Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.Cl.[NH2:13][CH2:14][C:15]#[N:16].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[C:14]([CH2:15][NH:16][C:7]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[C:10]([OH:9])=[O:11])=[O:8])#[N:13]
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Reactant: N#CCN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(+)-trans-Cyclohexane-1,2-dicarboxylic anhydride (100 mg, 0.65 mmol) was weighed into a 10 mL round bottom flask and aminoacetonitrile hydrochloride (135 mg, 1.46 mmol) and 4-(dimethylamino)pyridine (7.5 mg, 61 μmol) added. After adding tetrahydrofuran (2.0 mL) and triethylamine (0.20 mL, 1.4 mmol), the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between 1 M aqueous hydrochloric acid (30 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to give (1R,2R)-2-{[(cyanomethyl)amino]carbonyl}cyclohexanecarboxylic acid (as a colorless solid.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH:7]2[O:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[C:9](=[C:16]=[CH2:17])[CH2:8]2)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:25]1(I)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O.C(OCC)(=O)C.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>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([CH:7]2[O:11][CH:10]3[C:9]([C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH2:17])([O:14][C:13](=[O:15])[CH2:12]3)[CH2:8]2)=[CH:5][CH:6]=1
Reactant: Ic1ccccc1
Reactant: C=C=C1CC(c2ccc(C)cc2)OC1CC(=O)O
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: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(c1ccccc1)C12CC(c3ccc(C)cc3)OC1CC(=O)O2
Temperature: 85 °C
Reaction time: 4 h

Procedure:
(5-p-tolyl-3-vinylidene-tetrahydro-furan-2-yl)acetic acid (35 mg, 0.14 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol) and K2CO3 (84 mg, 0.61 mmol) were dissolved in 3 mL of dimethylformamide, followed by addition of PhI (68 μL, 0.61 mmol). The solution was stirred for 4 hours at 85° C. When the reaction was completed, H2O was added and the solution was stirred for 5 minutes. The mixture was diluted with ethyl acetate, washed with H2O and NaCl. Organic layer was separated and dried with anhydride MgSO4. Solvent was removed under reduced pressure, and the remnant was purified through silica gel tube chromatography (EtOAc:n-Hexane=1:15, v/v), thus providing products (27 mg, 58%).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH:6]([CH:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>CN(C=O)C.CCOC(C)=O>[CH2:10]([O:9][C:7](=[O:8])[CH:6]([NH2:1])[CH:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[CH3:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(Br)C(C)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)C(C)C(F)(F)F
Reaction time: 48 h
Yield: 49.7 %

Procedure:
Sodium azide (1.9 g, 28.7 mmol) and ethyl 2-bromo-3-methyl-4,4,4-trifluorobutyrate (5 g, 19.2 mmol) were placed in DMF (20 mL) and stirred for 48 h. The mixture was diluted with EtOAc (200 mL) and washed with brine (4×100 mL). The organic layer was dried over Na2SO4 and solvent was removed. The crude oil was placed in EtOH (20 mL) with 5% Pd/C (1.6 g) and shaken for 6 hours under H2 (50 psi). The reaction was filtered through the Celite® reagent and solvent was removed providing a clear oil (1.9 g) in 50% yield.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].[CH2:23](O)C>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]2[C:14](=[CH2:23])[C:15](=[O:16])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:10]2)=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: O=C(CO)c1ccccc1
Solvent: O
Product: C=C1C(=O)c2ccccc2OC1c1ccc(C(C)(C)C)cc1

Procedure:
A mixture of 22.7 g (0.14 mol) of 4-t-butylbenzaldehyde, 19 g (0.14 mol) of 2-hydroxyacetophenone, 38 g (0.1 mol) of borax, 250 ml of H2O and 150 ml of ethanol was refluxed for one day. The reaction was cooled and diluted with an equal volume of H2O and extracted with ether. The ether was washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to give a brown oil. The oil was chromatographed on 1200 g of silica gel, eluting with benzene. The desired product was obtained as an oil. Recrystallization from petroleum ether gave 2.8 g of 4'-t-butyl flavanone as white crystals, m.p. 103°-104° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][CH2:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]CC=C)=[CH:10][CH:9]=2)=[O:5])[CH3:2]>[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.ClCCl.N1CCOCC1.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][CH2:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C=CCOc1ccc2c(c1)cc(C(=O)OCC)n2CCc1ccsc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Solvent: O
Product: CCOC(=O)c1cc2cc(O)ccc2n1CCc1ccsc1
Reaction time: 18 h
Yield: 108.5 %

Procedure:
To 5-allyloxy-1-[(2-thiophen-3-yl)ethyl]-1H-indole-2-carboxylic acid ethyl ester (1.36 g, 3.8 mmol) was added a mixture of dichloromethane:morpholine:water (100:10:2, 50 mL) followed by the addition of tetrakis(triphenylphosphine) palladium (0) (300 mg). After stilling at room temperature for 18 h, the reaction was partitioned between dichloromethane and water. The organic layer was washed with HCl (3N), NaHCO3, brine and dried over Na2SO4. Purification by flash column chromatography (silica gel, 10-30% EtOAc/hexanes) yielded the desired product as a off-white solid (1.3 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[C:15]([CH3:18])=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1Cl>[Br:21][CH2:18][C:15]1[C:14]2[CH:19]=[CH:20][C:11]([O:10][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=3[C:7]#[N:8])=[CH:12][C:13]=2[O:17][N:16]=1
Reactant: Cc1noc2cc(Oc3ccc(F)cc3C#N)ccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: N#Cc1cc(F)ccc1Oc1ccc2c(CBr)noc2c1
Temperature: 150 °C
Yield: 26.1 %

Procedure:
5-fluoro-2-(3-methyl-benzo[d]isoxazol-6-yloxy)-benzonitrile (3v), (0.87 g, 3.2 mmol), N-bromosuccinimide (0.82 g, 4.6 mmol), benzoyl peroxide (0.12 g, 0.49 mmol) and o-dichlorobenzene (6 mL) were combined in a 15 mL pressure tube. The mixture was stirred and heated in a 150° C. bath. After 2.5 hours the reaction was cooled and the residue was purified directly by column chromatography (silica, 70% CH2Cl2/hexanes) to provide compound (4v) (0.29 g, 26% yield) plus recovered starting material (3v) (0.57 g, 65%). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=7.0 Hz, 1H), 7.45-7.43 (m, 1H), 7.35-7.31 (m, 1H), 7.16-7.13 (m, 2H), 7.08-7.05 (m, 1H), 4.72 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.N1C=CN=C1.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:6][CH:7]=1
Reactant: OCc1ccc(Br)cn1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1ccc(Br)cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (5-bromo-pyridin-2-yl)-methanol (300 mg) in dichloromethane (20 mL) was added imidazole (217 mg) and tert-butyldiphenylsilyl chloride (0.41 mL) and the reaction stirred at room temperature for 16 h. the reaction was quenched with water (20 mL) and extracted into dichloromethane (2×30 mL). The organic layers were dried (MgSO4) and reduced in vacuo to give 5-bromo-2-(tert-butyl-diphenylsilanyloxymethyl)-pyridine as an oil.
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH:15]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]([N:18]1[CH2:23][CH2:22][NH:21][C:20](=[O:24])[C:19]1([CH3:26])[CH3:25])=[O:17]>CO>[NH2:6][CH:15]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:16]([N:18]1[CH2:23][CH2:22][NH:21][C:20](=[O:24])[C:19]1([CH3:25])[CH3:26])=[O:17]
Reactant: CC1(C)C(=O)NCCN1C(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: CC1(C)C(=O)NCCN1C(=O)C(N)Cc1ccccc1

Procedure:
Hydrazine hydrate (2.0 g., 0.04 mole) is added to a stirred solution of 4-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-3,3-dimethylpiperazinone (XXIII, Example 57, 10.0 g., 0.025 mole) in methanol (200 ml.). After refluxing for 2 hours the solution is cooled and filtered to remove the 2,3-dihydro-1,4-phthalazinedione by-product. The methanol is evaporated and the residual oil is recrystallized from water to give the title compound as the dihydrate, m.p. 70°-73°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8]C(=O)C)[C:5]([NH:12]C(=O)C)=[CH:4][C:3]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.[OH-].[K+].O>C(O)CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:12])=[CH:4][C:3]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: CC(=O)Nc1cc(Cl)c(-n2cccc2)cc1NC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Nc1cc(Cl)c(-n2cccc2)cc1N

Procedure:
A solution 1.4 g (4.8 mmol) of N-(2-chloro-4,5-diacetamidophenyl)pyrrole and 0.4 g (9.8 mmol) of potassium hydroxide in 25 ml of ethylene glycol was stirred at 60° C. for 30 minutes. The reaction mixture was then poured into water, extracted with ethyl acetate and worked up.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.[CH2:23](I)[CH3:24]>>[CH2:23]([N:19]1[CH:20]=[CH:21][C:16]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:17][C:18]1=[O:22])[CH3:24]
Reactant: CCI
Reactant: Cc1cccc(C#Cc2cn(-c3cc[nH]c(=O)c3)c(C)n2)c1
Product: CCn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O

Procedure:
The title compound, light brown solid, MS: m/e=318.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-(2-Methyl-4-m-tolylethynyl-imidazol-1-yl)-1H-pyridin-2-one and ethyl iodide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]#[CH:23])[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.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.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]#[C:23][C:28]3[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc2nc(C3CCCN3C(=O)OC(C)(C)C)[nH]c2c1
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(C#Cc3ccc(I)cc3)cc2[nH]1
Temperature: 100 °C
Yield: 74.6 %

Procedure:
A mixture of 2-(6-ethynyl-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.321 mmol), 1,4-Diiodo-benzene (529 mg, 1.61 mmol), tetrakis(triphenylphosphine)palladium (37 mg, 0.03 mmol), copper(I) iodide (12 mg, 0.06 mmol) and triethylamine (0.135 mL, 0.96 mmol) in 2 ml DMF was heated to 100° C. in the microwave for 1 hour. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-[6-(4-Iodo-phenylethynyl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (123 mg, yield 75%). LCMS-ESI−: calc'd for C24H24IN3O2: 513.37. Found: 531.8 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:26])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].CN1CCOCC1.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.Cl.[NH2:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57]>CN1CCCC1=O>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:26])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[O:24])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(O)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: Cl
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=Cc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To an ice cold solution of 1.5 g (0.0043 mol) of 2-acetamido-4-hydroxy-6-[2-(4-carboxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine in 40 mL of N-methylpyrrolidone containing 1.4 mL of N-methylmorpholine was added 1.72 g (0.0064 mol) of phenyl N-phenylphosphoramidochloridate in a single portion. The resulting mixture was stirred at 0° C. for 30 minutes. Diethyl L-glutamate hydrochloride (1.53 g, 0.0064 mol) was then added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residual solid triturated with 50 mL of 1N aqueous sodium carbonate. The mixture was filtered and the collected solid dissolved in 20 mL of chloroform. The chloroform solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to dryness and chromatographed on silica gel. Elution with chloroform:methanol (95:5) gave 1.52 g (66%) of the title compound, which may be alternatively named as diethyl 2-acetyl-5,10-dideaza-9,10-didehydrofolate, mp >250° C.; NMR (CDCl3Me2SO-d6) delta 1.15-1.45 (2t, 6H, J=6 Hz), 2.0-2.65 (m, 4H), 2.3 (s, 3H), 4.0-4.35 (2q, 4H, J=6 Hz), 4.5-4.75 (m, 1H), 6.7, 6.9 (AB q, 2H, J=15 Hz), 7.33, 7.84 (AB q, 4H, J=9 Hz), 8.25-8.38 (m, 2H), 8.62 (d, 1H, J=2 Hz), 11.5-12.5 (br, 2H); IR (Nujol) 3320, 3150, 1730, 1680, 1630, 1600 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[I:22]I>C(Cl)Cl>[I:22][C:11]1[S:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:12]=1
Reactant: II
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2cc(I)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)thiophene (5.92 g, 20 mmole) in 70 ml methylene chloride was cooled in an ice bath and treated in portions with iodine (5.6 g, 20 mmole) and red mercuric oxide (4.32 g, 20 mmole). The reaction mixture was stirred at room temperature for 4 hours and then treated with additional portions of iodine (2.8 g, 10 mmole) and mercuric oxide (2.16 g, 10 mmole). After 2 hours additional, the reaction mixture was filtered through a celite pad.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:12]2=[N:13][C:14]([NH:17]CC3C=CC(OC)=CC=3)=[CH:15][CH:16]=[C:11]2[C:10]([C:27](=[O:29])[CH3:28])=[CH:9]1)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[C:27]([C:10]1[C:11]2[C:12](=[N:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[N:8]([CH2:7][C:6]([OH:30])=[O:5])[CH:9]=1)(=[O:29])[CH3:28]
Reactant: COc1ccc(CNc2ccc3c(C(C)=O)cn(CC(=O)OC(C)(C)C)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1cn(CC(=O)O)c2nc(N)ccc12

Procedure:
A solution of [3-acetyl-6-(4-methoxy-benzylamino)-pyrrolo[2,3-b]pyridin-1-yl]-acetic acid tert-butyl ester (51 mg, 0.125 mmol) and TFA (191 μL, 2.49 mmol) in CH2Cl2 (0.6 mL) was stirred at RT for 24 h. Volatils were removed under reduced pressure and the brown solid thus obtained was used without further purification in the next step. MS (UPLC/MS): 234.1 [M+H]+, 232.1 [M−H]−. 1H-NMR (400 MHz, DMSO): δ (ppm): 8.08 (d, 1H), 8.02 (s, 1H), 6.83 (m, 2H), 6.44 (d, 1H), 4.90 (s, 2H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH:29]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:32]([NH2:34])[CH3:33]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][NH:34][CH2:32][CH3:33])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2C=O)c1
Product: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: [4′-(6-ethoxy-pridin-3-yl)-2′-formyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[CH:21]([CH3:23])[CH3:22])=[CH:8][N:7]=[C:6](SC)[N:5]=1)[CH3:2].[CH2:26]1COCC1.O[O:32][S:33]([O-:35])=O.[K+]>O>[CH2:1]([NH:3][C:4]1[C:9]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[CH:21]([CH3:22])[CH3:23])=[CH:8][N:7]=[C:6]([S:33]([CH3:26])(=[O:35])=[O:32])[N:5]=1)[CH3:2]
Reactant: C1CCOC1
Reactant: CCNc1nc(SC)ncc1Cc1cc(OC)c(OC)cc1C(C)C
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CCNc1nc(S(C)(=O)=O)ncc1Cc1cc(OC)c(OC)cc1C(C)C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of ethyl-[5-(2-isopropyl-4,5-dimethoxy-benzyl)-2-methylsulfanyl-pyrimidin-4-yl]-amine (0.129 g, 0.4 mmol) in 20 mL 1:1H2O/THF was added OXONE® (0.461 g, 0.8 mmol) in 4.0 mL H2O. After 2 hours, 50 mL H2O was added and the mixture was extracted with ethyl acetate, washed with H2O and washed with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give ethyl-[5-(2-isopropyl-4,5-dimethoxy-benzyl)-2-methanesulfonyl-pyrimidin-4-yl]-amine (0.131 g, 92%) as a white foam.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]2[CH2:33][CH2:32][C:27]3(OCC[O:28]3)[CH2:26][CH2:25]2)[CH2:20][CH2:19]1.C(O)=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:14]2)[CH:5]=[CH:4][C:3]=1[CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]2[CH2:25][CH2:26][C:27](=[O:28])[CH2:32][CH2:33]2)[CH2:20][CH2:19]1
Reactant: CCCC1CCC(c2ccc(C3CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2F)CC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=CO
Product: CCCC1CCC(c2ccc(C3CCC(C4CCC(=O)CC4)CC3)c(F)c2F)CC1
Temperature: 25 °C
Yield: 61 %

Procedure:
The compound (36) (38.8 g), formic acid (120 g) and toluene (120 ml) were put in a reaction vessel under a nitrogen atmosphere, heated under reflux for 3 hours, and cooled slowly to room temperature. Water (300 ml) and toluene (300 ml) were added and mixed thereto. The mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from a mixed solvent of toluene and heptane (toluene: heptane=1:1 by volume), and dried, giving 21.4 g of 4′-[2,3-difluoro-4-(4-propylcyclohexyl)phenyl)bi(cyclohexane)-4-one (37). The yield based on the compound (36) was 60.9%.
Reaction SMILES: [NH:1]([C:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([CH3:17])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([N:10]1[C:11]([CH3:17])=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1c(Nc2ccccc2)n[nH]c1C
Product: COC(=O)c1c(Nc2ccccc2)nn(C(C)=O)c1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
23 g of 3-anilino-4-methoxycarbonyl-5-methylpyrazole is dissolved in 51 g of acetic anhydride and brought to the boil. After 15 minutes' boiling the mixture is allowed to cool, poured into ice water and stirred for 30 minutes. The solid which separates is isolated and recrystallized from methanol; m.p. 115°-116° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[C:10]([CH3:16])[N:11]=[C:12]([C@@H:14]3[CH2:15][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=2)[N:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(C)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (1-3) (1.00 g, 4.65 mmol, 1.0 eq.) in degassed toluene (20 mL) was added ethyl diazoacetate (0.98 mL, 9.30 mmol, 2.0 eq.) and the reaction was heated to 120° C. The reaction was monitored by LC-MS and after 2 h the mixture was cooled to room temperature and the toluene was removed by roto-evaporation. The resulting residue was purified by silica gel column chromatography (10-40% EtOAc/hexanes) to afford racemic ethyl trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylate as a white solid. Further purification by chiral SFC provided the active isomer (1-4) as the second eluting peak that was used in subsequent reactions. Analytical separation conditions are as follows: Chiralcel OJ-H, 4.6 mm×25 cm, 90/10 CO2/MeOH+0.1% diethylamine, flow rate=2.4 mL/min; peak 1=2.0 min, peak 2=2.6 min. 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 4.17 (q, 2H, J=7.1 Hz), 2.88 (s, 3H), 2.64-2.55 (m, 1H), 2.62 (s, 3H), 2.41 (s, 3H), 2.36 (ddd, 1H, J=8.6, 5.7, 3.8 Hz), 1.74-1.61 (m, 2H), 1.28 (t, 3H, J=7.1 Hz). MS: m/z=302 (M+H).