Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[C:15](=[O:16])[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:9]2[C:8]=1[NH2:17].[NH2:18][C:19]1[C:20]([Cl:27])=[C:21]([OH:26])[C:22]([CH3:25])=[CH:23][CH:24]=1.N.OO>O.C(O)C>[NH2:17][C:8]1[N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:15](=[O:16])[C:7]=1[N:6]=[C:24]1[CH:23]=[C:22]([CH3:25])[C:21](=[O:26])[C:20]([Cl:27])=[C:19]1[NH2:18]
Reactant: Cc1ccc(N)c(Cl)c1O
Reactant: Nc1c(N)n2n(c1=O)CCCC2
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: CC1=CC(=Nc2c(N)n3n(c2=O)CCCC3)C(N)=C(Cl)C1=O

Procedure:
0.68 mmol of 2,3-diamino-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazin-1-one methanesulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.68 mmol of 3-amino-2-chloro-6-methylphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:3]=1[C:4](F)=[O:5].[OH2:17]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:17])=[O:5]
Reactant: O
Reactant: O=C(F)c1ccc(OC(F)(F)F)c(Cl)c1Cl
Product: O=C(O)c1ccc(OC(F)(F)F)c(Cl)c1Cl
Reaction time: 24 h

Procedure:
A suspension of crude 2,3-dichloro-4-trifluoromethoxybenzoyl fluoride (2 g, containing mixed antimony halides) in water was stirred vigorously for 24 hours. The mixture was extracted with dichloromethane and filtered. The organic layer was washed with hydrochloric acid (2M), aqueous sodium chloride solution and extracted into sodium carbonate solution (2M). The aqueous extract was acidified to pH1 and the solid was filtered off and washed with water to give 2,3-dichloro-4-trifluoromethoxybenzoic acid (0.6 g) as a white solid mp 123°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])[CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:12])[CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC(CC(=O)Nc1ccc(Cl)cc1)c1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
3,4-Dichloro-beta-[2-[(4-chlorophenyl)amino]-2-oxoethyl]benzenepropanoic acid (4.0 g) in EtOAc (75 mL) was treated with carbonyldiimidazole (2.52 g) and N,N-dimethylaminopyridine (trace). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (2.59 g) in H2O (40 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with Et2O and washed with 1N HCl (100 mL), sat. NaHCO3 (100 mL) and water (100 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound (3.81 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]3[CH2:12][CH2:11][C:10](=[O:13])[C:8]3=2)[O:3][CH2:2]1.[CH3:14][C:15]([CH3:17])=O.IC#N>O1CCCC1>[CH3:14][C:15](=[C:11]1[C:10](=[O:13])[C:8]2=[C:9]3[CH2:1][CH2:2][O:3][C:4]3=[N:5][CH:6]=[C:7]2[CH2:12]1)[CH3:17]
Reactant: O=C1CCc2cnc3c(c21)CCO3
Reactant: CC(C)=O
Agent: N#CI
Solvent: C1CCOC1
Product: CC(C)=C1Cc2cnc3c(c2C1=O)CCO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
1,2,6,7-Tetrahydro-8H-cyclopenta[d]furo[2,3-b]pyridin-8-one (610 mg, 3.48 mmol), acetone (1.28 mL, 17.4 mmol) and ICN Alumina B (manufactured by ICN, Akt. 1, 10 g) were suspended in tetrahydrofuran (15 mL), and the suspension was stirred at room temperature for 3 hr. Acetone (1.28 mL, 17.4 mmol) was added, and the mixture was further stirred for 3 hr. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to give the title compound (539 mg, yield 72%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=2)[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[O:51]=[C:50]([N:52]1[CH2:53][CH2:54][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:66])[F:67])[CH:60]=2)[CH2:56][CH2:57]1)[CH2:49][NH:48][C:22]([C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=2)[NH:21][N:20]=1)=[O:24]
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)[nH]n1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccc(O)cc2)[nH]n1
Reaction time: 8 h
Yield: 55 %

Procedure:
DIPEA (150 mg, 1.2 mmol) was added to a stirred solution of 5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid (70 mg, 0.34 mmol) in DMF (2 mL) followed by HOBt (48 mg, 0.36 mmol) and EDCI.HCl (69 mg, 0.36 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (116 mg, 0.34 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. The residue was purified by washing with 1% MeOH in EtOAc to afford 92 mg (55% Yield) of 5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 489, 96%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 9.8 (s, 1H), 8.02 (t, 1H), 7.5 (m, 3H), 7.28 (t, 3H), 6.8 (m, 3H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:14]([O:16][P:17]([O-:21])[O:18][CH2:19][CH3:20])[CH3:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([O:16][P:17]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:15]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: CCOP([O-])OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cccc(P(=O)(OCC)OCC)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(3-bromophenyl)acetate, 35i-b, (22.1 g, 90 mmol), diethylphosphite (25.1 g, 180 mmol) and triethylamine (27.5 g, 270 mmol) in toluene (300 mL) was added [1,1′-bis(diphenylphosphino) ferrocene]dicholoropalladium (3 g). The mixture was allowed to stir overnight at 110° C. and was filtered. The solution was concentrated to afford the crude product which was purified by column chromatography to give the title compound, 35i-c as yellow brown oil (26 g, crude). 1H NMR (300 MHz, CDCl3): δ 1.20-1.32 (m, 9H), 3.62 (s, 2H), 4.00-4.16 (m, 6H), 7.36-7.47 (m, 2H), 7.64-7.71 (m, 2H). LC-MS (M+H)+ 301.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([N:13]1[C:17]2[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=2[C:15]([C:23]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([NH2:31])[CH:30]=2)=[O:24])=[CH:14]1)([CH3:12])[CH3:11])(C(C)(C)C)(C)C.[F:32][C:33]([F:44])([F:43])[C:34]1[N:35]=[N:36][N:37]([CH2:39][C:40](O)=[O:41])[CH:38]=1>>[NH2:22][C:19]1[N:20]=[CH:21][C:16]2[C:15]([C:23]([C:25]3[CH:30]=[C:29]([NH:31][C:40](=[O:41])[CH2:39][N:37]4[CH:38]=[C:34]([C:33]([F:43])([F:32])[F:44])[N:35]=[N:36]4)[CH:28]=[N:27][CH:26]=3)=[O:24])=[CH:14][N:13]([C:10]([CH3:11])([CH3:12])[CH2:9][OH:8])[C:17]=2[N:18]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnc(N)nc21
Reactant: O=C(O)Cn1cc(C(F)(F)F)nn1
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C(F)(F)F)nn3)c2)c2cnc(N)nc21

Procedure:
The title compound was prepared according to the method described for Example 9 using [7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl]{5-aminopyridin-3-yl}methanone (see Preparation 48a) and [4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetic acid (see Preparation 81) to afford the title compound as a brown solid in 85% yield, 62 mg.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)=[O:4].[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([NH:30][C:31]2[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=2)[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:19](=[O:29])[O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)=[CH:14][CH:13]=1>CCOC(C)=O>[Br-:1].[CH2:37]([O:36][C:34]([C:33]1[CH:32]=[C:31]([NH:30][CH:18]([C:15]2[CH:16]=[N:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:19]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N+:23]([CH2:2][C:3](=[O:4])[C:5]4[S:6][CH:7]=[CH:8][N:9]=4)([CH2:24][CH2:25]3)[CH2:22]2)=[O:29])[CH:41]=[CH:40][CH:39]=1)=[O:35])[CH3:38]
Reactant: O=C(CBr)c1nccs1
Reactant: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccc(OC)nc2)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2C[N+]3(CC(=O)c4nccs4)CCC2CC3)c2ccc(OC)nc2)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
2-Bromo-1-(thiazol-2-yl)ethanone (23.4 mg, 0.11 mmol) was added to a solution of ethyl 3-(1-(6-methoxypyridin-3-yl)-2-oxo-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoate (C65) (50 mg, 0.11 mmol) in EtOAc (2 ml). The reaction was stirred at room temperature overnight, and then the solvent was evaporated and the residue was triturated with Et2O, filtered and dried to obtain (3R)-3-(2-(3-(ethoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetoxy)-1-(2-oxo-2-(thiazol-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane bromide (46.5 mg, 63.3% yield).
Reaction SMILES: C([O-])(=O)C.[K+].[F:6][C:7]1[C:12](B(O)O)=[CH:11][CH:10]=[CH:9][N:8]=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:18]=1.CCO>C(Cl)Cl.O>[F:6][C:7]1[C:12]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[CH2:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)[N:18]=2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
A mixture of potassium acetate (0.38 g, 3.87 mmol), 2-fluoro-3-pyridineboronic acid (0.28 g, 1.987 mmol) and 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.60 g, 1.559 mmol) in DCM (8.0 mL) was evaporated under nitrogen to dryness. THF (5.0 mL) was added followed by the addition of bis[4-(di-tert-butylphosphino)-N,N-dimethylaniline]palladium dichloride (Am-phos) (0.060 g, 0.085 mmol). The mixture was heated in an oil bath at 80° C. After 1 h, EtOH (5 mL) was added and heating was continued overnight. The mixture was cooled to rt. Water (10 mL) and DCM (10 mL) were added. The organic layer was separated. The aqueous layer was extracted with CH2CL2 and the organic layer was dried over MgSO4. The solution was filtered and concentrated in vacuo. The orange oil was adsorbed onto a plug of silica gel and purified by chromatography eluting with 2:1 hexane-acetone to provide 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (80 mg, 0.180 mmol, 11.52% yield) as a white foam. LCMS (ES, pos.): calcd for C25H24FN5O2: 445.2. found: 446.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.49-8.62 (m, 1H); 7.86-7.99 (m, 1H); 7.27-7.36 (m, 1H); 7.23 (dd, J=8.31, 4.99 Hz, 4H); 6.87 (t, J=8.51 Hz, 4H); 3.81 (s, 3H) 4.81 (s, 4H); 3.80 (s, 3H); 2.55 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:30]=[N:29]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+].Cl>C1COCC1>[CH3:26][C:23]1[C:22]([CH2:27][N:28]2[CH:32]=[C:31]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:30]=[N:29]2)=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4cc(-c5ccccc5)cn4)cc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1Cn1cc(-c2ccccc2)cn1
Temperature: 25 °C

Procedure:
1-{4′-[3-Methyl-4-(4-phenyl-pyrazol-1-ylmethyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.051 g, 0.101 mmol) was dissolved in THF (1 mL) then MeOH (0.5 mL) and NaOH (3N aq., 0.5 mL) was added and the reaction stirred at room temperature. After 8 hours the reaction was acidified with 1N aq. HCl then submitted to standard workup procedures to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[S:18][C:6]2[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:19]([O:21][CH3:22])=[O:20].[CH3:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][C:25]1=[O:33]>>[CH3:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]([CH2:2][C:3]2[S:18][C:6]3[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=3[C:4]=2[C:19]([O:21][CH3:22])=[O:20])[C:25]1=[O:33]
Reactant: COC(=O)c1c(CBr)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reactant: Cn1c(=O)[nH]c2ccccc21
Product: COC(=O)c1c(Cn2c(=O)n(C)c3ccccc32)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
The subtitle compound was prepared by the method of example 1 step c) using the product of example 1 step b) and N-methylbenzimidazolone.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:22][CH2:21]2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1(C)CCC(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of Example 8A (0.28 g, 2.2 mmol) and 1-tert-butoxycarbonylpiperazine (0.42 g, 2.2 mmol) in dichloroethane (5 mL) at room temperature was treated with acetic acid (100 μL) and sodium triacetoxyborohydride (0.53 g, 2.5 mmol), stirred overnight, diluted with ethyl acetate (300 mL), washed sequentially with 1N NaOH, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (650 mg, 95%). MS (ESI) m/e 297 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:15])[CH3:14].C(O)(=O)C.[Br:20]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Br:20][C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13](=[O:15])[CH3:14])=[C:2]([CH3:1])[C:7]=1[C:8]([F:10])([F:11])[F:9]
Reactant: CC(=O)Nc1cccc(C(F)(F)F)c1C
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-[2-methyl-3-(trifluoromethyl)phenyl]acetamide (6.2 g) and acetic acid (40 ml) was added an acetic acid solution (10 ml) of bromine (1.8 ml) under water-cooling. The reaction liquid was stirred at room temperature overnight and then at 50° C. for 2 hours. In addition, to the reaction liquid was added bromine (1.5 ml) under water-cooling, followed by stirring at 50° C. for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under water-cooling, followed by stirring at 50° C. for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under water-cooling, followed by stirring at 50° C. for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under water-cooling, followed by stirring at 50° C. for 4 days. The reaction liquid was poured into ice water (about 200 g), ethyl acetate was added thereto, followed by neutralization with potassium carbonate. A liquid-separation operation was carried out, and the organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine in this order, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to obtain N-[4-bromo-2-methyl-3-(trifluoromethyl)phenyl]acetamide (9.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([CH3:17])=[N:14][C:13]=1[CH3:18]>C(O)C>[CH3:17][C:15]1[S:16][C:12]([C:4]2[CH:5]=[CH:6][C:7]([NH2:9])=[CH:8][C:3]=2[O:2][CH3:1])=[C:13]([CH3:18])[N:14]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1sc(C)nc1C
Solvent: CCO
Product: COc1cc(N)ccc1-c1sc(C)nc1C
Yield: 73.6 %

Procedure:
A suspension of 5-(2-methoxy-4-nitro-phenyl)-2,4-dimethyl-thiazole (415 mg, 1.6 mmol) and anhydrous stannous chloride (1.52 g, 7.9 mmol) in ethanol (25 mL) was stirred at reflux for 3 hours. The yellow solution was evaporated and the residue dissolved in ethyl acetate. This solution was washed with 1N aqueous sodium hydroxide solution, twice with water, with brine, dried with magnesium sulfate and the solvent was evaporated to dryness. Column chromatography (50 g silica, heptane/ethyl acetate 30-60% v/v) afforded the title compound (276 mg, 75%) as a pale yellow solid. MS ISP (m/e): 235.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.04 (d, 1H), 6.31 (m, 2H), 3.80 (s broad, 2H), 3.78 (s, 3H), 2.66 (s, 3H), 2.29 (s, 3H). mp 112-115° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.Cl>C(Cl)(Cl)(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[CH2:8][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(F)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
5-Fluoro-2-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.82 g, 10 mmol), and benzoyl peroxide (0.1 g, 0.4 mmol) were dissolved in CCl4 (50 mL), heated at reflux, and irradiated with light (100 W bulb) for 4 hours. The reaction mixture was filtered and concentrated. The residue was dissolved in THF (50 mL). Morpholine (1.9 g, 22 mmol) was added to the THF solution. The mixture was stirred at ambient temperature for 1 hour and then filtered. The solvent of the filtrate was evaporated. The bright orange residue obtained was then mixed with 5% HCl solution (30 mL) and extracted with ethyl acetate (2×25 mL). The aqueous layer was basified with NaOH solution to pH 8 and then extracted with methylene chloride. Both ethyl acetate solution and methylene chloride solution were dried over anhydrous Na2SO4 separately. Evaporation of ethyl acetate solution afforded an orange oil which was recrystallized from hexane:ether solution to yield 450 mg of a yellow solid, 4-(3-methyl-4-nitrophenyl)morpholine (18%), the by-product. Evaporation of methylene chloride solution afforded 660 mg of the desired compound, 4-(5-fluoro-2-nitrobenzyl)morpholine (27.5%).
Reaction SMILES: COC1C=CC(B2[O:13][C:12](C)(C)[C:11]([CH3:17])([CH3:16])O2)=CC=1CS(N)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]5)=[CH:46][CH:47]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.C1(C(Cl)=O)CC1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([C:12]([N:51]2[CH2:52][CH2:53][N:48]([C:45]3[CH:46]=[CH:47][C:42]([C:39]4[CH:40]=[C:41]5[C:33]([C:31]6[CH:30]=[N:29][N:28]([CH2:27][C:26]7[CH:64]=[CH:65][CH:66]=[C:24]([F:23])[CH:25]=7)[CH:32]=6)=[CH:34][N:35]([S:54]([C:57]6[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=6)(=[O:56])=[O:55])[C:36]5=[N:37][CH:38]=4)=[CH:43][N:44]=3)[CH2:49][CH2:50]2)=[O:13])[CH2:17][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)C6CC6)CC5)nc4)cnc32)cc1
Yield: 100 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (80 mg, 0.13 mmol) was acylated with cyclopropane carbonyl chloride (22 mg, 0.196 mmol) using triethylamine (40 mg, 0.39 mmol) in DCM (3 mL) to afford 100 mg (100% yield) of the titled compound. MS: m/z=676.2 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:41]=[O:42])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[O:43]1CCCC1>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:41]=[O:42])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:43])[C:25]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:35][CH:36]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(C)(C)O)cc5)n4)c3C=O)ncc2c1
Reactant: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(C)(C)O)cc5)n4)c3C=O)ncc2c1

Procedure:
1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-[4-(1-hydroxy-1-methyl-ethyl)-phenylamino]-1H-pyrazole-4-carbonitrile (78 mg, 0.14 mmol) and dihydrogen tris(dimethylphosphinito)hydroplatinate (7.1 mg, 0.12 eq) were taken up in tetrahydrofuran (3.1 ml) and water (0.31 ml). The material was stirred and heated to reflux (oil bath) for 1 hour. The mixture was cooled to ambient and the volatiles were stripped (rotary evaporator). The crude material was purified by preparative thin layer chromatography (2 plates, eluting first with 7% methanol in methylene chloride and then re-developing with 6% methanol in methylene chloride). The product band was collected, providing desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-[4-(1-hydroxy-1-methyl-ethyl)-phenylamino]-1H-pyrazole-4-carboxylic acid amide as a light yellow powder (41 mg). LC/MS calcd for C32H31FN6O4 (m/e) 582.62, obsd 581.0 (M−H, ES−).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5](N)[S:6][CH:7]=1.[C:11]([Cu])#[N:12]>>[F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([C:11]#[N:12])[S:6][CH:7]=1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: N#C[Cu]
Product: N#Cc1nc(C(F)(F)F)cs1
Yield: 33.7 %

Procedure:
4-(trifluoromethyl)thiazol-2-amine (2.52 g, 15 mmol) was reacted with CuCN (2.95 g, 33 mmol) according to the procedure as described in Example 61, Step A to give the title compound as brown oil (0.90 g, 34%). The compound was characterized by the following spectroscopic data: