Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:5][C:4]([CH3:19])=[C:3]1[C:20](O)=[O:21].COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=C(O)N=1)=O.CI.C(=O)([O-])[O-].[Cs+].[Cs+].COC(C1N(C)C(=O)C(C2C=CC=C(C(F)(F)F)C=2)=CC=1C)=O.[OH-].[Li+].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[N:89]1([CH:94]2[CH2:99][CH2:98][NH:97][CH2:96][CH2:95]2)[CH2:93][CH2:92][CH2:91][CH2:90]1>CN(C=O)C.C1COCC1.CO.C(Cl)Cl>[CH3:1][N:2]1[C:3]([C:20]([N:97]2[CH2:98][CH2:99][CH:94]([N:89]3[CH2:93][CH2:92][CH2:91][CH2:90]3)[CH2:95][CH2:96]2)=[O:21])=[C:4]([CH3:19])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:7]1=[O:8]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: COC(=O)c1[nH]c(=O)c(-c2cccc(C(F)(F)F)c2)cc1C
Agent: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)c(=O)n1C
Agent: COC(=O)c1nc(O)c(-c2cccc(C(F)(F)F)c2)cc1C
Solvent: C1CCOC1
Solvent: CI
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 13, 1,3-dimethyl-6-oxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-2-carboxylic acid [prepared by i) reaction of 6-hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester; 3-methyl-6-oxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-2-carboxylic acid methyl ester (tautomers, intermediate 15B) with methyl iodide, cesium carbonate in DMF in analogy to the procedure described for the preparation of intermediate 5F; ii) saponification of the thus formed 1,3-dimethyl-6-oxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-2-carboxylic acid methyl ester with lithium hydroxide in THF/MeOH in analogy to the procedure described for the preparation of intermediate 5G] was reacted with oxalyl chloride/DMF in CH2Cl2 followed by treatment with 4-pyrrolidin-1-yl-piperidine to give the title compound as colorless solid. MS: 448.2 (MH+).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10]Br.CCOCC>[Na].C(O)C>[C:1]1([S:7][CH2:10][CH2:9][Br:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: BrCCSc1ccccc1

Procedure:
33 g of thiophenol were dissolved in a solution of 6.9 g of sodium in 120 ml of ethanol and the solution was added dropwise to 129 ml of 1,2-dibromoethane. The mixture was heated under reflux for 1 hour and cooled and 250 ml of ether were added. The salt which had precipitated out was filtered off. The filtrate was concentrated and the evaporation residue was fractionated. 55.4 g of a colourless oil with a boiling point of 125° to 130° C. under 12 mm Hg were obtained.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([C:10]([NH2:12])=[O:11])[CH2:6][C@H:5]1[OH:13])=[N+]=[N-].CO.[CH3:16][C:17]([OH:19])=[O:18]>[Pd]>[C:17]([OH:19])(=[O:18])[CH3:16].[NH2:1][C@@H:4]1[CH2:9][CH2:8][C@@H:7]([C:10]([NH2:12])=[O:11])[CH2:6][C@H:5]1[OH:13]
Reactant: [N-]=[N+]=N[C@@H]1CC[C@@H](C(N)=O)C[C@H]1O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)[C@@H]1CC[C@@H](N)[C@H](O)C1
Reaction time: 22 h

Procedure:
To (1R,3R,4R)-4-azido-3-hydroxy-cyclohexanecarboxylic acid amide (351c) (765 mg, 4.15 mmol) in MeOH/AcOH (9:1, 30 mL) was added Pd/C (10%, 300 mg), and the mixture hydrogenated under atmospheric pressure for 22 h. On completion of reaction the mixture was filtered through Celite®, the filter pad washed with MeOH, and the combined organic solutions concentrated in vacuo to give a white solid in quantitative yield.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.[C:26]([NH:34]N)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19][NH:34][C:26]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=[O:33]
Reactant: NNC(=O)c1ccncc1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NNC(=O)c1ccncc1)C(=O)N2
Yield: 68 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and isonicotinic acid hydrazide and following the method described in Example 21, the desired compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH:8]=1)[CH3:2]>O1CCCC1.C(O)C.[H][H].[C].[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:16](=[O:20])[N:17]([CH3:18])[CH3:19])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N)c(C(=O)N(C)C)c1
Yield: 69.6 %

Procedure:
3-(3-Dimethylcarbamoyl-4-nitrophenyl)propionic acid ethyl ester (1.52 g) was dissolved in a mixed solution of THF (tetrahydrofuran) (15 mL) and ethanol (15 mL). 7.5% (w/w) palladium-carbon (300 mg) was added thereto, followed by stirring overnight at normal pressure in hydrogen atmosphere. The reaction solution was filtered through a Celite pad and concentrated to give the title compound (0.950 g) as a pale yellow oil.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[S:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:17][C:18](OCC)=[O:19]>C(O)C>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[S:14][CH:17]=[C:18]([OH:19])[N:15]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCl
Reactant: NC(=S)Nc1ccn(-c2ccccc2)n1
Solvent: CCO
Product: Oc1csc(Nc2ccn(-c3ccccc3)n2)n1

Procedure:
A solution of N-(1-phenyl-1H-pyrazol-3-yl)thiourea (4.2 g) and ethyl 2-chloroethanoate (3.0 g) in ethyl alcohol (50 ml) was heated under reflux for 2 hours. The mixture was cooled and the title compound collected by filtration as a yellow solid 4.0 g, mp >230°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Cl[C:15]1[C:16]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)[CH2:23][CH2:22]2)=[N:17][CH:18]=[CH:19][N:20]=1.CN(C)C(=O)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:33][N:31]1[CH:32]=[C:28]([CH2:27][N:24]2[CH2:23][CH2:22][N:21]([C:16]3[C:15]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=4)=[N:20][CH:19]=[CH:18][N:17]=3)[CH2:26][CH2:25]2)[CH:29]=[N:30]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1cc(CN2CCN(c3nccnc3-c3cccc(C(F)(F)F)c3)CC2)cn1
Temperature: 110 °C
Yield: 57.8 %

Procedure:
Charge a carousel tube with 3-trifluoromethylbenzeneboronic acid (136 mg, 0.66 mmol), 3′-chloro-4-(1-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (160 mg, 0.55 mmol) and N,N-dimethylacetamide (1 mL). Add N,N-dimethylacetamide (3 mL) and potassium carbonate (185 mg, 1.32 mmol) and purge with nitrogen for about 45 min. Add water (2 mL, purged with nitrogen for 1 hr.) then tetrakis(triphenylphosphine)palladium(0) (0.003 g, 0.0025 mmol) and purge the reaction vessel for about 30 min. Heat at 110° C. overnight. Cool to room temperature, add water and extract with DCM (3×30 mL), and then concentrate the combined DCM extracts. Purify using silica gel chromatography, followed by reverse phase HPLC, to give the title compound (128 mg, 58%). MS (ES): m/z=403.1 [M+H]+.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH3:19][S:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:22])=[O:21]>>[Cl:14][C:13]1[C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:27]3[CH:28]=[CH:29][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][CH:26]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: Clc1cccc2c1CCc1ccccc1C2=CBr
Product: CS(=O)(=O)Nc1ccc(C=C2c3ccccc3CCc3c(Cl)cccc32)cc1

Procedure:
Following procedures essentially as described in Example 219, below, and using 5-bromomethylene-1-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.313 mmol) and 4-methanesulfonylaminophenylboronic acid (74 mg, 0.344 mmol), affords 55 mg (43%) of a mixture of geometric isomers of the title compound as a brown oil. MS (ES) 408 (M−H); HPLC shows 96% purity.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[CH2:26][NH:25][CH2:24][CH:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]=3[N:22]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1.C(N(C(C)C)CC)(C)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[CH2:26][N:25]([C:42](=[O:44])[CH3:43])[CH2:24][CH:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]=3[N:22]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: CC(=O)Cl
Reactant: COc1cc(Nc2ncc3c(n2)C(c2ccccc2)CNC3)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(Nc2ncc3c(n2)C(c2ccccc2)CN(C(C)=O)C3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
To a suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(8-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-amine hydrochloride (65 mg, 0.15 mmol) in methylen chloride (2 mL) was added at room temperature NN,-diisopropyl ethyl amine (28 mg, 0.22 mmol) and after 2 minutes acetyl chloride (12.5 mg, 0.16 mmol). The reaction was stirred at room temperature over night. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (20 mg, 30%) as a yellow gum. MS ISP (m/e): 455.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.38 (s, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.20-7.33 (m, 3H), 7.05-7.08 (m, 3H), 6.81 (s, 1H), 6.79 (d, 1H), 5.18 (d, 1H), 4.46 (d, 1H), 4.21 (t, 1H), 3.90 (m, 2H), 3.46 (s, 3H), 2.27 (s, 3H), 1.71 (s, 3H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13](O)[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[C:5]([F:17])=[CH:4][N:3]=1.[F:18]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C(#N)C.O.CCOC(C)=O.CCCCCCC>[F:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@@H:13]([F:18])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[C:5]([F:17])=[CH:4][N:3]=1
Reactant: C[C@@H](O)[C@H]1COC(=O)N1c1nc(F)ncc1F
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: C[C@H](F)[C@H]1COC(=O)N1c1nc(F)ncc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 47.5 %

Procedure:
To a round bottom flask containing a solution of (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (4.64 g, 18.9 mmol) in Acetonitrile (63 mL) cooled to 0° C. was added perfluorobutanesulfonyl fluoride (10.2 mL, 56.8 mmol) followed by the addition of triethylamine trihydrofluoride (9.2 mL, 56.8 mmol) and triethylamine (23.7 mL, 170 mmol). The resulting reaction mixture allowed to stir at 0° C. for 4 hr. The reaction mixture was then diluted with water and the aqueous mixture was extracted with EtOAc. The organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided a white crystalline of (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one (2.24 g, 8.97 mmol, 47% yield). 1H NMR (400 MHz, CDCl3) 8.50 (s, 1H), 5.00-5.25 (m, 1H), 4.75-4.92 (m, 1H), 4.54-4.68 (m, 2H), 1.39 (dd, J=23.1, 7.0 Hz, 3H). LCMS m/z 248.0 (M+H)+, Rt 0.52 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCCC1>[ClH:24].[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH2:22])=[O:23])=[CH:17][N:16]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(N)=O)cn2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(OC2CCNCC2)nc1
Yield: 89 %

Procedure:
Combine 4-(5-carbamoyl-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (1559 mg, 4.85 mmol) in tetrahydrofuran (25 mL) with hydrochloric acid (4.0 M in dioxane, 15 mL). Stir the resulting reaction mixture for 48 h. Filter the white precipitate washing with EtOAc (10 mL). Redissolve the white solid in methanol and concentrate to provide the title compound (1195 mg, 89%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:6][CH2:7]1)(=[O:35])[CH3:34]
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH2:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:20]>>[C:22]([N:21]([CH2:19][CH3:20])[C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CCNC(C)(C)C
Product: CCN(C(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and N-ethyl-2-methylpropan-2-amine (CAN 4432-77-3) as starting materials and isolated (50 mg, 47%) as a light yellow solid; MS (ESI, m/z): 345.7 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CN(C=O)C>[C:35]([O:34][C:32](=[O:33])[CH2:31][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([O:12][CH3:13])=[O:11])=[CH:16]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1cn(CC(=O)OC(C)(C)C)c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a 0° C. solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)propanoate (4 g, 12.56 mmol) and cesium carbonate (4.50 g, 13.82 mmol) in DMF (40 mL) was added tert-butyl 2-bromoacetate (2.015 mL, 13.82 mmol) and was allowed to warm up to RT by removing from ice bath and stirred for 18 hrs. The reaction was poured into 1:1 ice water:1N HCl and extracted with EtOAc. The organic layer washed with brine, collected, dried over MgSO4, filtered and evaporated to give the crude product. The crude product was purified via silica gel chromatography (80 g column, 0-50% EtOAc:Hexanes over 20 CV) to get the product (S)-methyl 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (4.69 g, 86% yield). 1H NMR (400 MHz, chloroform-d) d 7.56 (d, J=7.8 Hz, 1H), 7.26-7.18 (m, 2H), 7.17-7.12 (m, 1H), 6.92 (s, 1H), 5.09 (d, J=7.6 Hz, 1H), 4.71 (s, 2H), 3.73-3.59 (m, 3H), 3.30 (d, J=5.1 Hz, 2H), 1.45 (s, 18H). ESI-MS(+) m/z=433 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)(C)(C)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29](O)=[O:30])=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24]([C:29]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]3[CH2:8][NH:7][C:6](=[O:15])[OH:5])=[O:30])=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:21][CH:22]=1
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCC[C@H]2CNC(=O)O)n1
Yield: 110 %

Procedure:
The title compound (3.96 g) was prepared from (S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.14 g) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl carboxylic acid (2.20 g) according to the method of D40.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([N:17]=[CH:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[N:3]=1.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>C(#N)C>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)=[CH:6][N:5]=[C:4]([N:17]=[CH:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[N:3]=2)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(C)N(C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Reactant: CC(=O)N1CCNCC1
Solvent: CC#N
Product: CC(=O)N1CCN(c2nc(N=CN(C(C)C)C(C)C)ncc2C#Cc2ccc(Cl)cc2)CC1

Procedure:
A mixture of 0.8 g of 4-chloro-5-(4-chlorophenylethynyl)-2-diisopropylaminomethyleneamino-pyrimidine, 35 mL acetonitrile and 0.71 g 1-acetyl piperazine was refluxed for one and one half hours. A green solution initially forms and the color changes to amber on continued heating. The solution was evaporated in vacuo and partitioned between dichloromethane and water. The organic phase was washed twice with water, dried over sodium sulfate, filtered and evaporated. The orange-brown brittle foam obtained was purified by column chromatography on silica gel, eluting initially with dichloromethane and then with 15% methanol/dichloromethane to give the intermediate derivative, 4-(-4-acetyl piperazino)-5-(4-chlorophenylethynyl)-2-diisopropylaminomethyleneaminopyrimidine. Heating 0.6 g of the intermediate with 40 mL methanolic ammonia in a bomb at 120° C. for 18 hours gave on evaporation in vacuo, a cocoa-colored residue which was purified by column chromatography on silica gel. The desired product 4-(4-acetylpiperazino)-2-amino-5-(4-chlorophenylethynyl)pyrimidine was obtained by elution with 5% methanol/dichloromethane, evaporation and trituration with methanol yielding 0.27 g, m.p. 165° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu]I.CCCCCC.C(OCC)(=O)C.O1CCOCC1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(Br)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2ccc3ccccc32)cc1
Yield: 95 %

Procedure:
Using the general procedure outlined in Example 63, indole (0.117 g, 1.00 mmol) was coupled with 4-bromotoluene (185 μL, 1.50 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-1,2-cyclohexanediamine (24 μL, 0.20 mmol, 20 mol %) and dioxane (1.0 mL) to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 50:1) provided 0.197 g (95% yield) of the product as a white solid. This product was pure by 1H NMR when compared to the known spetra.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]2[CH3:34])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH2:24][OH:25])[CH:23]=3)=[N:14][C:12]=2[N:13]=1.[P:35](=O)([OH:38])([OH:37])[OH:36]>C(OCC)(=O)C>[P:35]([O:25][CH2:24][C:22]1[CH:23]=[C:18]([C:15]2[CH:16]=[CH:17][C:11]3[C:10]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]4[CH3:34])=[N:9][C:8]([N:3]4[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]4[CH3:1])=[N:13][C:12]=3[N:14]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH3:27])([OH:38])([OH:37])=[O:36]
Reactant: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1CO
Reactant: O=P(O)(O)O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1COP(=O)(O)O
Temperature: 25 °C

Procedure:
On a 50 mg scale using a 1:1.1 molar ratio of (5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol:Phosphoric acid. 50 mg of (5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol was dissolved in the minimal amount of Ethyl Acetate, this solution was then added drop-wise to a vial containing the phosphoric acid which caused a yellow solid to immediately precipitate. The experiment was then left to stir over night at room temperature before filtering and isolating the precipitate.
Reaction SMILES: [O-][CH2:2]C.[Na+].[C:5]([C:10]1[O:11][C:12]([CH3:17])=[C:13]([OH:16])[C:14]=1[OH:15])([O:7][CH2:8][CH3:9])=[O:6].[I-].[Na+]>C(O)C>[C:5]([C:10]1([CH3:2])[C:14](=[O:15])[C:13]([OH:16])=[C:12]([CH3:17])[O:11]1)([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1oc(C)c(O)c1O
Reactant: CC[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C)OC(C)=C(O)C1=O

Procedure:
In a 250 ml three-necked flask fitted with a mechanical stirrer and a gas inlet tube is placed a solution of 3.4 g of sodium ethoxide in 100 ml of ethanol. To the stirred solution is added at room temperature, under nitrogen, 9.3 g of 2-carbethoxy-5-methyl-3,4-dihydroxy-furan and 0.5 g of sodium iodide. Gaseous methyl bromide is bubbled through the vigorously stirred reaction mixture at 50°-60° C. till the pH of the reaction mixture reaches 6.5-7.0. The solvent is removed under vacuum and the residue is dissolved in ether. The sodium bromide is filtered off, the ether solution is concentrated under vacuum and the residue is distilled through a short Vigreux column; 2-carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy-2H-furan is collected at 102°-105° C./0.2 mm. Yield 8.1 g (81%), recrystallized from cyclohexane, m.p. 89.8°-90.1° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:5][CH:4]=1>ClCCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccccc2NS(C)(=O)=O)cc1
Solvent: ClCCCl
Product: CS(=O)(=O)Nc1ccccc1-c1ccc(O)cc1
Yield: 90.1 %

Procedure:
The procedure of Preparation Example 2 was repeated, except that 208 mg of N-(4′-methoxybiphenyl-2-yl)methanesulfonamide was used in place of 4′-methoxy-2-biphenylacetonitrile, and 1,2-dichloroethane was used in place of methylene chloride. The resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 178 mg of N-(4′-hydroxy-biphenyl-2-yl)methanesulfonamide.