Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]OS(C)(=O)=O)=[CH:6][CH:5]=1.[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][CH2:31][CH:26]([NH:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:32])[CH2:27]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCCOS(C)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCCN2CCCC(NC(=O)OC(C)(C)C)C2)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
4-(3-Methanesulfonyloxy-propyl)-benzoic acid methyl ester (800 mg, 2.9 mmol), piperidin-3-yl-carbamic acid tert-butyl ester (290 mg, 1.45 mmol), potassium carbonate (500 mg, 3.6 mmol) and sodium iodide (100 mg 0.67 mmol) in acetonitrile (20 ml) are heated under reflux for two days and evaporated. The residue is taken up in dimethylsulfoxide (10 ml) and stirred at 90° C. for 5 h. The resulting mixture is purified by preparative HPLC-MS (MeOH/H2O+0.1% TFA). Potassiumcarbonate solution is added to the product, extracted with ethyl acetate, the organic phase is dried over Na2SO4 and concentrated in vacuo. LC (method F): tR=1.66 min; Mass spectrum (ESI+): m/z=377 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.O.[NH2:16][NH2:17]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][NH2:17])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: NN
Reactant: Clc1cc(-c2ccccc2)nc(Cl)n1
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc(-c2ccccc2)nc(Cl)n1

Procedure:
To a solution of 2,4-dichloro-6-phenylpyrimidine (224 mg, 1 mmol) in 1 mL of 1,4-dioxane was added 300 uL of hydrazine hydrate. Stirring was continued at room temperature and the reaction monitored by thin layer chromatography (30% ethyl acetate/hexanes). When the starting material was consumed, 2 mL of water was added and the resultant precipitate was collected on a filter to afford 2-chloro-4-hydrazinyl-6-phenylpyrimidine as a yellow solid. The damp solid was suspended in 2 mL of ethanol, to which was added 220 mg of 4-trifluoromethoxybenzaldehyde. Within 5 minutes the solution became clear and then reprecipitated material. The product, 2-chloro-4-phenyl-6-(2-(4-(trifluoromethoxy)benzylidene)hydrazinyl)pyrimidine (XX), was collected by filtration and dried to afford 150 mg of a solid. ESI/MS 392.973, 395.002 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH2:18])[C:9]=1[C:10]1[C:11](F)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1)[C:5]#[N:6].[Cl-].[NH+]1C=CC=CC=1>O1CCOCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]2[C:9]=1[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[N:12][C:11]=1[NH:18]2
Reactant: Cc1cnc(F)c(-c2c(N)cc(C#N)cc2N)c1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: C1COCCO1
Product: Cc1cnc2[nH]c3cc(C#N)cc(N)c3c2c1
Temperature: 180 °C
Yield: 87 %

Procedure:
Compound 123 (148 mg, 0.61 mmol) was dissolved in dioxane (2 mL) with pyridinium chloride (80 mg), and the solution was heated at 180° C. in the microwave for 15 minutes. The solution was concentrated in vacuo. Purification by flash chromatography (20% acetone/CH2Cl2) gave 118 mg (87%) of the title compound as an off-white solid. MS (ES) [m+H] calc'd for C13H10N4, 223; found 223.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]3[CH2:24][CH2:23]3)[C:17]=2[F:25])=[CH:12][C:11]1=[O:26])[CH2:6][CH:7]([CH3:9])[CH3:8])C.O.[OH-].[Li+]>O1CCCC1>[CH:22]1([C:18]2[C:17]([F:25])=[C:16]([CH:21]=[CH:20][CH:19]=2)[O:15][C:13]2[CH2:14][N:10]([C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:27])=[O:3])[C:11](=[O:26])[CH:12]=2)[CH2:23][CH2:24]1
Reactant: CCOC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(C3CC3)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C3CC3)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
To a solution containing (S)-2-[4-(3-cyclopropyl-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (0.800 g, 0.002 mol) in tetrahydrofuran (30 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 15 mL, 0.008 mol). The mixture was stirred at room temperature for 1 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(3-cyclopropyl-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.71 g, 96%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=4)=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(C)c4)nc23)cc(C)n1
Yield: 45.6 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg, 0.5 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (95 mg, 46%). MS (ISP) 417.2 [(M+H)+]; mp 254° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:23])[NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][NH:18]3)=[CH:8][C:9]=1[Cl:10])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[Cl:10][C:9]1[CH:8]=[C:7]([C:11](=[O:23])[NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][NH:18]3)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1cccc2[nH]ncc12)c1cc(Cl)c(C(=O)O)s1
Reaction time: 15 h

Procedure:
A mixture of 3-Chloro-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (73 mg, 0.21 mmol), lithium hydroxide monohydrate (88 mg, 2.09 mmol), THF (6 mL) and water (6 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 80 mg (100%). MS m/e 335.8 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH3:17])=[O:5])[CH3:2].C(Cl)Cl.[Br:21]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:21][CH2:17][C:7]1[N:8]=[C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[S:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2CCOCC2)nc1CBr
Yield: 71.2 %

Procedure:
To a round bottom flask containing a solution of ethyl-4-methyl-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (14.50 g, 56.57 mmol) in methylene chloride (400 mL, 6000 mmol) were added N-bromosuccinimide (10.07 g, 56.57 mmol) and 2,2′-azo-bis-isobutyronitrile (464 mg, 2.83 mmol). The mixture was stirred at reflux overnight. Reaction was quenched via addition of 10% aqueous sodium bisulfite (20 g in 200 ml water) and stirred for 20 minutes. Mixture was transferred to a separatory funnel, the layers separated, and the aqueous layer was extracted 2×DCM. Combined organic layers were dried with Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM and adsorbed onto silica gel. Purification via column chromatography (220 g Isco column, gradient elution 0-10% EtOAc in 1:1 DCM:hexanes) afforded ethyl 4-(bromomethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (13.5 g, yield 71.1%). LC/MS: (FA) ES+ 335, 337; 1H NMR (300 MHz, CDCl3) δ 4.76 (s, 2H), 4.30 (dd, J=7.1, 7.1, 2H), 3.88-3.72 (m, 4H), 3.62-3.49 (m, 4H), 1.35 (dd, J=7.1, 7.1, 3H).
Reaction SMILES: [I-:1].OC1C=CC=CC=1C=[N:6][C@@H:7]1[C:37](=[O:38])[N:9]2[C:10]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:11]([CH2:14][N+:15]3[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:12][S:13][C@H:8]12.[ClH:43]>O1CCCC1.C(O)C>[ClH:43].[I-:1].[NH2:6][C@@H:7]1[C:37](=[O:38])[N:9]2[C:10]([C:21]([O:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:22])=[C:11]([CH2:14][N+:15]3[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:12][S:13][C@H:8]12
Reactant: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N=Cc3ccccc3O)[C@H]2SC1
Agent: Cl
Agent: [I-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 1 h

Procedure:
To a solution of benzhydryl 7β-(2-hydroxybenzylideneamino)-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (1 g) in tetrahydrofuran (20 ml) and ethanol (3 ml) was added conc. hydrochloric acid (0.14 ml) at ambient temperature. After stirring at the same temperature for 1 hour, the mixture was poured into tetrahydrofuran (20 ml). The resulting precipitates were collected by filtration to give hydrochloric acid salt of benzhydryl 7β-amino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (0.65 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH3:13][CH:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[CH3:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:13][CH:14]([OH:15])[CH3:16]
Reactant: Cc1cccc2[nH]ccc12
Reactant: CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1cccc2c1ccn2CC(C)O
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A suspension of 0.26 g of sodium hydride dispersion in 35 ml of tetrahydrofuran was treated with 0.95 g of 4-methylindole at 0° as and stirred at this temperature for 1 hour. After the addition of 1 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.86 g (62.7%) of (RS)-1-(4-methyl-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: [NH2:1][C:2](=O)[C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].CC1C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:2]([C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4])#[N:1]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: C[C@H](C#N)NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
To a solution of (R)-tert-butyl 1-amino-1-oxopropan-2-ylcarbamate (Int-X-A, 1 g, 5.31 mmol) and 4-methylbenzene-1-sulfonyl chloride (4.05 g, 21.25 mmol) in CH2Cl2 (5 mL) was added pyridine (2.101 g, 26.6 mmol). After 3 h, acetic anhydride (0.651 g, 6.38 mmol) was added. This was stirred overnight before it was concentrated and EtOAc was added. Saturated NaHCO3 was added and the two phase mixture was stirred vigorously for 2 h. The organic layer was washed with 1 N HCl and then saturated NaHCO3. The organic layer was dried and concentrated. The resulting residue was purified by flash chromatography (Isco Combiflash Companion, 40 g silica gel, 15% ethyl acetate-hexane) to provide the product (R)-tert-butyl 1-cyanoethylcarbamate (Int-X-B, 336 mg, 1.974 mmol, 37.2% yield); [M+Na]+=193.2; 1H NMR (400 MHz, methanol-d4) δ ppm 4.51 (1 H, q), 1.34-1.58 (12 H, m).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=O>C1(C)C=CC=CC=1>[Br:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([Cl:3])=[O:13]
Reactant: O=C(O)c1ccsc1Br
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccsc1Br
Yield: 100 %

Procedure:
Add thionyl chloride (0.35 mL, 4.80 mmol) to a solution of 2-bromothiophene-3-carboxylic acid (500 mg, 2.41 mmol) and toluene (20 mL) with stirring. Purge the reaction vessel with nitrogen. Heat the mixture to reflux and stir for 3 hours. Concentrate the mixture to obtain the title compound (540 mg, 2.41 mmol). Use compound in next procedure without further purification.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C@@H:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>>[C:1]1([C:7]2[S:11][C:10]([C@@H:12]([NH2:14])[CH3:13])=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nnc(-c2ccccc2)s1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
To a solution of (S)-tert-butyl (1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethyl)carbamate (110 mg, 0.4 mmol, in 5 ml of DCM) was added 1 ml of TFA, the reaction mixture was stirred at room temperature for 3 hours, the solvent was removed to yield the desired product (52 mg) in 66.8% yield. LCMS m/z 206.0 (M+H)+ RT=0.97 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])=[N:7][CH:8]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC(=O)c1ccc(CO)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)c1ccc(COS(C)(=O)=O)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Dissolve 5-hydroxymethyl-2-(3-methyl-butyryl)-pyridine (210 mg, 1.086 mmol) in dichloromethane (5 mL). Cool to 0° C. and add triethylamine (0.167 mL, 1.195 mmol) and methanesulfonyl chloride (0.093 mL, 1.195 mmol). Allow the mixture to warm to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to provide the title compound (256 mg, 87%). GC-MS m/z: 271
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@H:6]([O:12][C:13]1[CH:20]=[C:19]([Cl:21])[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16])[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45]>O1CCCC1>[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45].[NH2:1][CH2:4][CH2:5][C@@H:6]([O:12][C:13]1[CH:20]=[C:19]([Cl:21])[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16])[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1
Reactant: N#Cc1cc(F)c(Cl)cc1O[C@H](CCN=[N+]=[N-])c1ccsc1
Agent: O=C(O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CCN)c1ccsc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
The product from step (a) (529 mg, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (80 ml), triphenylphosphine (1.235 g, 4.71 mmol) added and the reaction mixture stirred for 1 h at room temperature. Water (5 ml) was added and the reaction stirred for 64 h. Water (100 ml) was added and the reaction extracted with ethyl acetate (4×70 ml). The combined organic extracts were washed with water (3×25 ml), dried (sodium sulphate) and evaporated in vacuo. The residue was chromatographed on flash silica, eluting with 5% 7N ammonia in methanol in dichloromethane, and the product dissolved in methanol and treated with one equivalent of oxalic acid. The mixture was stirred for 10 minutes then the solvent removed in vacuo and the solid residue triturated with ethyl acetate. The white solid was filtered off and dried to give the title compound (380 mg, 60%).
Reaction SMILES: [OH:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.[C:15](Cl)(=[O:17])[CH3:16]>N1C=CC=CC=1.C(Cl)Cl>[C:15]([O:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: C=C1CC(C)(O)CCC2=C(C)CCC12
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C1CC(C)(OC(C)=O)CCC2=C(C)CCC12
Reaction time: 8 h

Procedure:
A solution of 2.0 g of 6-hydroxy-1,6-dimethyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene in 5 ml of pyridine and 50 ml of methylene chloride was treated at -10° with 1.1 ml of acetyl chloride. The mixture was left to stand overnight at room temperature, then poured on to ice and worked up in a conventional manner. The crude product (3.1 g) which was obtained in the form of a brown oil, was chromatographed on 50 times the amount of silica gel. By elution with hexane/ether (19:1) there was obtained pure 6-acetoxy-1,6-dimethyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.01 ca 70°; IR(film):νmax = 3090, 1735, 1640, 1445, 1368, 1270/50/30, 1095, 1065, 1020, 905/900 cm- 1. The compound has a flowery odour with a woody undertone.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:14][C:13](=[O:24])[CH:12]=2)C(=O)O1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:15]1[CH2:16][C:11]2[NH:10][CH:9]=[CH:5][C:6](=[O:8])[C:12]=2[C:13](=[O:24])[CH2:14]1
Reactant: CC1(C)OC(=O)C(=CNC2=CC(=O)CC(c3ccccc3Cl)C2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C1CC(c2ccccc2Cl)Cc2[nH]ccc(=O)c21
Temperature: 260 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A mixture of 2,2-dimethyl-5-[(3-oxo-5-(2-chlorophenyl)-1-cyclohexenylamino)methylene]-[1,3]dioxane-4,6-dione (1.6 g) in diphenylether (20 ml) was stirred at 260° C. for 30 minutes. Under reduced pressure, the solvent was evaporated, and the resulting crystals were washed with petroleum ether and recrystallized from ethanol to give 7-(2-chlorophenyl)-1,4,5,6,7,8-hexahydroquinoline-4,5-dione (1.1 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42]CC)[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.[I-].[Na+:51]>CC(=O)CC>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:42])([O-:45])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.[Na+:51]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOP(=O)([O-])Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1

Procedure:
A suspension of diethyl (4-{[4-({7-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1B, 255 mg, 0.36 mmol) and sodium iodide (606 mg, 4.04 mmol) in 2-butanone (5 mL) was subjected to 7 hours of microwave irradiation at 120° C. A solid precipitated, which filtered off, rinsed several times with ice cold acetone, and dried thoroughly to afford the desired compound as 277 mg as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.26 (br s, 1H), 9.08 (s, 1H), 8.34 (s, 1H), 8.15 (br s, 2H), 7.71 (s, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.08 (s, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.45 (br s, 1H), 4.60 (s, 2H), 4.19 (t, J=6.1 Hz, 2H), 3.68 (s, 3H), 3.60-3.67 (m, 2H), 3.45 (q, J=5.9 Hz, 2H), 3.09 (s, 3H), 2.77 (d, J=19.7 Hz, 2H), 1.94 (quin, J=5.9 Hz, 2H), 0.94 (t, J=7.1 Hz, 3H). MS (ESI): m/z 676.30 [M+H]+. UPLC: tR=1.06 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)=[O:6].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:5]([OH:6])[C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:8]2)[CH:20]=[C:21]([CH3:23])[CH:22]=1
Reactant: Cc1cc(F)cc(C(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(F)cc([C@H](O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a solution of (R)-tert-butyl 3-(3-fluoro-5-methylbenzoyl)piperidine-1-carboxylate (1.7 g, 5.3 mmol) in MeOH (30 mL), NaBH4 (1.61 g, 42.3 mmol) was added in portions and stirred overnight. The reaction was quenched with the addition of water (50 mL) and evaporated in vacuo until MeOH was removed. The aqueous layer was extracted with EA, washed with brine and dried over Na2SO4. The crude product was purified by chromatography to give (R)-tert-butyl 3-((R)-(3-fluoro-5-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylate (730 mg, 42.9%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[C:10]=1[CH3:11])=[O:5])C.[CH:19]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCC[CH2:20]1.C(B1OC(C)(C)C(C)(C)O1)=C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[CH3:11][C:10]1[N:9]([C:12]2[CH:13]=[CH:14][C:15]([CH:19]=[CH2:20])=[CH:16][CH:17]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:3])=[O:5]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C
Agent: [Pd+2]
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(-n2ncc(C(=O)O)c2C)cc1
Temperature: 100 °C
Reaction time: 7 h
Yield: 461.5 %

Procedure:
Tetrahydrofuran (10 ml) was added to 1-(4-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.5 g) described in Reference Example 26(1), palladium (II) acetate (108 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (198 mg), vinylboronic acid pinacol ester (1.04 g) and tripotassium phosphate (2.6 g), and stirred at 100° C. for 7 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate). 4N Aqueous solution of sodium hydroxide (4 ml) and ethanol (10 ml) were added to the purified yellow oily product, stirred at 80° C. for two hours and the reaction solution was washed with ethyl acetate. 1N Hydrochloric acid aqueous solution was added to the aqueous layer at 0° C., and the precipitated solid was washed with diethyl ether and water to give 5-methyl-1-(4-vinylphenyl)-1H-pyrazole-4-carboxylic acid (508 mg).