Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:14][Mg]Br>C1COCC1.O>[F:1][C:2]1[C:7]([C:8]2[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Mg]Br
Reactant: O=C1C=C(c2cccnc2F)CC1
Solvent: C1CCOC1
Solvent: O
Product: CC1(O)C=C(c2cccnc2F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2-fluoropyridin-3-yl)cyclopent-2-enone (1 g, 5.64 mmol) in THF (28.2 mL) was added methylmagnesium bromide (4.70 mL, 14.11 mmol) dropwise over 5 minutes. The dark brown solution was stirred for 3 h at room temperature before. slowly quenching with aqueous ammonium chloride. The crude reaction was diluted with water and extracted with ethyl acetate, drying over magnesium sulfate, filtering, and concentrating to a dark brown oil under reduced pressure. The crude compound was purified by column chromatography (ethyl acetate/dichloromethane) to afford 3-(2-fluoropyridin-3-yl)-1-methylcyclopent-2-enol as a clear oil. MS (ESI, pos. ion) m/z: 194.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH:14]=[O:15])[CH3:2].[BH4-].[Na+].Cl>CCO>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])=[C:8]([CH2:14][OH:15])[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COc1ccc(Br)cc1CO
Temperature: 0 °C
Yield: 89.1 %

Procedure:
Ethyl (4-bromo-2-formylphenoxy)acetate (Example 1, 6.00 g, 21.0 mmol) in 200 mL abs EtOH was stirred under Ar and the mixture was cooled to 0° C. To this mixture was added NaBH4 (199 mg, 5.24 mmol) in portions. The reaction was stirred for 1 hour where TLC (25% EtOAc/hexanes) revealed complete reaction. At this point, 1 N HCl was added dropwise until slightly acidic and the EtOH was removed under reduced pressure. Water (100 mL) was added and the reaction transferred to a separatory funnel where it was extracted 3×100 mL with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and removed in vacuo to provide the product (5.41 g, 89%) as a pure white solid. 1H-NMR (acetone-d6, δ): 1.24 (t, 3H), 4.21 (q, 2H), 4.76 (s, 2H), 4.85 (s, 2H), 6.98 (d, 1H), 7.46 (dd, 1H); 7.61 (d, 1H); LRMS (GC/MS/EI) 308 [M]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])/[CH:11]=[CH:12]/C2C=CC=CC=2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC1C=C(NC(=O)C=CC2C=CC=CC=2)C=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].FC1C(F)=C2C(C=CC(=O)N2)=CC=1>>[F:8][C:6]1[CH:5]=[C:4]2[C:3]([CH:12]=[CH:11][C:10](=[O:19])[NH:9]2)=[CH:2][CH:7]=1
Reactant: O=C(/C=C/c1ccccc1)Nc1cc(F)cc(F)c1
Agent: O=C(C=Cc1ccccc1)Nc1cccc(F)c1
Agent: O=c1ccc2ccc(F)c(F)c2[nH]1
Agent: [Al+3]
Product: O=c1ccc2ccc(F)cc2[nH]1

Procedure:
The compound was prepared from 2E)-N-(3-fluorophenyl)-3-phenylacrylamide (Intermediate 30) (13.8 g, 57.2 mmol) and aluminium trichloride (30.5 g, 229 mmol) in a similar way as described for Intermediate 21 to give a mixture of the title compound together with the corresponding 5-fluoro regioisomer in a ratio of 3:1. This mixture was vigorously stirred in dichloromethane (100 mL) for 3 hours at room temperature and then filtered. The solid obtained was resuspended in diethyl ether (200 mL) and stirred like above and filtered to give 3.63 g (34%) of the crude product containing 12% of the 5-fluoro regioisomer. This was used without further purification for the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])C.C(O)(=O)C.Cl>O1CCOCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2)n1
Temperature: 60 °C

Procedure:
A mixture of 2.13 g (4.68 mmol) 2-[(2,4-Dichloro-benzoyl)-(4-chloro-phenyl)-amino]-thiazole-4-carboxylic acid ethyl ester, 2.5 ml acetic acid and 7.5 ml HCl conc. in 10 ml dioxane was heated to 60° C. for 2 h. The mixture was subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 0.955 g (48%) of the title compound. MS (m/e): 429.1 (MH+, 100%)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1.CN(C(N1CC1)=O)C.[CH2:25]([CH:28]1[CH2:33][CH2:32][CH:31]([CH:34]2[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41]I)[CH2:36][CH2:35]2)[CH2:30][CH2:29]1)[CH2:26][CH3:27]>C1COCC1.CCCCCC.C1COCC1>[CH2:25]([CH:28]1[CH2:33][CH2:32][CH:31]([CH:34]2[CH2:35][CH2:36][CH:37]([CH2:40][CH2:41][C:15]3[C:10]([F:9])=[N:11][C:12]([F:16])=[CH:13][CH:14]=3)[CH2:38][CH2:39]2)[CH2:30][CH2:29]1)[CH2:26][CH3:27]
Reactant: Fc1cccc(F)n1
Reactant: CCCC1CCC(C2CCC(CCI)CC2)CC1
Agent: CC(C)[N-]C(C)C
Agent: CN(C)C(=O)N1CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC1CCC(C2CCC(CCc3ccc(F)nc3F)CC2)CC1
Reaction time: 1.5 h

Procedure:
A solution of 0.02 mol of lithium diisopropylamide in THF/hexane (prepared analogously to Example 1) is added dropwise at 25° C. to a mixture of 0.2 mol of 2,6-difluoropyridine, 0.02 mol of N,N-dimethylethyleneurea, 0.02 mol of 2-(4'-propylbicyclohexyl-4-yl)-1-iodoethane and 25 ml of THF. Stirring for 1.5 hours and workup as described in Example 1 give the pure product.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[C:19]([O:21]CC)=[O:20].[OH-].[Na+].C(O)C>O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:17])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[CH:4][C:3]=1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1c(C(=O)O)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 5 °C

Procedure:
35.4 g (0.1 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-carbethoxy-pyrazole are heated under reflux for 24 hours in a solution of 8 g (0.2 mol) of sodium hydroxide, 24 ml of water and 100 ml of ethanol. 450 ml of water are subsequently added, and the mixture is washed twice with 70 ml of diethyl ether. The alcohol is removed from the aqueous phase by distillation, and 20 ml of concentrated hydrochloric acid are then added with ice cooling. The suspension is cooled to 5° C., and the precipitate is filtered off under suction, washed with water until neutral, and dried. 26.2 g (74% of theory) of the compound 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-carboxy-pyrazole of melting point 158° C. (decomposition) are obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[CH:21]1([SH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(N(CC)CC)C.O1CCOCC1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([N:14]2[C:18](=[O:19])[CH2:17][CH:16]([S:27][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:15]2=[O:20])[CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(N2C(=O)CCC2=O)ccc1C(=O)O
Reactant: SC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Oc1cc(N2C(=O)CC(SC3CCCCC3)C2=O)ccc1C(=O)O
Reaction time: 4 h

Procedure:
8.24 g. (0.03 mole) of 1-(3-acetoxy-4-carboxyphenyl)-pyrroline-2,5-dione are dissolved in 80 ml. of dioxane and 3.6 ml. (0.03 mole) of cyclohexane-thiol are added. Two drops of triethylamine catalyst are then added dropwise to the reaction mixture and the mixture is kept at 80°-90° C. for 4 hours. The solvent is distilled off in vacuo. As a residue an oily 1-(3-acetoxy-4-carboxy-phenyl)-3-cyclohexylthio-pyrrolidine-2,5-dione is obtained. The product is dissolved in a mixture of 30 ml. of glacial acetic acid and 30 ml. of acetic anhydride and under cooling with icy water and stirring 14.4 ml. (0.15 mole) of a 30% hydrogen peroxide solution are added dropwise. The cooling is ceased and the reaction mixture is allowed to warm up to 30° C. The mixture is the cooled again with icy water to 0° to 5° C. and stirred at this temperature for 5 hours. The reaction mixture is allowed to stand overnight. The next day the pure solution is poured on ice and the precipitated product is filtered and washed with water to remove acid. M.p.: 155°-158° C. Yield: 6.7 g. (52.9%). After recrystallization from 50% ethanol the product melts at 160°-161° C.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][Si:9](Cl)(Cl)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C(C1C=CC=CC=1)(=O)C>>[CH2:1]([CH:6]1[CH2:7][CH2:8][SiH2:9][CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CC[Si](Cl)(Cl)CC1
Solvent: CC(=O)c1ccccc1
Product: CCCCCC1CC[SiH2]CC1
Reaction time: 1 h

Procedure:
14.6 g of acetyl chloride was added to a solution, in 200 ml of dichloromethane, of 30.0 g of 4-n-pentyl-1,1-diphenyl-1-silacyclohexane obtained in Preparatory Example 3 and 24.8 g of aluminium chloride at room temperature, followed by agitation for 1 hour to obtain a mixture of 4-n-pentyl-1,1-dichloro-1-silacyclohexane and acetophenone. The reaction mixture was concentrated, after which the acetophenone was distilled off under reduced pressure. The residue was dissolved in 100 ml of THF, to which a solution of 10.0 g of lithium aluminium hydride in 100 ml of THF was added. The reaction mixture was agitated under reflux for 1 hour, followed by pouring into 200 ml of 5% hydrochloric acid and extraction with ethyl acetate. The resultant extract was washed with brine, dried and concentrated by a usual manner, followed by purification through silica gel chromatography to obtain 15.0 g of 4-n-pentyl-1-silacyclohexane.
Reaction SMILES: [CH3:1][C:2]([S:26]([CH3:29])(=[O:28])=[O:27])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[CH:17][CH:16]=1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl.CO>C(Cl)Cl>[OH:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: CC(CCc1ccc(-n2cccn2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(CCc1ccc(-n2cccn2)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Methyl-2-(methylsulfonyl)-4-[4-(1H-pyrazol-1-yl)phenyl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (302.9 mg, 0.719 mmol) was dissolved in methylene chloride (10 mL) at ambient temperature. To this solution was added HCl (4M in 1,4-dioxane, 5.39 mL, 21.6 mmol) and the solution was stirred at RT for 5 minutes. Methanol (500 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with methylene chloride/methanol to afford N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4-(1H-pyrazol-1-yl)phenyl]butanamide as a solid. 67.8 mg. LCMS: (M−1) 336.3 1H NMR (CD3OD) 8.16 (1H, d, J=2.54 Hz), 7.69 (1H, d, J=1.17 Hz), 7.64 (2H, d, J=8.59), 7.36 (2H, d, J=8.40) 6.50 (1H, t), 3.03 (3H, s), 2.80-2.72 (1H, m), 2.61-2.52 (2H, m), 2.11-2.03 (1H, m), 1.65 (3H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.Cl.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[N:3]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Agent: Cl
Solvent: CCN(CC)CC
Product: Oc1ccc(CCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1

Procedure:
2-Chloro-6-[(4-hydroxyphenyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, tyramine hydrochloride, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:12](=O)[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:4]3[C:3]4[C:26](=[CH:25][CH:29]=[CH:7][CH:2]=4)[CH2:27][C:12]=3[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc(Br)cc2)oc1=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc(Br)cc2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 6-(4-bromophenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (358 mg), indanone-2 (132 mg) and NaH (31 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 212-212° C.; ESIMS 430 (M++2); IR (KBr) 2211 cm−1 (CN).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23]([NH:25][CH:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:33][CH:32]=1)[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:18]([O:22][C:23](=[O:24])[NH:25][CH:26]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:35][CH:36]=1)[C:27](=[O:28])[N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][N:9]=1)([CH3:20])([CH3:21])[CH3:19]
Reactant: c1ccc(-c2cnc(C3CCCCN3)o2)cc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N1CCCCC1c1ncc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.20 g (0.88 mmol) of 2-(5-phenyl-oxazol-2-yl)-piperidine, 0.36 g (1.05 mmol) of 2-tert-Butoxycarbonylamino-3-(4-tert-butoxy-phenyl)-propionic acid, 0.49 g (1.05 mmol) of PyBrop and 0.287 mL of diisopropylethylamine was added 1 ml of dimethylformamide. The resulting mixture was allowed to stir under argon at room temperature overnight. The following morning, LC analysis indicated that about 20% of starting material remained. An additional 0.09 g (0.26 mmol) of 2-tert-Butoxycarbonylamino-3-(4-tert-butoxy-phenyl)-propionic acid, 0.12 g (0.26 mmol) of PyBrop and 0.072 ml (0.45 mmol) of diisopropylethylamine was added. After stirring for 3 hours, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated. The product was taken to the next step as is without further purification.
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]([CH3:7])[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:30]1([C:36]#[C:37][C:38]2[N:43]=[C:42]([NH2:44])[CH:41]=[C:40]([C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)[CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN1C(=O)CCC1>[C:11]([O:10][C:8](=[O:9])[N:2]([CH3:1])[CH:3]([C:4](=[O:6])[NH:44][C:42]1[CH:41]=[C:40]([C:45]2[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=2)[CH:39]=[C:38]([C:37]#[C:36][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:43]=1)[CH3:7])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1cc(-c2ccncc2)cc(C#Cc2ccccc2)n1
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C(=O)Nc1cc(-c2ccncc2)cc(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (1.44 g, 7.1 mmol) and N,N′-dicyclohexylcarbodiimide (0.73 g, 3.55 mmol) in DCM (4 ml) is stirred for 30 minutes at RT. This mixture is added in 4 portions over 48 h via syringe filter to a mixture of 6-(2-phenylethynyl)-4-(pyridin-4-yl)pyridin-2-amine G1 (0.24 g, 0.89 mmol), DIPEA (166 μl, 0.98 mmol) and NMP (2 ml) at 50° C. After stirring for another 16 h at 50° C. the mixture is filtered and the product purified by RP HPLC. Yield: 56 mg (14%). HPLC-MS: M+H=457; tR=.2.08 min (METHOD—2).
Reaction SMILES: Br[C:2]1[C:7]2[C:8]([NH2:11])=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:43])[NH:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=3[NH:39][C:40](=[O:42])[CH3:41])=[CH:22][CH:21]=2)O1>>[NH2:11][C:8]1[C:7]2[C:2]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:43])[NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=4[NH:39][C:40](=[O:42])[CH3:41])=[CH:22][CH:21]=3)=[N:3][CH:4]=[CH:5][C:6]=2[NH:10][N:9]=1
Reactant: Nc1n[nH]c2ccnc(Br)c12
Reactant: CC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(-c2nccc3[nH]nc(N)c23)cc1

Procedure:
4-Bromo-1H-pyrazolo[4,3-c]pyrid-3-ylamine and N-(2-{3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureido}-4-trifluoromethylphenyl)acetamide are coupled by Suzuki reaction according to a protocol similar to that for the preparation of Example 10. A yellow powder of N-(2-{3-[4-(3-amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]ureido}-4-trifluoromethylphenyl)acetamide is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[C@H:9]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH2:8][C@H:7](O)[CH2:6]1.COCCN(S(F)(F)[F:27])CCOC.C(=O)([O-])O.[Na+]>ClCCl>[F:27][C@H:7]1[CH2:8][C@H:9]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[C@@H:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COCO[C@@H]1C[C@@H](O)C[C@H]1c1ccnn1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCO[C@H]1C[C@@H](F)C[C@@H]1c1ccnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a solution of the (1S*,3R*,4S*)-3-(methoxymethoxy)-4-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (150 mg, 0.663 mmol) prepared in Example 106b in dichloromethane (2.0 mL), bis(2-methoxyethyl)amino sulfur trifluoride (0.26 mL, 1.33 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution, an aqueous sodium hydrogencarbonate solution (10 mL) was added, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=2:3) to yield the title compound (132 mg, 87%) as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:23])[N:10]([CH2:12][C:13]2[NH:14][C:15]3[C:16]([N:22]=2)=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=3)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9](=[O:23])[N:10]([CH2:12][C:13]2[N:22]([CH2:31][O:30][CH2:29][CH2:28][Si:27]([CH3:34])([CH3:33])[CH3:26])[C:16]3=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=[C:15]3[N:14]=2)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CN(Cc1nc2ncc(Br)cc2[nH]1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1nc2cc(Br)cnc2n1COCC[Si](C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of phenylmethyl[(6-bromo-1H-imidazo[4,5-b]pyridin-2-yl)methyl]methylcarbamate (0.22 g, 0.59 mmol) in N,N-dimethylformamide (3.0 mL) was added 60% sodium hydride in mineral oil (56 mg, 1.48 mmol) and the reaction mixture was stirred for 30 minutes at room temperature, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (0.11 mL, 0.62 mmol). The reaction mixture was stirred at room temperature for 16 hours then it was quenched by the careful addition of saturated aqueous ammonium chloride and partitioned with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and washed with 10% aqueous citric acid (2×20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated. Gradient flash chromatography (15% to 35% ethyl acetate in hexane) gave phenylmethyl{[6-bromo-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}methylcarbamate (0.28 g, 93%). MS (EI) for C22H29BrN4O3Si: 506 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:19]([CH:20]([CH3:30])[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:5]2[O:6][C:7]([CH3:17])([CH3:16])[C:8]3[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[C:9]=3[C:4]=2[CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(#N)C>[C:31]([O:15][CH2:14][CH:10]1[C:9]2[C:4]3[CH:3]=[C:2]([OH:1])[C:19]([CH:20]([CH3:30])[CH2:21][CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:18][C:5]=3[O:6][C:7]([CH3:16])([CH3:17])[C:8]=2[CH2:13][CH2:12][CH2:11]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CCCc1ccccc1)c1cc2c(cc1O)C1=C(CCCC1CO)C(C)(C)O2
Solvent: CC#N
Product: CC(=O)OCC1CCCC2=C1c1cc(O)c(C(C)CCCc3ccccc3)cc1OC2(C)C

Procedure:
A solution of 0.1 mole of dl-7,8,9,10-tetrahydro-2-hydroxy-10-hydroxymethyl-6,6-dimethyl-3-(1-methyl-4-phenylbutyl)-6H-dibenzo[b,d]pyran in 100 ml. of acetonitrile is treated with 0.1 mole of acetic anhydride and the mixture heated for 12 hours under nitrogen. It is then poured onto ice/water and extracted with ethyl acetate (2×100 ml.), the extracts combined, washed with brine and dried MgSO4). Evaporation under reduced pressure followed by silica gel chromatography affords the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][N:12](C(=O)C(F)(F)F)[CH2:13]2.C(=O)([O-])[O-].[K+].[K+]>CO.ClCCl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][NH:12][CH2:13]2
Reactant: CC(C)C(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCNC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
CO-AAW0001 (100 mgs, 0.24 mmoles) was dissolved in methanol (5 mls) followed by the addition of anhydrous potassium carbonate (50 mgs, 0.36 mmoles). The solution was stirred at room temperature for 2 hours. Silica thin layer chromatography in dichloromethane/methanol (95:5) showed reaction to be complete. The reaction was evaporated and the residue dissolved in ethylacetate (20 mls) and water (10 mls). The aqueous layer was re-extracted with ethylacetate (2×10 mls) and the combined organic phases washed with brine (10 mls), dried of magnesium sulphate, filtered and evaporated to produce a yellow oil (˜80% pure, CO-AAW0003). This was used for the next reaction without further purification.