Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[O:11])[CH:7]=[CH:6][C:5]=1[F:13].O>C(O)(=O)C>[Br:1][CH2:12][C:10]([C:8]1[CH:7]=[CH:6][C:5]([F:13])=[C:4]([CH3:3])[CH:9]=1)=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1ccc(F)c(C)c1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)CBr)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.1 mL bromine was added to 15 g 4-fluor-3-methylacetophenone in 80 mL concentrated acetic acid. The reaction was stirred 3 h at RT. The reaction was added to water. The precipitate was filtered and dried to give 20.6 g desired product. Rt: 1.37 min (method I), (M+H)+: 231
Reaction SMILES: [NH2:1][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][C:6]([CH3:9])([OH:8])[CH3:7].[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>C(#N)C>[OH:8][C:6]([CH3:9])([CH3:7])[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])[CH3:10]
Reactant: O=S1(=O)CCCO1
Reactant: CC(N)CCCC(C)(C)O
Solvent: CC#N
Product: CC(CCCC(C)(C)O)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 70.2 %

Procedure:
To a solution of 6-amino-2-methyl-2-heptanol (2.5 g, 17.2 mmol) in acetonitrile (22 mL) was added 1,3-propane sultone (2.0 g, 16.4 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was filtered and washed with acetonitrile (2×20 mL). The solid was dissolved in 20% MeOH (75 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (150 mL), and then the solid material was filtered and dried in vacuo, affording the title compound (3.08 g, 70%). 1H NMR (D2O, 500 MHz) δ ppm 3.19 (m, 1H), 3.08 (m, 2H), 2.88 (t, 2H, J=7.3 Hz), 1.99 (m, 2H), 1.60 (m, 2H), 1.36 (m, 4H), 1.18 (d, 3H, J=6.8 Hz), 1.07 (s, 6H). 13C (D2O, 125 MHz) δ ppm 71.63, 54.73, 48.08, 43.46, 42.27, 32.97, 27.78, 27.73, 21.64, 19.67, 15.43. ES-MS 268 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O)=[O:11].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C(CCO)=CC=CC=1>C(Cl)Cl.[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>[F:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:10]=[O:11]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: O=Cc1ccccc1B(O)O
Agent: [Pd]
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C=O)c(F)c1
Temperature: 100 °C
Yield: 71.5 %

Procedure:
A mixture of 2 g of 4-bromo-3-fluorotoluene, 1.75 g of 2-formylbenzeneboronic acid, 0.36 g of tetrakis(triphenylphosphine)-palladium (0) and 11.6 ml of 2N aqueous sodium carbonate, in 50 ml of a 9:1 mixture of toluene-ethanol was heated to 100° C. for 3 h. The mixture was cooled to room temperature, diluted with 100 ml of methylene chloride and washed with 50 ml of 5% sodium bicarbonate containing 5 ml of 0.880 ammonia. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The resulting oil was purified by chromatography on silica gel eluting with ethyl acetate-heptane (1:3) to give 1.62 g of 2-(2-fluoro4-methylphenyl)benzaldehyde as an oil, GC-M.S. (E.I.) (M/Z): 214 [M+].
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([N:1]2[CH2:2][CH:3]([N:5]3[C:9]4=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]4[C:7]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:19][CH:20]=4)=[N:6]3)[CH2:4]2)[CH2:31][CH2:30]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCC(N2CC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Temperature: 25 °C
Yield: 37.6 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.06 g, 0.00017 mol), 1-methyl-4-piperidinone (0.057 g, 0.0005 mol), and acetic acid (0.03 g, 0.0005 mol) in dichloroethane (2.5 mL) was stirred at room temperature under an atmosphere of nitrogen for one and a half hours. Sodium triacetoxyborohydride (0.072 g, 0.00034 mol) was added to the mixture and stirred at ambient temperature under an atmosphere of nitrogen for two hours. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel using ammonium hydroxide/methanol/dichloromethane (2:15:83) as mobile phase to yield 1-[1-(1-methyl-4-piperidyl)-3-azetanyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.029 g, 0.000064 mol).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[F:19].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:21]3[CH:31]=[C:25]4[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]4[C:23](=[O:32])[N:22]=3)=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[F:19]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Cl)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(4-chloro-3-fluorophenoxy)-5-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: N[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:4]([CH3:18])[N:3]=1.N([O-])=[O:20].[Na+]>Cl.O>[CH2:11]([O:10][C:8]([C:7]1[C:2](=[O:20])[NH:3][C:4]([CH3:18])=[CH:5][C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cc(C)nc(N)c1C(=O)OCC
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(C)[nH]c(=O)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 90 ml of 2% hydrochloric acid was dissolved 2.52 g (10 mmol) of 2-amino-3,4-diethoxycarbonyl-6-methylpyridine. A solution of 0.83 g (1.2 eq.) of sodium nitrite dissolved in 3 ml of water was added dropwise to the solution. The mixture was stirred at room temperature for 1 hour and left standing in a refrigerator overnight. The resulting crystals were collected by filtration. The crystals were recrystallized from ethyl acetate to give colorless plates.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2].[C:28](OCC)(=O)C.CCCCCC>>[CH:1]([C:4]1[C:9]([CH:10]([OH:11])[CH3:28])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCc1c(C(C)C)nc(C(C)C)c(C(C)O)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-hexylpyridine (Example 23) according to the procedures described in Example 101. 1H NMR (300 MHz, CDCl3): δ 7.13 (m, 3 H), 7.04 (m, 1 H), 4.65 (m, 1 H), 3.73 (sept, J=6.6 Hz, 1 H), 3.19 (sept, J=6.6 Hz, 1 H), 2.18 (m, 2 H), 1.39 (d, J=6.6 Hz, 3 H), 1.30 (m, 13 H), 1.18 (m, 4 H), 1.09 (m, 4 H), 0.81 (t, J=7 Hz, 3 H). FAB-MS: calcd for (C25H36FNO) 385, found 386 (M+H). Anal. Calcd for C25H36FNO: C, 77.88; H, 9.41; N, 3.63. Found: C, 77.84; H, 9.49; N, 3.65. mp 96-99° C. Rf=0.3 (10% ethyl acetate/hexane).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=23)[CH:5]=[CH:4][CH:3]=1.[CH:19]1([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C.O>CS(C)=O>[CH:19]1([CH2:25][NH:26][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]4[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=34)[CH:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NCC1CCCCC1
Reactant: N#Cc1ccn2ncc(-c3cccc(Cl)n3)c2c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccn2ncc(-c3cccc(NCC4CCCCC4)n3)c2c1
Temperature: 140 °C
Yield: 32.7 %

Procedure:
A mixture of 3-(6-chloropyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 6, 30 mg, 0.12 mmol), cyclohexylmethanamine (46 μL, 0.35 mmol) and triethylamine (50 μL, 0.36 mmol) in dimethylsulfoxide (0.5 mL) was heated at 140° C. for 20 hours. The mixture was then cooled, water was added and the resultant precipitate was filtered and dried in vacuo. Purification of the solid by flash chromatography (dichloromethane to 150:1 dichloromethane/methanol) gave the title compound (13 mg, 33%) as a yellow foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[SH:43][CH2:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([NH:53][S:54]([C:57]2[CH:62]=[CH:61][C:60]([O:63][C:64]([F:67])([F:66])[F:65])=[CH:59][CH:58]=2)(=[O:56])=[O:55])=[CH:49][CH:48]=1)=[O:46]>C(Cl)Cl>[O:46]=[C:45]([C:47]1[CH:52]=[CH:51][C:50]([NH:53][S:54]([C:57]2[CH:62]=[CH:61][C:60]([O:63][C:64]([F:67])([F:65])[F:66])=[CH:59][CH:58]=2)(=[O:56])=[O:55])=[CH:49][CH:48]=1)[CH2:44][S:43][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(CS)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CSC(=O)c1ccccn1)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.33 h
Yield: 14 %

Procedure:
Picolinic acid (0.25 g, 2.04 mmol) was dissolved in anhydrous, degassed DCM (5 ml), HATU (775 mg, 2.04 mmol) was added followed by DIEA (0.53 g, 4.1 mmol). The mixture was stirred for 20 min and N-[4-(2-Mercapto-acetyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide SII-4 (0.725 g, 1.85 mmol) was added in 5 ml anhydrous, degassed DCM and the mixture was stirred for 16 hours. The reaction was filtered and the solvent evaporated. The product was purified by flash chromatography (1:1 EtOAc:hexanes) to afford 125 mg (0.25 mmol, 14%) product as a white solid. 1H-NMR: (400 MHz, DMSO): 11.12 (s, 1H), 8.89 (d, 1H), 8.03 (t, 1H), 8.01 (d, 2H), 8.00 (d, 2H), 7.90 (d, 1H), 7.78 (t, 1H), 7.60 (d, 2H), 7.14 (d, 2H), 4.60 (s, 2H); LC-MS (ES+): 497 [MH]+ m/e.
Reaction SMILES: N1(C[CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)CCCCCC1.NC1CCN(C[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)CC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:9]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:12][CH2:11]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(Cc5ccccc5)CC4)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-p-tolyloxy-1H-indole-2-carboxylic acid (137) (850 mg, 3.2 mmol) and 4-amino-N-benzylpiperidine (605 mg, 3.2 mmol) are dissolved in 5 ml of DMF and after addition of TBTU (1.2 g, 3.5 mmol) and ethyldiisopropylamine (2.2 ml, 12.8 mmol) the mixture is stirred at room temperature for 2 h. Then the mixture is evaporated at high vacuum. The residue is dissolved in ethyl acetate and washed with saturated NaHCO3-solution and brine. The organic layers are dried over Na2SO4, filtrated and evaporated under reduced pressure. Yield: 1.47 g (100%) of a yellow foam. MS (ESI): 438 [M−H]−.
Reaction SMILES: [NH3:1].[CH3:2][C:3]1[S:4][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:6]([CH3:8])[N:7]=1>C1COCC1>[CH3:2][C:3]1[S:4][C:5]([S:9]([NH2:1])(=[O:11])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: N
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: C1CCOC1
Product: Cc1nc(C)c(S(N)(=O)=O)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Liquid ammonia was added dropwise via a CO2/acetone condenser to a solution of 2,4-dimethylthiazole-5-sulfonyl chloride (260 mg, 1.228 mmol) in THF (3 mL) at −78° C. until the volume had approximately doubled (˜10 min). The reaction was stirred at −78° C. for 1 h and then allowed to slowly warm to rt. The reaction was concentrated to dryness and the residue was diluted with CH2Cl2. The slurry was filtered to remove the solids and the solution was concentrated to yield 2,4-dimethylthiazole-5-sulfonamide (230 mg, 1.2 mmol, 97% yield) as a light yellow solid. LC-MS retention time 0.43 min; m/z 191 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C(O)C.[CH2:4]([CH:7]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]=[O:19])[CH2:14][CH2:13]2)[CH2:8]1)[CH2:5][CH3:6].[BH4-].[Na+]>O>[CH2:4]([CH:7]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[CH2:8]1)[CH2:5][CH3:6]
Reactant: CCCC1CCC(C2CCC(C=O)CC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC1CCC(C2CCC(CO)CC2)C1
Temperature: 0 °C
Reaction time: 20 h
Yield: 90.5 %

Procedure:
Ethanol (30 ml) was added to 4-(3-propylcyclopentyl)cyclohexanecarboaldehyde (2.3 g) obtained in the second step in Example 3, in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to 0° C., and sodium borohydride (0.22 g) was added slowly. After the mixture had been returned to room temperature and stirred for another 20 hours and water (30 ml) was added. The mixture was separated, and the water layer was extracted with diethyl ether three times, and then the combined organic layer was washed with brine. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=½ by volume) to give (4-(3-propylcyclopentyl)cyclohexyl)methanol (2.1 g).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[F-:16].[K+].[K]>O1CCOCCOCCOCCOCCOCC1>[F:16][C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: [F-]
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [K]
Product: CCOC(=O)c1sc(F)nc1C(F)(F)F
Yield: 56.3 %

Procedure:
A mixture of 26 g (0.1 mole) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate, 37 g (0.55 mole) of potassium fluoride, and 0.11 g of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-CROWN-6, Aldrich Chemical Company) was held at reflux for 23 hours. Since an analysis showed the reaction to be incomplete, another 45 g (0.77 mole) of potassium fluoride was added and the reaction mixture held at reflux for 64 hours. To said mixture, 0.15 g of 18-CROWN-6 and an additional 27 g (0.40 mole) of potassium was added and held at reflux for 22 hours. Due to poor cooling overnight some of the solvent had evaporated. The reaction mixture was cooled and 300 ml. of acetonitrile added. The acetonitrile was filtered and concentrated. The residue was Kugelrohr distilled to give 13.7 g of a material which was separated by spinning band column at 15 mm Hg to give 4.2 g of the desired product, nD24 =1.4348.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:35]=[CH:34][C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[S:20][C:16]=3[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:35]=[CH:34][C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[S:20][C:16]=3[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)c2ccc3nc(N4CCN(C(=O)OC(C)(C)C)CC4)sc3c2)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COc1ccc(NC(=O)c2ccc3nc(N4CCNCC4)sc3c2)cc1OC
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate (507.1 mg, 1.15 mmol) was treated with trifluoroacetic acid (24 mL). The resulting homogenous mixture was stirred for 30 min, then diluted with diethyl ether and cooled in ice bath. The resulting solid was collected by filtration and dried in vacuum oven at room temperature to yield N-(3,4-dimethoxyphenyl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide as a khaki colored amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][C:50]1[CH:51]=[CH:52][C:53]([NH2:56])=[N:54][CH:55]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:49][C:50]1[CH:51]=[CH:52][C:53]([NH:56][C:22]([C:21]2[CH:20]=[N:19][N:16]3[CH:17]=[CH:18][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:8]4[C:4]4[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:14][C:15]=23)=[O:24])=[N:54][CH:55]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: Nc1ccc(F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cn1)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Temperature: 70 °C
Yield: 78.1 %

Procedure:
To a DMF (0.25 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 25 mg, 0.076 mmol) and HATU (35 mg, 0.092 mmol) was added 5-fluoropyridin-2-amine (10 mg, 0.092 mmol), followed by drop-wise addition of DIEA (0.040 mL, 0.23 mmol) at ambient temperature. The reaction was heated at 70° C. overnight, cooled, and directly purified by reverse-phase chromatography (5 to 66% acetonitrile/water) to yield the final product as white solid (25 mg, 78%). LCMS (apci) m/z=422.0 (M+H).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(N(CC)CC)C>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([NH:19][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(C2(N)CCCC2)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C2(NC(=O)C(C)(C)C)CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), 1-(p-methylphenyl)cyclopentylamine (8.8 g) and triethylamine (6.1 g), and trimethylacetyl chloride (6.0 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 10.8 g of N-[1-(p-methylphenyl)cyclopentyl]trimethylacetamide. M.P., 166°-167° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH:13]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH2:15][CH3:16])[CH3:14]>CN(C)C=O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:18][CH:19]=1)=[O:4]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 80 °C

Procedure:
To a solution of isatoic anhydride (4.00 g, 24.0 mmol) in N,N-dimethyl formamide (80 mL) under nitrogen atmosphere was added 4-sec-butylaniline (3.66 g, 24.0 mmol). The reaction mixture was heated at 80° C. for 24 hours, then the solvent was removed under reduced pressure and the residue was diluted with ethyl acetate, washed with 1 N aqueous solution of sodium hydroxide, water, and dried over sodium sulfate. The crude oil (7 g) was purified by column chromatography (silica gel 230-400 mesh; 10/0 to 4/1 hexanes/EtOAc as eluent) to give pure 2-amino-N-(4-sec-butylphenyl)-benzamide as a brown solid. Yield: 1.8 g (27.3%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][CH2:10][CH:9]2[CH:7]([O:8]2)[CH2:6]1)(=[O:4])=[O:3].[Br-:12].[Li+].Cl>O1CCCC1.[Cu](Br)Br>[Br:12][CH:9]1[CH2:10][CH2:11][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]1[OH:8]
Reactant: CS(=O)(=O)N1CCC2OC2C1
Reactant: [Br-]
Agent: Br[Cu]Br
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Br)C(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the epoxide (177 mg, 1 mmol, Example 303) in tetrahydrofuran (8 mL), lithium bromide (543 mg, 6.25 mmol, Aldrich) and copper(II)bromide (725 mg, 3.25 mmol, Aldrich) were added and the mixture was stirred at room temperature overnight. The mixture was poured into 0.1N hydrochloric acid (33 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, washed with water, brine and dried with MgSO4. The solvent was removed to give the desired product as colorless oil after passing through an aluminum column (eluted with 5% methanol/dichloromethane). 237 mg, 92%. H1NMR (300 MHz, CDCl3), ppm: 2.00-2.20 (m), 1 H; 2.38-2.52 (m), 1 H; 2.70 (br), 1 H (OH); 2.99 (s), 3H; 3.0-3.20 (m), 2 H; 3.50-3.51 (m), 1 H; 3.80-3.97 (m), 2 H; 4.0-4.10 (m), 1 H. The compound was used directly for the next step.