Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH2:20])[N:19]=[C:15]4[CH:14]=[CH:13][N:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>C(#N)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH:20][C:31]([CH:28]5[CH2:30][CH2:29]5)=[O:32])[N:19]=[C:15]4[CH:14]=[CH:13][N:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccnc(-c3ccc4c(c3)OCCO4)n2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2ccnc(-c3ccc4c(c3)OCCO4)n2n1)C1CC1
Temperature: 25 °C

Procedure:
To a solution of 5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-ylamine (0.04 g, 0.148 mmol) in dry acetonitrile (2 mL) was added triethylamine (0.052 mL, 0.371 mmol) followed by cyclopropanecarbonyl chloride (0.034 mL, 0.371 mmol). The reaction mixture was then allowed to warm to ambient temperature, and the solvent removed under reduced pressure. The crude product was purified by preparatory HPLC. 1H NMR (300 MHz, DMSO): 1.84-1.88 (m, 4H), 2.00-2.08 (m, 1H), 4.31-4.36 (m, 4H), 7.06 (d, 1H), 7.64 (d, 1H), 8.21 (dd, 1H), 8.35 (d, 1H), 8.39 (d, 1H), 11.37 (s, 1H). LCMS Method: 2: RT: 3.51 min, MI: 338 [M+1].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:12]Br>C(Cl)(Cl)Cl.ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrBr
Reactant: COC(=O)c1ccccc1O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of methyl 2-hydroxybenzoate (152 g, 1.0 mol) in chloroform (500 mL) was added dropwise with stirring a solution of bromine (172 g, 1.08 mol) in chloroform (300 mL) at 10° C. After the addition, the solution was stirred at room temperature overnight. The mixture was diluted with dichloromethane (500 mL), washed with water (1 L×3), saturated sodium bicarbonate solution (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was re-crystallized from methanol to give methyl 5-bromo-2-hydroxybenzoate (192 g, yield 83%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 3.96 (s, 3H), 6.89 (d, J=8.8 Hz, 1H), 7.52-7.55 (dd, J=8.8 Hz, J=2 Hz, 1H), 7.96 (d, J=2.8 Hz, 1H), 10.7 (s, 1H); LC-MS (ESI) m/z 233 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Si:11]([O:18][C@H:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C=O)C>[Si:11]([O:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNCC[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 98 %

Procedure:
Method 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl (3S,4S)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and triethylamine in DMF yielding tert-butyl(3S,4S)-4-(tert-butyldimethylsilyloxy)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (98%). LCMS (m/z): 453.3 (MH+); LC Rt=4.01 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1.Cl>CN(C)C(=O)C.O>[CH:31]([C:30]1[CH:33]=[CH:34][C:27]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:28][CH:29]=1)=[O:32]
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(C=C(C(=O)O)c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(C=O)cc3)cc2)cc1
Temperature: 190 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of 38 (7.27 g, 28.6 mmol) and potassium carbonate (8.68 g, 62.9 mmol) in 200 mL N,N-dimethylacetamide was added 4-fluorobenzaldehyde (3.9 mL, 36.4 mmol). The reaction mixture was heated to 190° C. for 1.5 h under argon then cooled to room temperature. The addition of 5% HCl in water to pH 1 resulted in the product separating out as oil. Approximately 50 mL ethyl acetate was added to the mixture which is allowed to stir 16 h. The solid was collected and recrystallized out of toluene, rinsed with hexane and dried under vacuum to yield a white powder (8.1 g, 79.0%). 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.94 (s, 1H), 7.97(d, J=8.8 Hz, 2H), 7.76 (s, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.18 (d, J=6.8 Hz, 2H), 7.16 (d, J=6.4 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 2.25 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:9][C:10]1[CH:15]=[CH:14]C=[CH:12][CH:11]=1.Cl.[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[CH:2]1([CH:1]2[CH2:14][CH2:15][CH:10]([NH2:9])[CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1CCCCC1=O
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC1CCC(C2CCCCC2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-cyclohexanone (112 g, 1.0 mol), aniline (186 g, 2 mol) and ethanol (26 mL) was stirred at room temperature and 12 M hydrochloric acid (167 mL) was added during 30 min. The dark yellow solution was refluxed at 85° C. for seven days. The solution was cooled and diluted with ethyl acetate. The mixture was stirred in an ice bath and made alkaline (pH=9) with a 27% sodium hydroxide solution, keeping the temperature below 30° C.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22]>>[N+:5]([CH:4]=[C:3]([NH:8][C:9]#[C:10][CH3:11])[NH:22][CH2:21][CH2:20][S:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)([O-:7])=[O:6]
Reactant: NCCSCc1ccccn1
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Product: CC#CNC(=C[N+](=O)[O-])NCCSCc1ccccn1

Procedure:
A solution of the product of Step A is treated with about an equimolar amount of 2-[(2-pyridyl)methylthio]-ethylamine to produce, after workup, the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH3:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+].Cl>C(O)C.O>[Cl:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH:22]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=CC(=O)C(CCC(=O)O)(Cc2ccccc2Cl)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Methoxybenzaldehyde (3.4 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of levo-4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam, bath for 24 hours. The reaction solution is cooled to room temperature, acidified with dilute hydrochloric acid (10 ml.), and the sticky solid which forms after scratching is filtered and air-dried. Recrystallization from n-butyl chloride yields 3.2 g., m.p. 152°-157°C. An additional recrystallization from n-butyl chloride yields material with m.p. 159°-160.5°C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.[NH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][CH:54]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60]3[C:55]2=[CH:56][CH:57]=[CH:58][CH:59]=3)=[O:51])[CH2:46][CH2:45]1>CN(C)C=O>[CH:65]1[C:66]2[CH:54]([CH2:53][O:52][C:50]([N:47]3[CH2:48][CH2:49][CH:44]([NH:43][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][C:22]([NH:21][C:19]5[N:18]=[CH:17][C:8]6[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]7[CH2:5][CH2:4][CH2:3][CH2:2]7)[C:7]=6[N:20]=5)=[C:23]([O:31][CH3:32])[CH:24]=4)[CH2:45][CH2:46]3)=[O:51])[C:55]3[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:61]=2[CH:62]=[CH:63][CH:64]=1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a mixture of 0.15 g (0.34 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.24 mL (1.3 mmole) of ethyldiisopropyl amine and 0.13 g (0.37 mmole) of 4-amino-1-Fmoc-piperidine hydrochloride in 5.0 mL of dimethylformamide was added 0.16 g (0.37 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum to give 0.25 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (I-70) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([NH2:24])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:25]1(O)OC2OC(O)C(O)OC2O[CH:26]1O>O.C(O)C.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[CH:26][CH:25]=[N:24]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OC1OC2OC(O)C(O)OC2OC1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nccnc4c3O2)cc1
Temperature: 60 °C

Procedure:
To a solution of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (2.226 g, 5.258 mmole) in water (50 mL) was added a solution of glyoxal trimeric dihydrate (1.104 g, 5.258 mmole) in ethyl alcohol (50 mL) and the reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and was diluted with aqueous sodium hydrogen carbonate (250 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 7:3) gave 1.135 g (58%) of the (R)-enantiomer of the title compound as a brown crystalline solid. Rf=0.27 (silica, ethyl acetate:hexanes 3:2); mp 124-127° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Cl[C:7]1[C:12]([Cl:13])=[C:11]([Cl:14])[CH:10]=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16].O>C1(C)C=CC=CC=1>[Cl:13][C:12]1[C:11]([Cl:14])=[CH:10][CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[C:7]=1[NH:5][CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Reactant: CC(C)CN
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CNc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 60 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
Forty-eight grams of isobutylamine and 75.5 gm of 2,3,4-trichloronitrobenzene were dissolved in 200 ml of toluene and kept at room temperature for 3 days. The mixture was then treated with a further 5 gm of isobutylamine and heated to 60° C. for 4 hours. The toluene solution was shaken with water, dried, and evaporated. The yield was 86 gm of 2,3-dichloro-6-nitro-N-isobutylaniline (98% of theory), which was obtained as a brownish oil.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[C:22]([O:31][CH3:32])=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)[CH2:16][CH2:15]2)[CH2:10][C:11]([OH:13])=O)=[N:5]1)([CH3:3])[CH3:2].[N:33]1([CH2:38][CH2:39][NH2:40])[CH2:37][CH2:36][CH2:35][CH2:34]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[C:22]([O:31][CH3:32])=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)[CH2:16][CH2:15]2)[CH2:10][C:11]([NH:40][CH2:39][CH2:38][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)c2ccn(C(C)C)n2)CC1
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)NCCN2CCCC2)c2ccn(C(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
(±)-3-(1-Isopropyl-1H-pyrazol-3-yl)-3-[4-(7-methoxyquinolin-8-yl)-1,4-diazepan-1-yl]propanoic acid (220 mg, 0.50 mmol) and 2-(pyrrolidin-1-yl)ethanamine (114 mg, 1.0 mmol) were suspended in anhydrous DMF (6 mL) N,N-Diisopropylethylamine (0.2 mL, 1.2 mmol) was added and the mixture was stirred at ambient temperature for 5 min followed by addition of HATU (300 mg, 0.79 mmol). After 1 h at ambient temperature, LC-MS and TLC indicated completion of reaction (LC/MS [M+H]+ 534.6). Water (5 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was washed with brine (3×30 mL) and concentrated. The residue was purified by silica gel chromatography using 2 to 5% MeOH in CH2Cl2 containing 0.5% aqueous NH4OH to afford the title compound (230 mg, 86%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.20 (br, 1H), 8.81 (d, 1H, J=2.8 Hz), 8.03 (d, 1H, J=8.4 Hz), 7.51 (d, 1H, J=8.4 Hz), 7.34 (d, 1H, J=2.8 Hz), 7.27 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=4.0 and 8.0 Hz), 6.16 (s, 1H), 4.52 (septet, 1H, J=6.8 Hz), 4.34 (br, 1H), 3.90 (s, 3H), 3.58 (m, 2H), 3.52-3.40 (m, 4H), 3.20-2.80 (m, 4H), 2.63 (t, 2H, J=6.8 Hz), 2.54 (br s, 4H), 2.20 (br s, 2H), 2.02 (m, 2H), 1.78 (br s, 4H), 1.47 (d, 6H, J=6.8 Hz). MS (ES) m/z 534.6 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C>C1COCC1>[F:21][C:22]1[CH:27]=[C:26]([B:29]([OH:34])[OH:30])[C:25]([F:28])=[CH:24][N:23]=1
Reactant: Fc1ccc(F)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OB(O)c1cc(F)ncc1F
Temperature: -20 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
Diisopropylamine (1.74 ml, 1.24 g, 12.20 mmol) was dissolved in anhydrous THF (22 ml) and placed under argon. The solution was cooled to −20° C. and then treated with n-butyllithium (7.66 ml, 12.25 mmol, 1.6 M in hexanes) by slow addition over 10 min. The newly formed LDA (LDA= lithium diisopropylamide, this acronyl should be listed in the general session) was then cooled to −78° C. and treated with a solution of 2,5-difluoropyridine (1.05 ml, 1.33 g, 11.56 mmol) dissolved in anhydrous THF (3 ml) by slow addition over 30 min. Once the addition was complete the reaction mixture was allowed to stir at −78° C. for 4 hr. At this time the reaction mixture was treated with a solution of triisopropyl borate (5.90 ml, 4.78 g, 25.4 mmol) dissolved in anhydrous THF (8.6 ml) by dropwise addition. Once the addition was complete the reaction mixture was allowed to warm to ambient temperature then stirred at ambient temperature for an additional hour. The reaction mixture was then quenched by adding 4% aq NaOH (34 ml). The layers were separated and the aqueous layer was cooled in an ice bath. It was then acidified to pH= 4 with 6N HCl (˜10 ml) not letting the temperature go above 10° C. This was then extracted with EtOAc (3×50 ml). The extracts were then washed with brine (1×50 ml), dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was triturated with Et2O to give 0.8084 g (44%) of 2,5-difluoropyridin-4-ylboronic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([OH:24])=O)[C:17]=1[CH3:25].[N:26]1([CH2:33][CH2:34][OH:35])[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:29]2[CH2:30][CH2:31][CH2:32][N:26]([CH2:33][CH2:34][OH:35])[CH2:27][CH2:28]2)=[O:24])[C:17]=1[CH3:25]
Reactant: Cc1c(C(=O)O)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Reactant: OCCN1CCCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCCN(CCO)CC2)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a suspension of 0.060 g (0.18 mmol) of 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid in 2 ml of CH2Cl2 was added 0.031 g (0.22 mmol) of 2-(1,4-diazepan-1-yl)ethan-1-ol, diluted in 1.7 ml of CH2Cl2. This solution was treated at 0° C. with 0.048 g (0.23 mmol) of DCC. The reaction was allowed to warm up over night to RT, then partitioned between aqueous saturated NaHCO3/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, dried (Na2SO4) and evaporated. The residue was suspended in EtOAc and filtered to remove the DCC urea. Purification by flash chromatography (SiO2—NH2, n-heptane/EtOAc 1:4) gave 0.033 g (39%) of [5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-[4-(2-hydroxy-ethyl)-[1,4]diazepan-1-yl]-methanone as white oil. MS: 459.3 (MH+).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[N:11]1([C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C([O-])(=O)C.[Na+]>O>[OH:23][C:19]1[CH:18]=[C:17]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:22]=[CH:21][C:20]=1[CH:4]=[O:5]
Reactant: CN(C)C=O
Reactant: Oc1cccc(N2CCOCC2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
DMF (10 mL) was treated dropwise with phosphorus oxychloride (2.3 g, 15 mmol). The reaction was kept at 25° C. by cooling on ice. The reaction mixture was treated with 3-(4-morpholinyl)phenol (2.5 g, 14 mmol) in small portions, stirred for 30 min at room temperature, then stirred at 100° C. for 8 h. After cooling, the mixture was poured into aqueous sodium acetate (1 M, 40 mL) and 10 mL of water was added. The resulting precipitate was collected by filtration, washed with water (10 mL), air dried, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 90/10 CHCl3/ether) to yield the product as a light gray solid (0.66 g, 23%). See U.S. Pat. No. 4,147,552.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(OCC)(=O)C>CN(C)C=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc(N2CCNCC2)nc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 10.5 %

Procedure:
To a solution of 2,5-dichloropyridine (2 g) in dimethylformamide (30 mL) was added potassium carbonate (3.73 g) and piperazine (1.16 g) and the mixture was stirred at 110° C. for 4 hours. After cooling the reaction mixture, thereto was added ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, solvent: chloroform/methanol=100/0 to 99/1) to obtain 5-chloro-2-(1-piperazinyl)pyridine (0.28 g, Yield: 10%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]12([NH2:32])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>C(O)C>[C:22]12([NH:32][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([C:6]4[C:5]5[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=5[O:8][N:7]=4)=[CH:10][CH:11]=3)[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCO
Product: O[C@H](CNC12CC3CC(CC(C3)C1)C2)COc1ccc(-c2noc3cc(F)ccc23)cc1
Yield: 88.4 %

Procedure:
Combine (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole (29) (250 mg, 0.86 mmol), 1-adamantanamine (530 mg, 3.50 mmol), ethanol (4.0 ml) and heat (˜80° C.) for 16 hours. Cool reaction to room temperature and concentrate (in vacuo). Purify the compound by column chromatography (silica) eluting with 28% aqueous ammonia/ethanol/chloroform (1:19:180) to obtain a white solid. Dry (50° C. at 0.5 mm Hg) to give 332 mg (86% yield) of the title compound. Purity by LC/MS=92%, [M+H]+=437.
Reaction SMILES: C(O)(=O)C.Cl[C:6]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[NH2:19]>O1CCOCC1>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][C:6]2[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][N:7]=2)[CH:20]=[C:21]([CH3:23])[CH:22]=1
Reactant: Cc1cc(N)cc(Br)c1
Reactant: CC(C)c1ccnc(Cl)n1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(Nc2nccc(C(C)C)n2)c1
Temperature: 120 °C
Yield: 98.1 %

Procedure:
Acetic acid (0.192 mL, 3.35 mmol) was added to commercially available 2-chloro-4-(propan-2-yl)pyrimidine (0.5 g, 3.19 mmol) and 3-bromo-5-methylaniline (0.900 g, 3.19 mmol) suspended in dioxane (6.39 mL). Reaction was heated to 120° C. (bath temp) overnight. Then, the reaction was cooled to room temperature and purified by column chromatography on silica gel eluting with ethyl acetate and hexanes to give N-(3-bromo-5-methylphenyl)-4-(propan-2-yl)-pyrimidin-2-amine (959.8 mg, 3.13 mmol, 98%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:30])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(c1ccccn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(c1cccc[n+]1[O-])C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 54.8 %

Procedure:
A solution of 2-(2,4-difluorophenyl)-3-(pyridin-2-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (diasatereoisomeric pair B from Example 1) (1.60 g) and 85% w/w 3-chloroperoxybenzoic acid (1.60 g) in dichloromethane (10 ml) was stirred at room temperature for 36 hours and then worked up as described in Example 15(i) to give the title compound, (0.92 g), m.p. 159°-160°.