Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>O.C(O)COCCO>[CH2:1]([C:9]1[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1C(=O)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 4-benzoyl-3-n-butoxy-5-sulfamylbenzoic acid (0.94 g), 98% aqueous hydrazine hydrate (1.5 ml), potassium hydroxide (0.5 g) in water (1.0 ml) and diethylene glycol (6.5 ml) is stirred at about 130° C. for 3 hours. The temperature is then slowly raised to 215° C. allowing volatile material to distil off. The stirring at 215° C. is continued for a further 2-3 hours until the nitrogen evolution has ceased. After cooling and dilution with water (10 ml), the resulting solution is acidified with conc. hydrochloric acid (1 ml). The resulting precipitate is collected by filtration and washed with water. After drying and recrystallization twice from aqueous ethanol, 4-benzyl-3-n-butoxy-5-sulfamylbenzoic acid is obtained with a melting point of 228°-229° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:36])[CH:14]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)=[O:17].C(=O)([O-])[O-].[Na+].[Na+].Cl>CO.C1(C)C=CC=CC=1.[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>[CH3:11][O:12][C:13](=[O:36])[CH:14]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=1)[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: COC(=O)C(CC(=O)c1ccc(Br)cc1)Cc1cccc(C(F)(F)F)c1
Reactant: OB(O)c1ccc(O)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(CC(=O)c1ccc(-c2ccc(O)cc2)cc1)Cc1cccc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
A solution of 4-hydroxyphenylboronic acid (160 mg, 1.2 mmol) in MeOH (3 mL) was added to a stirred solution of methyl-4-(4-bromophenyl)-4-oxo-2-(3-trifluoromethyl-benzyl)butyrate (270 mg, 0.6 mmol) in toluene (10 mL). Tetrakis-(Triphenylphosphine)-palladium(0) (21 mg, 4 mol %) and 2 N sodium carbonate (0.75 mL, 1.5 mmol) were added and then the reaction was heated to 90° C. (oil bath temp.) for 4-5 h until complete (TLC control). The reaction mixture was cooled to room temperature, acidified to pH 3 with 0.5 N hydrochloric acid and partitioned between water and ethyl acetate. The phases were separated, the aqueous phase being further extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water and sat'd aq NaCl, dried over anhyd MgSO4, filtered and concentrated. Trituration and filtration from MeOH afforded the title compound has a white solid (200 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[F:36][C:37]1([F:42])[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:36][C:37]1([F:42])[CH2:41][CH2:40][N:39]([C:29](=[O:31])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:34])([F:33])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:38]1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: FC1(F)CCNC1
Agent: Cl
Product: CC(C(=O)N1CCC(F)(F)C1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 3,3-difluoropyrrolidine hydrochloride (Matrix and Cat. No. 008716). LCMS (M+H)+: m/z=563.3.
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][S:11][C:5]2=[N:4][C:3]=1/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=1[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29].[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:25][O:24][C:20]1[C:19]([O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:18](/[CH:17]=[CH:16]/[C:3]2[N:4]=[C:5]3[S:11][CH:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:6]3[C:7](=[O:8])[C:2]=2[C:37]2[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[CH:35][CH:36]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(/C=C/c2nc3scc(C(F)(F)F)n3c(=O)c2I)c1OCC(C)(C)C
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(/C=C/c2nc3scc(C(F)(F)F)n3c(=O)c2-c2ccc(C#N)cc2)c1OCC(C)(C)C
Yield: 65.9 %

Procedure:
This compound was prepared from Intermediate 21 (100 mg, 0.197 mmol) and 4-cyanophenylboronic acid (35 mg, 0.204 mmol) using Pd[(C6H5)3P]4 (8 mg, 0.007 mmol) and sodium carbonate (112 mg, 1.053 mmol) in toluene (10 ml) and ethanol (5 ml) and water (4 ml) according to the procedure outlined in Example 1 to afford crude residue which was purified by column chromatography using 1% ethyl acetate in chloroform to afford 70 mg of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 9H), 3.53 (m, 2H), 3.77 (m, 2H), 6.72-6.77 (m, 1H), 6.98-7.02 (m, 2H), 7.52-7.55 (m, 2H), 7.91-7.94 (m, 2H), 8.24 (s, 1H), 8.30 (s, 2H); ESI-MS (m/z) 540.53 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:8]=2)[C@H:4]([CH2:20][OH:21])[CH2:3]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:21][CH2:20][C@@H:4]1[CH2:3][C:2]([F:1])([F:22])[CH2:6][N:5]1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([C:16]([F:18])([F:19])[F:17])[CH:8]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CC(F)(F)C[C@H]2CO)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1CC(F)(F)CN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of (S)-(4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol (275 mg, 0.84 mmol) in anhydrous DCM was added triethylamine (171 mg, 235 μL, 1.7 mmol) followed by methane sulfonyl chloride (106 mg, 72 μL, 0.93 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with DCM and quenched with 3 mL saturated NaHCO3. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and concentrated to obtain (S)-(4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methyl methanesulfonate as a yellow solid (330 mg, 96%). LC/MS: m/z 405 (M+H)+ at 1.71 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]1([CH:7]2[N:12]([CH2:13][C:14]#[N:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[S:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>>[CH3:22][CH:21]([CH3:23])[C:20]([NH:15][CH2:14][CH2:13][N:12]1[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[S:9][CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:24]
Reactant: N#CCN1c2ccccc2SCC1c1ccccc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)NCCN1c2ccccc2SCC1c1ccccc1

Procedure:
The procedure is as in Example 15, starting from the compound obtained in Step A and with the replacement of benzoyl chloride with isobutyryl chloride.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Br[CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32]>[Cl-].[Na+].O>[CH3:34][O:33][C:31](=[O:32])[CH:30]([N:10]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:2]1[CH3:1])[CH3:35]
Reactant: Cc1[nH]c2ncccc2c1C(=O)OC(C)(C)C
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Yield: 62.5 %

Procedure:
To a pyrex vial was added tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (2.491 g, 10.72 mmol) and cesium carbonate (4.54 g, 13.94 mmol). The atmosphere in the vial was vac/purged 3× with N2 then DMF (24 mL) and methyl 2-bromopropanoate (2.393 ml, 21.45 mmol) were added. The reaction was mixed at ambient temperature overnight. The reaction was poured into half-saturated brine and extracted with EtOAc. The combined organic layer was washed 1× each with water then brine, dried over Na2SO4, filtered, deposited onto silica gel and purified by CC (Biotage, 100 g column) using 25% EtOAc in Hex (6 CV) then 50% (6 CV) as eluent to provide (±)-tert-butyl 1-(1-methoxy-1-oxopropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (2.132 g, 64%). LRMS (M+H+) m/z: calcd 319.37. found 319.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:24][CH:20]3[CH2:21][NH:22][CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:15])=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:24][CH:20]3[CH2:21][N:22]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:15])=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CC3CNCC3C2)n1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CC3CN(C(=O)CC#N)CC3C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of 5-chloro-N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (186.6 mg, 0.54 mmol) and 2-cyanoacetic acid (64.8 mg, 0.76 mmol) in a mixture of DCM (20 mL) and DMF (5 mL) were added HATU (374.3 mg, 0.98 mmol) and Et3N (151.8 mg, 1.50 mmol). After addition, the reaction mixture was stirred at rt for 1 h, quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/50) to give the title compound as a beige solid (124.5 mg, 55.9%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([Br:10])=[CH:4][C:3]=1[O:11][CH3:12].C([Li])CCC.CN([CH:21]=[O:22])C>CCOCC>[Br:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([CH:21]=[O:22])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc(Br)c(OC)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C=O)c(OC)cc1Br
Reaction time: 0.17 h

Procedure:
A solution of 1,4-dibromo-2,5-dimethoxybenzene (7.00 g, 23.65 mmol) in 100 mL ether was cooled to −78° C. and was treated with n-butyllithium (10.41 ml, 26.0 mmol). After stirring for 10 minutes, the reaction mixture was quenched with DMF (3.66 ml, 47.3 mmol), and the cooling bath was removed. After stirring for an additional hour, LC/MS showed mostly product, so the reaction mixture was washed with 1N citric acid solution, the organics dried over MgSO4 and concentrated. The crude product was carried forward in step two without purification. (M+H)+=245.1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[C:18]([C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])[CH:25]=O)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[CH3:21][C:18]([C:22]1[CH:23]=[C:24]([CH:25]=[C:3]2[CH2:4][CH2:5][NH:1][C:2]2=[O:6])[CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])([CH3:19])[CH3:20]
Reactant: O=C1CCCN1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: COC(=O)[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C=C2CCNC2=O)cc(C(C)(C)C)c1O
Temperature: 0 °C
Yield: 21 %

Procedure:
Under a nitrogen atmosphere, 1.52 ml of 2-pyrrolidinone was added to a solution of 32 ml of 2M magnesium methyl carbonate in DMF and 5.86 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde. The resultant mixture was stirred at reflux temperature for six days and then allowed to cool. The cooled reaction mixture was poured into 40 g of ice containing 10 ml concentrated hydrochloric acid and then extracted with chloroform. The chloroform layer was collected, filtered and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography and recrystallized from ethyl acetate to give the desired titled product (21% yield), m.p. 216°-218° C.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1)[CH3:3].Br[C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31]([NH2:33])=[O:32])[CH:30]=1)[NH:27][CH:26]=[C:25]2[CH:34]1[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH2:43]([S:40]([N:37]1[CH2:36][CH2:35][CH:34]([C:25]2[C:24]3[C:28](=[C:29]([C:31]([NH2:33])=[O:32])[CH:30]=[C:22]([C:10]4[CH:9]=[N:8][CH:7]=[C:6]([CH2:5][NH:4][CH:2]([CH3:1])[CH3:3])[CH:11]=4)[CH:23]=3)[NH:27][CH:26]=2)[CH2:39][CH2:38]1)(=[O:42])=[O:41])[CH3:44]
Reactant: CC(C)NCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNC(C)C)c4)cc23)CC1
Temperature: 150 °C
Reaction time: 0.13 h
Yield: 70.3 %

Procedure:
To a CEM microwave tube containing (1-methylethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine (22 mg, 0.080 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (50 mg, 0.121 mmol), K2CO3 (100 mg, 0.724 mmol), dioxane (1.5 mL), H2O (0.5 mL), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (7.3 mg, 0.012 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 50° C. and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×100 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 50° C. to give 27.2 mg of the title compound (70%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21].Cl>CN(C)C=O>[C:20](#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCOCCCCCO
Reactant: N#CCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCOCCCCCOCCCCC#N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60%, 0.75 g) was added to a solution of 3 g of 5-pentyloxy-l-pentanol prepared in the above-described step (1) in 50 ml of N,N-dimethylformamide. Then 2 ml of 5-bromopentanenitrile was added thereto and the mixture was stirred at 60° C. for 2 h. 3% hydrochloric acid was added to the reaction solution. After extraction with ether, the organic layer was dried and concentrated and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1) to obtain 1 g of the intended product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](Cl)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20].[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([F:29])[CH:23]=1.Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[C:7]([O:19][CH3:20])[CH:8]=3)[N:13]=[CH:12][C:11]=2[C:16]#[N:17])=[C:24]([F:29])[CH:23]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cc1OCCCCl
Yield: 68.8 %

Procedure:
A mixture of 3.1 g (9.96 mmol) of 7-(3-Chloro-propoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 1.6 g (10.96 mmol) of 4-chloro-2-fluoro-aniline, and 1.2 g (10 mmol) of pyridine hydrochloride in 31 ml of 2-ethoxyethanol was stirred at reflux for 1.5 hr. The mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution was dried and solvent was removed. The residue was purified on a silica gel column eluting with chloroform-ether mixtures to give 2.88 g of the title compound as an off-white solid powder: mass spectrum (electrospray, m/e) M+H 419.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[O:16][C:17]([CH2:20][C:21]([O:23]C)=O)=[CH:18][N:19]=3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:28].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([N:14]=[C:15]3[NH:19][CH:18]=[C:17]([CH2:20][C:21]([NH2:28])=[O:23])[O:16]3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Nc2ncc(CC(=O)OC)o2)nc(-c2cccc(Cl)c2)n1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: CCc1cc(N=c2[nH]cc(CC(N)=O)o2)nc(-c2cccc(Cl)c2)n1
Temperature: 100 °C
Reaction time: 65 h
Yield: 71.3 %

Procedure:
A 20-mL vial was charged with methyl 2-(2-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)oxazol-5-yl)acetate (0.073 g, 0.20 mmol) and ammonium chloride (0.031 g, 0.59 mmol). To this was added methanol (4 mL) followed by NH3 (5.6 mL, 7N in methanol, 39 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 65 h. The crude reaction solution concentrated under reduced pressure. The residue was adsorbed onto silica then purified by chromatography on silica using dichloromethane/methanol (10:0 to 8:2) as eluent to afford 2-(2-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)imino)-2,3-dihydrooxazol-5-yl)acetamide (0.051 g, 72%) as an off-white solid. MW=357.79. M.p.>260° C. 1H NMR (DMSO-d6, 300 MHz) δ 8.68 (s, 1H), 8.61 (s, 1H), 8.37-8.32 (m, 2H), 8.00 (s, 1H), 7.63-7.52 (m, 2H), 5.34 (d, J=8.1 Hz, 1H), 5.19 J=8.1, 8.1, 3.3 Hz, 1H), 2.99 (dd, J=18.0, 8.4 Hz, 1H), 2.76 (q, J=7.5 Hz, 2H), 2.44 (dd, J=18.3, 3.6 Hz, 1H), 1.27 (t, J=7.5 Hz, 3H); APCI MS m/z 358 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[C:8]([NH:15][CH2:16][CH2:17][CH2:18]Br)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[NH:1]=[C:2]1[N:6]([CH2:18][CH2:17][CH2:16][NH:15][C:8](=[O:9])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:7])[S:3]1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Cc1cnc(N)s1
Product: Cc1cn(CCCNC(=O)OC(C)(C)C)c(=N)s1
Temperature: 85 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A mixture of 2-amino-5-methylthiazole (0.58 g, 5.0 mmol) and 3-(Boc-amino)propyl bromide (1.2 g, 5.0 mmol) was warmed to 85° C. and was allowed to stir for 4 h. The mixture was cooled to ambient temperature and was purified via column chromatography (SiO2, 9:1:0.1 CH2Cl2:methanol:ammonium hydroxide) to give the title compound (0.96 g, 3.5 mmol, 70% yield). MS (DCI/NH3) m/z 272 (M+H)+.
Reaction SMILES: C([N:8]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[CH:11][CH:10]=[N:9]1)C1C=CC=CC=1.C(O)(=O)C.C([O-])=O.[NH4+].C(OCC)(=O)C>C(O)C.[OH-].[Pd+2].[OH-]>[Si:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[NH:8][N:9]=[CH:10][CH:11]=2)=[CH:15][CH:16]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2ccnn2Cc2ccccc2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2ccn[nH]2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
To a suspension of 1-benzyl-N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1H-pyrazol-5-amine (4.9 g) and palladium hydroxide (10 wt %, 5.0 g) in ethanol (22.5 mL)-acetic acid (2.5 mL) was added ammonium formate (2.4 g) at 80° C. After stirring at 80° C. for 3 hr, the mixture was allowed to cool, ethyl acetate was added, and the insoluble material was filtered off. Saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (2.8 g, 74%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17])[CH3:2]>[Pd].CO>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17])[CH3:20]
Reactant: CCOC(COc1cc([N+](=O)[O-])ccc1OC)OCC
Agent: [Pd]
Solvent: CO
Product: CCOC(COc1cc(N)ccc1OC)OCC
Reaction time: 2 h

Procedure:
A mixture of 10.70 g 2-(2,2-diethoxy-ethoxy)-1-methoxy-4-nitro-benzene and 1.20 g of 10% palladium on carbon in 150 ml methanol was stirred for 2 hours under hydrogen atmosphere. The reaction mixture was filtered through a chem elut cartridge and the compound eluted with additional methanol. After contration under reduced pressure the residue was directly subjected to the subsequent reaction without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[Br:20][C:21]1[O:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1>>[Br:20][C:21]1[O:22][CH:23]=[C:24]([C:26]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=3[CH3:18])=[N:5]2)=[O:27])[N:25]=1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: O=C(O)c1coc(Br)n1
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3coc(Br)n3)n2)ccc(C#N)c1Cl
Yield: 6.2 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from ((S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (742 mg, 2.70 mmol) and 2-bromooxazole-4-carboxylic acid (492 mg, 2.56 mmol). The product was purified by Flash-chromatography. Yield 6.2%. m/z [448.7+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[O:13]=[C:14]1[C:19]2=[CH:20][NH:21][C:22]([CH:23]=O)=[C:18]2[CH2:17][CH2:16][O:15]1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[CH:23][C:22]3[NH:21][CH:20]=[C:19]4[C:14](=[O:13])[O:15][CH2:16][CH2:17][C:18]=34)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: COc1ccc2c(c1)NC(=O)C2
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-Methoxy-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.