Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([C:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=3)[N:19]([CH2:30][C:31]#[CH:32])[C:18]=2[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[CH2:41][OH:42])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(CC)CC>C(Cl)Cl>[CH:11]1([C:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=3)[N:19]([CH2:30][C:31]#[CH:32])[C:18]=2[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[CH:41]=[O:42])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C#CCn1c(-c2ccc(OC)cc2CO)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C#CCn1c(-c2ccc(OC)cc2C=O)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.5 eq., 2M solution in DCM) was added at −70° C. under nitrogen atmosphere over a solution of DMSO (5 eq.) in anhydrous DCM and the mixture was stirred for 30 min; a solution of methyl 3-cyclohexyl-2-[2-(hydroxymethyl)-4-methoxyphenyl]-1-prop-2-yn-1-yl-1H-indole-6-carboxylate in DCM was then added and stirring was continued at the same temperature for 30 min. before NEt3 (8 eq.) was added. After stirring at 0° C. for 20 min. the mixture was diluted with DCM, washed with water, 1N HCl, saturated aq. NaHCO3 solution and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The obtained yellow solid was used in the next step without purification. MS (ES+): 430.5 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([O:15][C:16]2[C:17]([N:22]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([O:15][C:16]2[C:17]([N:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1
Reactant: OC1CCN(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CCN(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
1-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)piperidin-4-ol (see EXAMPLE 1.1; 94 mg, 0.25 mmol) was dissolved in anhydrous CH2Cl2 (10 mL), treated with Dess-Martin periodinane (DMP) (195 mg, 0.50 mmol, 2.0 equiv) and stirred at room temperature until complete conversion. The organic layer was washed with an aqueous solution of NaHCO3/Na2S2O3 (3×10 mL)), dried over Na2SO4, filtered and evaporated. The resulting residue was purified by flash chromatography (20% to 40% EtOAc in petroleum ether) to 1-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)piperidin-4-one (75 mg, 0.20 mmol, 80% yield) as a white solid. ESI-MS (M+1): 376 calc. for C21H21N5O2 375.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:23][OH:24])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)CC(CC(=O)c1ccncc1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)CC(CC(=NO)c1ccncc1)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-5-methyl-1-pyridin-4-yl-hexan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.7:1) as a colorless oil, MS (ESI+): m/z=361.2 ([M+H]+, 1Br).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].C(=O)=O.CC(C)=O.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40]2[C:36]=1[CH2:37][CH2:38][C:39]2=[O:45].[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40]2[C:36]=1[CH2:37][CH2:38][C:39]2([CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])[OH:45]
Reactant: O=C1CCc2c(Cl)cc(F)cc21
Reactant: CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC1(O)CCc2c(Cl)cc(F)cc21
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
Ethyl acetate (5.9 g, 0.07 mol) was added dropwise to a stirred, chilled (dry ice-acetone bath) solution of lithium diisopropylamide (prepared by dropwise addition of a 2.5M solution of n-butyllithium (26.8 ml, 0.07 mol) in hexane to a chilled (dry ice-acetone bath) solution of diisopropylamine (6.8 g, 0.07 mol) in tetrahydrofuran (35 ml) ). After 30 min, a solution of 4-chloro-6-fluoro-1-indanone (12.4 g, 0.07 mol) in tetrahydrofuran (100 ml) was added dropwise and the mixture was stirred for 1 h (dry ice-acetone bath). A solution of ammonium chloride (10.6 g, 0.20 mol) in water (80 ml) was added and the mixture was allowed to come to ambient temperature. The aqueous phase was separated and extracted with diethyl ether. The combined organic phase was dried (sodium sulphate), filtered and concentrated in vacuo to give 19.5 g of crude ethyl 2-(4-chloro-6-fluoro-1-hydroxy-1-indanyl)acetate. Chromatography on silica gel with hexanes:ethyl acetate (8:2) as eluent gave 15.2 g (83%) of a yellow oil; NMR (DMSO-d6): a 7.13-7.28 (m, 2H), 5.55 (s, 1H), 3.98 (m, 2H), 2.79 (2m's, 4H), 2.50 (m, 1H), 2.11 (m, 1H). 1.08 (t, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([CH2:26][C:27](OCC)=[O:28])([CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([CH2:20][CH2:21][OH:22])([CH2:26][CH2:27][OH:28])[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC1(CC(=O)OCC)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1(CCO)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a slurry of LAH (656 mg, 17.3 mmol, 3.0 eq) in THF (50 ml) was added dropwise diethyl 2,2′-(1-benzylpiperidine-4,4-diyl)diacetate (2 g, 5.76 mmol) in THF (10 ml) at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with THF/water (0.7 ml water in 7 ml THF). Then the mixture was stirred for 1 h at room temperature, filtered through celite and concentrated to dryness to yield the desired compound. The crude product was used directly in next step without further purification. Yield: 80%
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)(O)=O.Cl.[O:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[CH:11]1[CH:4]=[CH:5][C:6](/[CH:7]=[C:17]2/[C:18]([C:14]3[C:15]([O:16]/2)=[CH:10][CH:11]=[CH:4][CH:5]=3)=[O:13])=[CH:9][CH:10]=1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: C1COCCO1
Agent: Cl
Product: O=C1/C(=C/c2ccccc2)Oc2ccccc21

Procedure:
This product was immediately dissolved in dioxane (50 ml.), 3-carboxybenzaldehyde (4.5 g., 0.03 mole) added, followed by concentrated hydrochloric acid (10 ml) and the solution heated on a steam bath for 15 minutes. Work up was as Example 49 with recrystallisation from dimethylformamide to give the desired aurone, m.p. 280° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[CH2:28][CH2:27]2)[N:10]=1
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 28 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and ethanesulfonyl chloride (Aldrich), to give [4-amino-2-(1-ethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone. HRMS, observed: 420.1704; Calcd for (M+H)+: 420.1700.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[F:13][C:14]([F:30])([F:29])[CH:15]([NH2:28])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:28][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:17]=1)[C:14]([F:13])([F:30])[F:29])=[O:8]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: NC(c1cccc(N2CCOCC2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1F)NC(c1cccc(N2CCOCC2)c1)C(F)(F)F
Reaction time: 16 h

Procedure:
A mixture of 2-fluorocinnamic acid (33 mg), 2,2,2-trifluoro-1-(3-morpholin-4-yl-phenyl)-ethylamine, Preparation 23 (52 mg), DMAP (24 mg), EDC.HCl (80 mg), and Et3N (80 mg) in CH2Cl2 (4 mL) was stirred for 16 hours. Purification by flash chromatography over silica gel (elution with 50% ethyl acetate in hexane) gave 65 mg of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[CH3:2].[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[F:19])[CH3:2]
Reactant: CCOC(=O)Nc1cc2ccccc2cc1Cl
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1c(Cl)cc2ccccc2c1F
Temperature: 25 °C

Procedure:
A mixture of 2.50 g (10 mmol) of N-(3-chloro-2-naphthyl)carbamic acid ethyl ester and 7.1 g of Selectfluor® (20 mmol) in 30 mL of CH2CN is heated to reflux under an atmosphere of nitrogen for 16 hours. After cooling to room temperature, the solids are filtered and the solvent is evaporated to give a residue that is diluted with 200 mL of EtOAc. The mixture is washed 3 times with 50 mL of H2O, once with 50 mL of saturated brine and dried over MgSO4. Evaporation of the solvents gives a residue that is purified by flash chromatography on silica gel (100% CH2Cl2) to give N-(1-fluoro-3-chloro-2-naphthyl)carbamic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[Cl:17][C:8]1[NH:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)[nH]1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A stirred solution of 5.0 grams (0.0272 mole) of ethyl 4-nitropyrrole-2-carboxylate (commercially available) and 5.5 grams (0.0408 mole) of sulfuryl chloride in 150 mL of acetic acid was warmed to 80° C., where it was maintained during a 3.5-hour period. After this time the reaction mixture was allowed to cool to ambient temperature as it stirred during an 18-hour period. The reaction mixture was concentrated under reduced pressure to a residue, and the residue was stirred with 250 mL of ethyl acetate and 100 mL of water. The organic layer was separated and washed with 150 mL of a solution of 75 mL of water and 75 mL of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel. Elution was accomplished using mixtures of 15% to 20% diethyl ether in hexane as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[O:12]=[P:13](Cl)([Cl:15])[Cl:14]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][P:13]([Cl:15])([Cl:14])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=P(Cl)(Cl)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 60 g (0.37 m) of 3-trifluoromethylaniline and 300 ml of POCl3 was heated at reflux for 3 hours. The excess POCl3 was removed by vacuum distillation to yield 102 g of a red-brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([Cl:18])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C1\CCc2c(Cl)cccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C1\CCc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of (E)-2-(4-chloro-1-indanylidene)acetic acid (5.5 g, 0.03 mol) in a mixture of dimethylformamide: dichloromethane (5 drops: 50 mL) was treated with oxalyl chloride (6.6 g, 0.05 mol) and allowed to stir at room temperature for 18 h. The resulting solution was concentrated in vacuo and the residue used without further purification.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[CH2:16][O-:17].[Na+].[C]=O.[Na]>C1(C)C=CC=CC=1>[OH:17][CH:16]=[C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:12]([OH:14])=[O:13]
Reactant: CC[O-]
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: [C]=O
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=C(O)C(=CO)c1cccc2ccccc12
Temperature: 0 °C

Procedure:
174 Parts by weight of the methyl ester of α-naphthylacetic acid, 48.1 parts by weight of sodium ethylate, and 450 parts by weight of toluene were heated to 80° C. under a carbon monoxide pressure of 100 bar. Since the carbon monoxide consumed was replaced, the pressure varied between 90 and 100 bar. Upon completion of the reaction the batch was cooled and the unreacted carbon monoxide pumped off. The suspension of the sodium salt in toluene was added to 1 l of ice water and, after dissolution of the sodium salt, the toluene phase separated. Acidifying the aqueous phase yielded the (gas chromatographically) 99.5% pure methyl ester of α-hydroxymethylene-α-naphthylacetic acid, which had a melting point of from 124° to 126° C.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]#[N:24])[CH:17]=[C:18]([CH3:20])[CH:19]=1)=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:32][CH3:33]>CN(C=O)C>[CH2:32]([N:6]1[C:5]([C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]#[N:24])[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]1=[O:11])[CH3:33]
Reactant: CCI
Reactant: Cc1cc(C=CC#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(C(=O)c2cc(C)cc(C=CC#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a stirred solution of 3-[3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (Compound 55) (323 mg, 1 mmol) and anhydrous powdered potassium carbonate (165 mg, 1.2 mmol) in DMF at room temperature, was added iodoethane (97 μL, 1.2 mmol). After stirring overnight, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to give 190 mg (54%) of 3-[3-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (73) as a white solid. The product was recrystallized from chloroform-ether. m.p. 174-176° C.; 1H-NMR (200 MHz, CDCl3) δ 1.12-1.30 (9H, m), 2.29 (1H, m), 2.51 (3H, s), 3.25 (1H, m), 3.90 (1H, m), 6.06 (1H, d, J=16.8 Hz), 7.47 (1H, d, J=16.8 Hz), 7.64 (1H, s), 7.80 (1H, s), 7.92 (1H, s), 10.08 (1H, s); m/z (EI) 351 (M+).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])N.N([O-])=O.[Na+]>O.[Cu]Cl.S(N)(=O)(=O)O>[Br:2][C:3]1[CH:4]=[C:5]([Cl:1])[CH:7]=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)c1ccc(N)cc1Br
Reactant: Cl
Agent: Cl[Cu]
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Solvent: O
Product: CC(C)c1ccc(Cl)cc1Br
Temperature: 5 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Hydrochloric acid (152 g, 31% strength, 1.29 mol) was added dropwise to a suspension of 3-bromo-4-isopropylaniline (VII) (100 g, 0.43 mol) and water (150 g) at room temperature. The suspension was subsequently cooled to 5° C. and a solution of sodium nitrite (32.7 g, 0.46 mol) in water (140 g) was added dropwise over a period of 2 hours. After stirring for another 1 hour, amidosulphuric acid (2.5 g, 0.026 mol) was added. Copper(I) chloride (10.8 g, 0.11 mol), hydrochloric acid (202 g, 31%, 1.72 mol) and water (75 g) were placed in a second flask and the diazonium salt generated previously was added dropwise over a period of 30 minutes. After stirring for another 1.5 hours, the mixture was extracted with dichloromethane (250 g), the phases were separated and dichloromethane was distilled off under reduced pressure. The crude product obtained was purified by distillation. 2-Bromo-4-chloro-1-isopropylbenzene (62.6 g, 94.8 GC-% by area. 59% of theory) was obtained as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][NH:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33].[O-]P([O-])([O-])=O.[K+].[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>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][NH:10][C:11]1[CH:16]=[C:15]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([F:34])([F:35])[F:33])=[C:26]([F:25])[CH:27]=2)[N:14]=[CH:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: CC(C)(C)OC(=O)NC(CNc1cc(Cl)ncn1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@@H](CNc1cc(-c2ccc(C(F)(F)F)c(F)c2)ncn1)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
[2-(6-Chloro-pyrimidin-4-ylamino)-1-phenyl-ethyl]-carbamic acid tert-butyl ester (87 mg, 0.25 mmol), 3-fluoro-4-(trifluoromethyl)-phenyl boronic acid (57 mg, 0.28 mmol), Pd(PPh3)4 (2.9 mg, 2.5 μmol) and K3PO4 (110 mg, 0.50 mmol) were placed in a sealed tube which was evacuated and refilled with N2. 1,2-Dimethoxyethane (2 mL) and water (0.5 mL) were added to the sealed tube. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was cooled to rt and was filtered through a pad of MgSO4. The pad was washed with CH2Cl2. The crude filtrate was concentrated under reduced pressure and the residue was purified via reverse phase chromatography to yield the title compound (87.0 mg, 59%).
Reaction SMILES: Cl[Si:2]([CH3:8])([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[Cl:9][C:10]1[C@@H:14]([OH:15])[CH2:13][C:12](=[O:16])[CH:11]=1>CN(C)P(=O)(N(C)C)N(C)C.O>[Cl:9][C:10]1[C@@H:14]([O:15][Si:2]([CH3:8])([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:13][C:12](=[O:16])[CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C=C(Cl)[C@@H](O)C1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)C=C1Cl
Reaction time: 20 h
Yield: 99.1 %

Procedure:
Chlorodimethyl-t-butylsilane (485 mg, 3.22 mmol) was added over 5 min to the crude (4S)-enone (7) (247 mg) in hexamethylphosphoric triamide (2 ml) at 0°. After stirring at 4° for 20 h the solution was diluted with water (10 ml) and extracted with ether (3×10 ml). The combined ether extracts were washed with water (3×10 ml), dried (MgSO4) and evaporated to give a pale yellow oil (456 mg) which was chromatographed on a column of silica gel (25 g) with methylene dichloride-methanol (50:1) as eluant. The (4S)-enone (8; R1 =Me2ButSi) [243 mg, 61% from the 3,5,5-trichloro-4-hydroxycyclopent-2-en-1-one (6)] was obtained as a colourless oil, [α]35225 +1050° (c. 9.14×10-2, hexane), [α]23425 -16,140° (c 1.83×10-3, hexane), [θ]33325 +6700° (c 9.14×10-2, hexane), [θ]22225 -80,330° (c 1.83 ×10-3, hexanel). (Found: C, 53.65; H, 7.95; Cl, 14.6. C11H19ClO2Si requires C, 53.55; H, 7.75; Cl, 14.35%)
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][Cl:17]>C(O)C>[ClH:17].[C:1]1([S:7][CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1ccccn1
Reactant: Sc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: c1ccc(SCc2ccccn2)cc1
Yield: 5.9 %

Procedure:
Thiophenol (21 ml) was added to a solution of sodium (4.6 g) in ethanol (100 ml). To the resulting solution was added 2-picolyl chloride, hydrochloride (15 g) and the mixture was heated at reflux for 2 hours. Precipitated sodium chloride was removed by filtration and the solution was acidified with ethereal HCl. The solvent was removed by evaporation and the residue induced to crystallise by trituration with ether. Recrystallisation from ethanol-ether gave 2-((phenylthio)-methyl)pyridine, hydrochloride (5.0 g) mp 142°-4° C. (Found: C,60.6; H,5.25; N,5.5, C12H11NS,HCl requires C,60.6: H,5.1: N,5.9%).
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C([O:8][C:9]([C:11]1([C:39](OCC)=[O:40])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:17]=[N:18][C:19]([O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:27]=[CH:26]3)=[CH:20][CH:21]=1)=O)C>C(O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([N:28]2[C:29]3[C:25](=[CH:24][C:23]([O:22][C:19]4[N:18]=[CH:17][C:16]([N:12]5[C:11]6([C:39](=[O:40])[NH:5][C:3](=[O:4])[NH:2][C:9]6=[O:8])[CH2:15][CH2:14][CH2:13]5)=[CH:21][CH:20]=4)=[CH:31][CH:30]=3)[CH:26]=[N:27]2)=[CH:33][CH:34]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)nc1
Agent: [Na]
Solvent: CCO
Product: O=C1NC(=O)C2(CCCN2c2ccc(Oc3ccc4c(cnn4-c4ccc(F)cc4)c3)nc2)C(=O)N1
Temperature: 80 °C

Procedure:
To a flame dried flask is added ethanol (6 mL) and freshly cut sodium metal (62.4 mg, 2.71 mmol). The solution is stirred until homogenous. Recrystallized urea (98 mg, 1.63 mmol) is added and the solution is stirred at room temperature for 5 minutes. 1-{6-[1-(4-Fluoro-phenyl)-1H-indazol-5-yloxy]-pyridin-3-yl}-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.54 mmol) is added, and the solution is heated to 80° C. for 30 minutes, then cooled to 50° C. and stirred for 16 hours. The reaction is then quenched by the addition of 10 mL water, and 1N hydrochloric acid is added to adjust the pH to 5. The aqueous layer is extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers are washed with saturated sodium chloride, dried with magnesium sulfate, filtered, and concentrated under vacuum to produce crude product. This material is chromatographed on silica gel (ISCO MPLC purification, 30 minutes, 50-100% ethyl acetate gradient, Biotage flash 40s column) to provide 1-{6-[1-(4-Fluoro-phenyl)-1H-indazol-5-yloxy]-pyridin-3-yl}-1,7,9-triaza-spiro[4.5]decane-6,8,10-trione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6](Cl)=[O:7].N1C(C)=CC=CC=1C.[H][H]>[Pd].C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH:6]=[O:7]
Reactant: [H][H]
Reactant: COc1cc(C(=O)Cl)ccc1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: COc1cc(C=O)ccc1C

Procedure:
A mixture of 5.0 g (27.08 mmol) of 3-methoxy-4-methylbenzoyl chloride, 4.0 ml (34.34 mmol) of 2,6-lutidine and 400 mg of 10% palladium on carbon in 40 ml of THF was rapidly stirred under an atmosphere of hydrogen until no more hydrogen was taken up. Filtration and extraction with ethyl acetate gave title compound as a light yellow oil.