Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].C(#N)C>ClCCl>[CH3:10][C@@H:11]([CH2:12][CH3:13])[CH2:14][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CC[C@H](C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC[C@H](C)COc1ccc(O)cc1
Yield: 47.9 %

Procedure:
A reaction mixture of hydroquinone (18.2 grams); (S)-(+)-1-bromo-2-methylbutane (4.55 grams); anhydrous potassium carbonate (23 grams); and acetonitrile (250 mls.) was allowed to reflux for 40 hours. Flash chromatography using dichloromethane eluant yielded 2.6 grams (48%) of white crystals exhibiting a Fisher-Johns melting point of 44°-45° C. and having the structure ##STR24## confirmed by TLC, NMR, IR and mass spectral analyses.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:29]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])[CH3:30].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:35][CH2:34][CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:36])=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2ncccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ncccc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a mixture of 4-{[cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)methyl]amino}benzoic acid (300 mg) synthesized above, β-alanine ethyl ester hydrochloride (181 mg), 1-hydroxybenzotriazole monohydrate (181 mg), triethylamine (329 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-100% ethyl acetate/hexane) to give the title object compound (335 mg, 89%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:27][CH:28]4[CH2:30][CH2:29]4)=[CH:23][CH:24]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1
Reactant: BrCC1CC1
Reactant: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1c(-c2ccc(OCC3CC3)cc2)nn2c1NCCC2c1ccccc1N
Temperature: 56 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a solution of 7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (331 mg, 1.0 mmol) in acetone (15 mL) was added (bromomethyl)cyclopropane (135 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol). After stirring at 56° C. for 16 hr, the mixture was filtered. The cake was washed with acetone (20 mL×2). The filtrate was concentrated to afford 300 mg of desired product (78%) as a yellow solid. MS (ESI) m/e [M+1]+ 386.0.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH:15]=[C:14]([CH3:16])[NH:13][CH:12]([CH2:17][O:18][CH2:19][CH2:20][OH:21])[C:11]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])C(OC)=O.Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:26]([O:28][CH3:29])=[O:27])=[C:14]([CH3:16])[NH:13][C:12]([CH2:17][O:18][CH2:19][CH2:20][O:21][C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[C:11]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Clc1ncccn1
Reactant: CCOC(=O)C1(C(=O)OC)C(COCCO)NC(C)=CC1c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCCOc2ncccn2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.3 %

Procedure:
Sodium hydride (90 mg. of an 80% by weight dispersion in oil) was added to a solution of 4-(2-chlorophenyl)-3-ethoxycarbonyl-2-(2-hydroxyethoxymethyl)-3-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.60 g) in tetrahydrofuran (20 ml) and the mixture stirred at room temperature for 45 minutes and then treated with 2-chloropyrimidine (0.17 g). The mixture was stirred at room temperature for 3 days and evaporated. The residue was dissolved in ethyl acetate and the solution washed successively with 2M hydrochloric acid, 5% aqueous sodium carbonate solution and brine, dried over MgSO4 and evaporated. The residue was crystallised from ether to give the title compound (90 mg), m.p. 101°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH3:6][O:7][CH2:8][CH2:9]Br.C(N(CC)CC)C>C(#N)C>[CH3:6][O:7][CH2:8][CH2:9][N:2]([CH2:3][CH2:4][OH:5])[CH3:1]
Reactant: CNCCO
Reactant: COCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCN(C)CCO
Temperature: 25 °C
Yield: 31.3 %

Procedure:
A mixture of 2-methylaminoethanol (5.4 g), 2-bromoethyl methyl ether (10 g), triethylamine (10 ml) and acetonitrile (70 ml) was stirred and heated to reflux for 16 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was triturated under diethyl ether. The organic solution was separated and evaporated to give 2-[N-(2-methoxyethyl)-N-methylamino]ethanol (3 g, 31%); NMR Spectrum: (CDCl3) 2.35 (s, 3H), 2.6 (t, 2H), 2.65 (t, 2H), 3.35 (s, 3H), 3.5 (t, 2H), 3.6 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[N:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=424.1, tR (minutes, Method F)=3.19
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=O)=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.Cl.[CH:56]1([C:59]([NH2:63])([CH3:62])[CH2:60][NH2:61])[CH2:58][CH2:57]1>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[NH2:63][C:59]([CH:56]1[CH2:58][CH2:57]1)([CH3:62])[CH2:60][NH:61][C:17]([C:13]1[N:8]2[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:23][CH:22]=[CH:21][C:20]=3[F:24])[C:7]2=[N:15][C:14]=1[CH3:16])=[O:19]
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(N)(CN)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC(C)(N)C3CC3)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
160 mg (0.48 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid Example 21A, 162 mg (0.51 mmol) of TBTU and 292 mg (2.89 mmol) of 4-methylmorpholine were initially charged in DMF (1.7 ml), and 99 mg (0.53 mmol) of rac-2-cyclopropylpropane-1,2-diamine dihydrochloride were added at 0° C. The reaction mixture was allowed to warm to room temperature and then stirred at RT overnight. Another 50 mg (0.27 mmol) of 2-cyclopropylpropane-1,2-diamine dihydrochloride and 49 mg (0.48 mmol) of 4-methylmorpholine were added, and the mixture was stirred at RT for 1.5 h. The mixture was diluted with a few drops of water/TFA and purified by prep. RP-HPLC (acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off and concentrated. This gave 156 mg (76% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:12]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([S:20]([C:18]3[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=3[O:24][CH3:25])(=[O:21])=[O:22])[C:6]=2[CH:12]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: Brc1ccc2c(c1)NCCCC2
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCCCc2ccc(Br)cc21

Procedure:
8-Bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine was reacted with 5-chloro-2-methoxybenzenesulfonyl chloride in analogy to example 34, step 2, yielding 8-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine. Off-white solid, MS (ISP): m/e 430.2 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH:10]([O:13][C:14]1[CH:15]=[C:16]([N:22]2[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])([CH3:12])[CH3:11]>>[NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH:10]([CH3:11])[CH3:12])[CH:15]=3)[CH2:23][C@@H:24]2[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:9])[N:3]=[CH:2]1
Reactant: COc1ccc(N2CCN[C@@H](CC(C)C)C2)cc1OC(C)C
Reactant: O=C(O)Cc1c[nH]cn1
Product: COc1ccc(N2CCN(C(=O)Cc3c[nH]cn3)[C@@H](CC(C)C)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using 2-(1H-imidazol-4-yl)acetic acid and (S)-1-(3-isopropoxy-4-methoxy-phenyl)-3-isobutyl-piperazine (Example 35, Compound 123) as starting materials. Product as an off-white solid (32%). LC/MS (Method B) 2.52 min, [M+1]+ 415.1. Potency class B.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:14][O:15][C@H:16]([CH3:29])[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6].Cl[C:31]1[N:36]=[CH:35][N:34]=[C:33]2[N:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[Cl:46])[N:38]=[CH:39][C:32]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[N:37]1[C:33]2=[N:34][CH:35]=[N:36][C:31]([O:3][C@@H:4]([CH2:14][O:15][C@H:16]([CH3:29])[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:20]([CH3:21])[CH3:22])[CH:23]([CH3:25])[CH3:24])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[O:6])=[C:32]2[CH:39]=[N:38]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: CC(C)[Si](OC[C@@H](C)OC[C@H](O)C(=O)Nc1ccccn1)(C(C)C)C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](OC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccccn1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
Sodium hydride (78 mg, 1.95 mmol) was added to (S)-2-hydroxy-N-(pyridin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AQ4) (387 mg, 0.98 mmol) in anhydrous THF (20 mL). The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (250 mg, 0.89 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% EtOAc in isohexane to afford the product (329 mg, 59.4%). 1H NMR (400 MHz, CDCl3) δ 1.01-1.15 (24H, m), 3.55-3.78 (3H, m), 4.19-4.35 (2H, m), 6.03 (1H, t), 7.05 (1H, t) 7.40-7.65 (4H, m), 7.7 (1H, t), 8.2-8.3 (2H, m), 8.43 (1H, s), 8.58 (1H, s), 8.75 (1H, s); m/z (ES+) M+=625.44; HPLC tR=4.02 min.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:27][CH:26]=4)[CH2:24][CH2:23]2)[N:16]=3)=[C:9]([F:39])[CH:8]=1>C1COCC1.Cl>[CH2:32]([O:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2([C:17]3[N:16]=[C:15]4[S:14][C:13]([C:10]5[CH:11]=[CH:12][C:7]([CH:2]=[O:1])=[CH:8][C:9]=5[F:39])=[N:21][C:20]4=[CH:19][CH:18]=3)[CH2:23][CH2:24]2)=[CH:30][CH:29]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccc(OCc5ccccc5)cc4)CC3)nc2s1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3ccc(C4(c5ccc(OCc6ccccc6)cc5)CC4)nc3s2)c(F)c1
Temperature: 65 °C

Procedure:
A suspension of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(4-(benzyloxy)-phenyl)cyclopropyl)thiazolo[5,4-b]pyridine (0.305 g, 0.566 mmol) in 5 mL THF and 5 mL 5N aq. HCl was heated in a sealed vial to 65° C. for 1 h. The reaction mixture was cooled, poured onto ice, quenched with 10 N NaOH, sonicated in 5 mL MTBE, filtered, and rinsed with 1 mL MTBE. The solid was collected to give 4-(5-(1-(4-(benzyloxy)-phenyl)cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzaldehyde as an orange solid. MS (ESI) m/z: calculated: 480.1; Observed: 481.1 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Li+]>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(O)cc(C(=O)O)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To dimethyl 5-hydroxyisophthalate (4.0 g, 19.03 mmol, 1.00 equiv) in THF (10 mL) was added lithium hydroxide (20 mL, 2M in water) and the resulting solution was stirred overnight at 40° C. The mixture concentrated under vacuum to remove the organic solvents and then the pH of the solution was adjusted to ˜2 with 6N hydrochloric acid. The resulting solids were collected by filtration and dried in a vacuum oven to afford 2.0 g (58%) of 5-hydroxyisophthalic acid as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[N:25]1[N:29]2[CH2:30][CH2:31][CH2:32][NH:33][C:28]2=[CH:27][CH:26]=1>>[N:25]1[N:29]2[CH2:30][CH2:31][CH2:32][N:33]([C:19]([C:18]3[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[CH:23][CH:22]=3)=[O:21])[C:28]2=[CH:27][CH:26]=1
Reactant: c1cc2n(n1)CCCN2
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCCn3nccc32)cn1
Yield: 31 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 4,5,6,7-tetrahydropyrazolo(1,5-a)-pyrimidine hydrochloride instead of methylamine, to the title compound (41 mg, 31%) which was obtained as a light yellow solid after crystallisation from ethyl acetate:hexane. MS: m/e=416.4 [M+H]′.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:22]=[CH:21][C:20]3[NH:19][CH2:18][CH:17]4[CH2:23][CH2:24][CH2:25][C:15]=2[C:16]=34)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([C:26](=[O:28])[CH3:27])[CH2:18][CH:17]4[CH2:23][CH2:24][CH2:25][C:15]=2[C:16]=34)=[O:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc3c4c2CCCC4CN3)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(CCC(=O)c2ccc3c4c2CCCC4CN3C(C)=O)CC1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A mixed solution of 3-(1-acetyl-4-piperidinyl)-1-(1,2,2a,3,4,5-hexahydrobenz[cd]indol-6-yl)-1-propanone (free base, 0.15 g, 0.44 mmol) and acetic anhydride (0.066 ml, 0.69 mmol) in ethyl acetate (20 ml) was heated at 70-75° C. with stirring for 1 hour. The solvent was then distilled off and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=20:1) to provide the title compound (0.155 g) as colorless crystals melting at 130-132° C.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([O:13][C:14]([F:17])([F:16])[F:15])[C:7]=1[C:18]#[C:19][Si](C)(C)C)C.[OH-].[K+]>CC(O)(C)C>[F:12][C:11]1[CH:10]=[CH:9][C:8]([O:13][C:14]([F:15])([F:16])[F:17])=[C:7]2[C:6]=1[NH:5][CH:19]=[CH:18]2
Reactant: CCOC(=O)Nc1c(F)ccc(OC(F)(F)F)c1C#C[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Fc1ccc(OC(F)(F)F)c2cc[nH]c12
Temperature: 70 °C
Yield: 91.7 %

Procedure:
A mixture of 4 (28.9 g, 79.6 mmol) and KOH (35.7 g, 636.7 mmol) in degassed t-BuOH (300 mL) is heated at 70° C. overnight. LC/MS indicates the reaction is completed. The mixture is cooled to rt, and then partitioned between H2O and Et2O. The two layers are separated, and the aqueous layer was extracted with Et2O (2×). The combined organic layers are washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material is purified on silica gel with heptane/EtOAc (100/0 to 60/40) as eluant to give 16 g (91%) of 5 as a yellow liquid. 1H NMR (CDCl3) δ 8.47 (br s, 1H), 7.35-7.20 (m, 1H), 6.95-6.80 (m, 2H), 6.68 (d, J=2.5 Hz, 1H); 19F NMR (CDCl3) δ −57.63 (s, 3F), −136.10 (d, J=8.5 Hz, 1F); MS 220 (M+1, 100%), 200.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:25])[F:23])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: FC(F)(F)c1ccccc1Cc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2ccccc2C(F)(F)F)ncn1
Temperature: 25 °C
Yield: 106.8 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.06 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(2-trifluoromethylbenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.24 g of 4-(2-butynyloxy)-6-(2-trifluoromethylbenzyl)pyrimidine (the present compound (95)).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])[CH3:33]>COCCOC.O.[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>[CH:32]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:3]=2)=[CH:37][CH:36]=1)([CH3:34])[CH3:33]
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C(C)C)cc1
Yield: 72.3 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 4-isopropylphenylboronic acid (0.082 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.074 g (71%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][C:10]([CH3:13])([O-])[CH3:11].[K+]>C(O)(C)(C)C>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:10]([CH3:13])([CH3:11])[CH3:9])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cccc(Br)n1
Yield: 47.4 %

Procedure:
2,6-Dibromopyridine (50 g) was added to a solution of potassium tert-butoxide (35.5 g) in tert-butanol (300 ml). The mixture was heated to reflux for 3.5 hours then cooled and concentrated. The residue was quenched with water and extracted into ethyl acetate. The combined organic extracts were washed with brine, dried and concentrated to give 2-bromo-6-tert-butylpyridine (21.4 g, 44% yield ) as a clear oil; 1H NMR (270 MHz): δ 1.55(9H,s), 6.58(1H,d), 6.98(1H,d), 7.33(1H,t)ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[N:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[CH:22]3)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]1([C:4]2[N:3]=[C:2]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][N:23]=[CH:22]4)[CH:7]=[N:6][CH:5]=2)[CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: Brc1cncc(C2CC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1cc2[nH]ncc2cc1-c1cncc(C2CC2)n1
Temperature: 100 °C
Yield: 45.6 %

Procedure:
A reaction vessel was charged with 2-bromo-6-cyclopropylpyrazine (1.27 g, 6.39 mmol, Combi-Phos Catalysts Inc.) and Pd(PPh3)4 (308 mg, 0.27 mmol). The tube was sealed. A solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.30 g, 5.33 mmol) in dioxane (18 mL) and 2 M Na2CO3 (aq.) (8.0 mL, 16.0 mmol) were added. The reaction was stirred and heated at 100° C. overnight. After cooling to RT, the organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-50% EtOAc in hexanes, to provide 5-(6-cyclopropylpyrazin-2-yl)-1H-indazole (575 m g, 2.43 mmol, 46% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 237.2 (M+1).