, 0.123 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. The resulting mixture was stirred for an additional 15 minutes and then cooled to -70° C. using a solid carbon dioxide-acetate bath. A solution of N-methyl-4-chloro-benzylamine (9.6 g, 0.06 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2 hours at 26° C. and then cooled to -70° C. using a solid carbon dioxide-acetone bath. A solution of phenylphosphonic dichloride (12.5 g, 0.064 mol) in 60 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to -20° C. The reaction mixture was allowed to cool to -70° C., after which time the solid carbon dioxide-acetone bath was removed and the reaction mixture was stirred for 2.5 hours. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 12 ml. of acetic acid. The cyclohexane was removed on a rotary evaporator, and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to yield a red oil. Distillation of the red oil at 180° C. and 0.25 mm yielded a yellow solid which was slurried in ether to yield 1-phenyl-2-methyl-6-chloro-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.2 g, 13% yield) as a pale yellow solid having a melting point of 159°-162° C. and the following analysis:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][OH:17])=[O:7].CC(C)([O-])C.[K+]>C1COCC1>[OH:17][CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1=[O:7]
Reactant: O=C(CCCCBr)Nc1ccccc1CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCCCN1c1ccccc1CCO
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A solution of 5-bromo-N-[2-(2-hydroxyethyl)phenyl]pentanamide a2-1 (938 g, 3.28 mol, 1 eq) in THF (6 l) is cooled at −5° C. Potassium tert-butoxide (552 g, 4.92 mol, 1.5 eq) is added portionwise, without exceeding 0° C., then the mixture is warmed up to room temperature. The reaction mixture is washed with a saturated aqueous solution of NaCl (3×2 l). The aqueous layers are extracted with dichloromethane (2×2 l), the combined organic layers are dried over MgSO4, filtered and condensed under reduced pressure. The residue is recrystallized from tert-butyl methyl ether to afford 510 g of 1-[2-(2-hydroxyethyl)phenyl]piperidin-2-one a2-2.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:11][C@H:10]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[N:12]1[CH2:13][C@H:14]([CH3:15])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:10]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:11]1
Reactant: C[C@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 99.7 %

Procedure:
A mixture of tert-butyl [(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate (13.4 g, 28.7 mmol) in MeOH (80 mL) was hydrogenated in the presence of 10% palladium on carbon (4.6 g) under 60 psi of hydrogen for 16 h. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to give the sub-title compound (12.5 g, 99%). LCMS calc. for C22H41N4O3Si (M+H)+: m/z=437.3. Found: 437.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[C:5](/[O:15][CH2:16][CH3:17])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])/[C:5](/[O:15][CH2:16][CH3:17])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)/C(=C/c1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCOC(=O)/C(=C/c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 1 f], (Z)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-acrylic acid ethyl ester (example 1a c]) was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole (example 3 a]) in the presence of cesium carbonate and potassium iodide to yield (Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acrylic acid ethyl ester as colorless solid.