Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][C:3]=1[CH3:19].C([Li])CCC.[C:25](=[O:27])=[O:26].[OH-].[Na+]>C1COCC1.CCOCC>[C:8]([C:6]1[C:5]([O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][C:3]([CH3:19])=[C:2]([CH:7]=1)[C:25]([OH:27])=[O:26])([CH3:11])([CH3:10])[CH3:9]
Reactant: COCCOCOc1cc(C)c(Br)cc1C(C)(C)C
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCOCOc1cc(C)c(C(=O)O)cc1C(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-bromo-5-tert-butyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-benzene from Example ZZ (44.7 g, 135 mmol) in dry THF was cooled to -78° C. under nitrogen and treated with 1.6M n-butyllithium (93 mL, 149 mmol). The solution was stirred at -78° C. for 45 minutes and then poured over crushed dry ice. The mixture was allowed to warm to room temperature. Et2O (100 mL) and 2N NaOH (200 mL) were added; the organic layer was separated and re-extracted with 2N NaOH. The aqueous layers were combined, acidified to pH 2 with 6N HCl, and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.35 (s, 9 H), 2.57 (s, 3 H), 3.37 (s, 3 H), 3.57 (m, 2 H), 3.81 (m, 2 H), 5.35 (s, 2 H), 6.98 (s, 1 H), 8.01 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[CH3:13])=[N:4][C:3]=1[C:14](=[O:16])[CH3:15].C([O-])(=O)C.[Na+].Cl.[NH2:23][OH:24]>O>[OH2:16].[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[CH3:13])=[N:4][C:3]=1[C:14](=[N:23][OH:24])[CH3:15]
Reactant: NO
Reactant: CC(=O)c1nc(-c2ccncc2C)[nH]c1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=NO)c1nc(-c2ccncc2C)[nH]c1C
Temperature: 25 °C

Procedure:
To a 1.0 g (0.005 mole) amount of 1-[5-methyl-2-(3-methyl-4-pyridinyl)-1H-imidazol-4-yl]ethanone (prepared as described in Example 27) dissolved in 200 ml of boiling water, were added 1.0 g (0.012 mole) of sodium acetate and 0.7 g (0.01 mole) of hydroxylamine hydrochloride. The mixture was stirred and heated for 3 hours, then cooled at room temperature. The resulting precipitate was collected by filtration and when dried at 60° C. for 18 hours gave 0.6 g of the desired product as its hydrate, a yellowish powder, mp 195°-197° C. (dec.).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[C:8]2[CH:9]=[C:10]([CH2:13][N:14]3[C:18]([C:19]([O:21]CC)=[O:20])=[C:17]([CH:24]4[CH2:26][CH2:25]4)[N:16]=[C:15]3[CH2:27][CH3:28])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[NH:39][N:38]=[N:37][N:36]=1>O.C(O)C>[Br:3][C:4]1[C:8]2[CH:9]=[C:10]([CH2:13][N:14]3[C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH:24]4[CH2:26][CH2:25]4)[N:16]=[C:15]3[CH2:27][CH3:28])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[NH:39][N:38]=[N:37][N:36]=1
Reactant: CCOC(=O)c1c(C2CC2)nc(CC)n1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1nc(C2CC2)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Reaction time: 18 h
Yield: 61.1 %

Procedure:
Potassium hydroxide (1.2 g) in water (5 ml) was added to a suspension of the product of Example 1 (0.5 g) in ethanol (15 ml) and the mixture stirred at 55° for 18 h. The solvent was evaporated and the residue partitioned between water (25 ml) and ether (3×25 ml). The aqueous phase was acidified to pH1 with hydrochloric acid (2N, 15 ml) and extracted with ethyl acetate (3×30 ml). The combined ethyl acetate extracts were washed with brine (50 ml) and dried. The solvent was concentrated in vacuo resulting in the precipitation of a colourless solid which was filtered off and washed with ether (2×5 ml) to give the title compound as a colourless solid (290 mg) m.p. 198°.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[C:13]1([C:10]2[CH:11]=[CH:12][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:20][CH:19]=3)[N:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(Cn2ccc(-c3ccccc3)n2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(Cn2ccc(-c3ccccc3)n2)cc1
Yield: 52.6 %

Procedure:
The title compound (1.0 g, 53%) was prepared from the product of step 1 (2.0 g, 7.6 mmol) and BBr3 (1M in CH2Cl2, 23 mL, 23 mmol) using the procedure of Example 146, step 2.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[C:4]1([CH2:10][C:11](Cl)=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC>[N+:1](=[CH:3][C:11](=[O:12])[CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[N-:2]
Reactant: C=[N+]=[N-]
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)Cc1ccccc1
Yield: 95.2 %

Procedure:
To diazomethane (40 mmol) in ether (100 ml) at 0° C. was added phenylacetyl chloride (2.65 ml, 20 mmol). After 30 min at 0° C. the excess diazomethane and the ether were blown off with nitrogen, and then under vacuum to leave 1-diazo-3-phenyl-2-propanone as a yellow oil (3.05 g, 95%); δH (CDCl3) 7.2(5H, S, aryl), 5.1(1H, S, CH=N2), 3.5(2H, S, CH2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C:8]([C:9]#[N:10])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:17]
Reactant: N#CCc1ccccc1F
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1F

Procedure:
Prepare by the method of example 1.1.2 using 2-fluorophenylacetonitrile (0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [N+:1]([CH2:4][C:5]([S-:7])=S)([O-:3])=[O:2].[K+].[K+].[N+]([CH2:13]C([S-])=S)([O-])=O.[CH:17]([NH2:23])([C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:18].S(OC)(OC)(=O)=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH3:18][CH:17]([NH:23][C:5]([S:7][CH3:13])=[CH:4][N+:1]([O-:3])=[O:2])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: O=[N+]([O-])CC(=S)[S-]
Reactant: CC(N)C(C)(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: CSC(=C[N+](=O)[O-])NC(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To an aqueous solution of dipotassium nitrodithioacetate (300 g 15% by weight) was added pinacolylamine (32 g) over 1 hour. After heating to 60° C. and maintaining this temperature for 4 hours, the reaction mixture was cooled to ambient temperatures and stirred overnight. Benzyltrimethylammonium chloride (3 g ), was then charged, followed by dimethyl sulphate (66 g) over one hour. After stirring overnight, the reaction mixture was extracted three times with 50ml aliquots of dichloromethane. After drying over MgSO4, the combined organic phases were concentrated and the residue recrystallised from 2-propanol to give 13 g (33%) of the title compound (m.p. 69° C.) which is believed to be novel.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[NH:20]2)=[CH:9]1)(C)(C)C.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:20]2[CH:19]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[CH:9]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:28])=[O:29])=[CH:34][CH:33]=1
Reactant: COc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Reactant: Fc1ccc(CBr)cc1
Product: COc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1Cc1ccc(F)cc1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 4, step c) and 4-fluorobenzyl bromide. MS: ESI (negative): 479 (M−H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13](I)[CH:14]=1)=[O:8])[CH3:5].[CH3:23][N:24]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1COCC1.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>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([C:27]2[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=2)[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Reactant: Cn1cc(B(O)O)cn1
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: [Cs+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-c2cnn(C)c2)c1
Temperature: 130 °C
Yield: 55.9 %

Procedure:
A mixture solution of 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (85.9 mg, 0.2100 mmol), 1-methyl-pyrazol-4-boronic acid (31.28 mg, 0.2300 mmol), Cs2CO3 (0.23 mL, 1 N, 0.23 mmol) and Pd(Ph3P)4 (17.0 mg, 0.0146 mmol) in toluene (1.5 mL) and THF (1.5 mL) was stirred under microwave heating for 30 minutes at 130° C. After reaction mixture was cooled to room temperature, the solvent was removed under vacuum and the residue was purified by preparative HPLC to afford 4′-methyl-5-(1-methyl-1H-pyrazol-4-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as white solid (42.68 mg, 56%). MS (M+H)=364.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>C(O)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:9]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: Nc1ccc(Cl)cc1C(=O)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 7.92 g of 5-chloroisatoic anhydride, 5.0 g of 1H-imidazole-1-propanamine and 75 ml of ethanol was stirred at room temperature for 20 hours and concentrated. The residue was washed onto a filter with ethanol, then washed with ether to give the desired product, mp 155°-157° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:24])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCCOc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid ethyl ester (4.2 g, 9.1 mmol) dissolved in THF:Methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (75%); off white powder, mp 195° C.; MS: 434.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>CCOC(C)=O>[CH3:3][C:2]([CH3:29])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:25][CH:26]=3)=[O:28])=[CH:17][CH:18]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 108.1 %

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added N-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenyl)-4-hydroxybenzamide (0.56 g, 1.41 mmol) DMF (35 mL), Cs2CO3 (0.49 g, 1.51 nmmol) and tert-butyl bromoacetate (0.28 mL, 1.75 mmol). This mixture was stirred at ambient temperature for 18 h. The mixture was diluted with EtOAc and washed with H2O and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave 0.78 g of tert-butyl 4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenylaminocarbonyl)phenoxyacetate which was used in the next step without purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[I-].[K+].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[N:31]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:21]=[CH:20][C:19]3[O:18][C:17]4[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:15][CH:16]=4)[CH2:11][C:10]=3[CH:9]=2)=[O:7])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1O2
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCCN3CCCCC3)ccc1O2
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 30 g. (0.07 mole) of 2,7-bis(5-chlorovaleryl)-xanthene, 2 g of potassium iodide, 100 ml. of piperidine, and 200 ml. of tetrahydrofuran was heated and stirred at 100°C. for 24 hours. After cooling, the tetrahydrofuran was evaporated off and the resulting mixture was poured into water. The resulting solid was filtered off and recrystallized twice from heptane to give the desired product after drying at 80°C. under vacuum. M.P. 129°-130°C.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25](O)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25]([NH:37][CH2:31][C:32]4[O:36][CH:35]=[CH:34][CH:33]=4)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCc1ccco1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)NCc2ccco2)c1
Yield: 10.5 %

Procedure:
To solution of 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-nicotinic acid (40 mg, 0.098 mmol), furfuryl amine (19.11 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.4 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-furan-2-ylmethyl-nicotinamide as a colorless solid (5 mg, 25.3% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.[CH3:15]O>>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:5]=[C:4]([O:11][CH3:12])[C:3]([OH:13])=[C:2]([Cl:1])[CH:10]=1
Reactant: COc1cc(C(=O)O)cc(Cl)c1O
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(Cl)c(O)c(OC)c1

Procedure:
A mixture of 5-chlorovanillic acid (5.0 g, 24.6 mmol) and conc. HCl (5 ml) in MeOH (100 ml) is heated at reflux for 48 hours. The solvent is removed in vacuo and water is added to the residue to yield a white precipitate, which is collected by filtration, washed with water, and then dissolved in Et2O. The solution is dried (Na2SO4) and the solvent removed in vacuo to yield 3-Chloro-4-hydroxy-5-methoxy-benzoic acid methyl ester as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][C@H:25]4[CH3:37])[CH:19]=[N:20][C:21]=3[F:22])[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.[CH3:56][S:57](Cl)(=[O:59])=[O:58]>C(Cl)Cl>[F:22][C:21]1[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH2:7][C:6]3[CH:47]=[CH:48][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)=[CH:17][C:18]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:26][C@H:25]2[CH3:37])=[CH:19][N:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)C[C@H]4C)cnc3F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@H]4C)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a slightly cooled stirred solution of (R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (1.01 g, 1.535 mmol) in DCM (5.0 mL, 78 mmol) was added slowly TFA (4.00 mL, 51.9 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and the sticky residue was taken up in a solution of DCM (10.0 mL) to which TEA (2.140 mL, 15.35 mmol) and methanesulfonyl chloride (0.598 mL, 7.68 mmol) was slowly added subsequently at 0° C. The mixture was stirred at the same temperature for 1 h, concentrated, and the crude product was partitioned between 1 N NaOH(aq) and DCM (20 mL each). The separated aqueous layer was extracted with DCM (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was purified by flash column chromatography (ISCO Combiflash system, 10% ethyl acetate/hexanes to 70% ethyl acetates in hexanes) to obtain the desired product (R)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.4779 g, 0.752 mmol, 49.0% yield) as a pale yellow foam. m/z (ESI, +ve ion) 636 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:20](O)(=[O:22])[CH3:21].C(OC(=O)C)(=O)C>O>[C:20]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9]1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)O)ccc21
Temperature: 80 °C
Yield: 100 %

Procedure:
To a flask containing 3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (5.0 g, 0.02 mol) was added acetic acid (100 mL). The flask was placed under nitrogen and to the flask was added acetic anhydride (5.6 mL, 0.06 mol). The reaction refluxed at 80° C. for three hours. The flask was cooled to room temperature and the reaction was diluted with water. The product was collected by vacuum filtration and rinsed with additional amounts of water to yield the title compound (5.96 g, 100% yield) 1H NMR (DMSO-d6) δ 8.6 (s, 1H), 8.45–8.5 (d, 1H), 8.2–8.25 (d, 1H), 8.1 (m, 2H), 7.5 (t, 2H), 2.8 (s, 3H).
Reaction SMILES: CO.[OH:3][C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:10][C:11]([C@@H:13]1[C@@H:15]([CH2:16][CH2:17][CH2:18][CH3:19])[O:14]1)=[O:12].[N-:20]=[N+:21]=[N-:22].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O>[OH:3][C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:10][C:11](=[O:12])[C@@H:13]([OH:14])[C@@H:15]([N:20]=[N+:21]=[N-:22])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC[C@H]1O[C@@H]1C(=O)N[C@H]1CCCC[C@@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCC[C@H](N=[N+]=[N-])[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Reaction time: 2 h
Yield: 72.8 %

Procedure:
30 ml of a methanol suspension containing 1.64 g (7 mmol) of (2S)-trans-N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-butyloxiranecarboxamide, 910 mg (14 mmol) of sodium azide and 868 mg (7.2 mmol) of anhydrous magnesium sulfate was refluxed for 5 hours. After the temperature of the reaction mixture was returned to room temperature, the reaction mixture was poured into 300 ml of water and the resulting mixture was stirred for 2 hours. The resulting crystals were collected by filtration and washed with water, and dried to obtain 1.45 g (Yield: 73%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: Nc1cc(N)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)cc(N)c1

Procedure:
3,5-Diaminobenzoic acid (Sigma-Aldrich) was esterified using a known procedure (Electrochimica Acta 2001, 46, 3955-3962) with thionyl chloride and anhydrous methanol to give the corresponding methyl ester, methyl 3,5-diaminobenzoate. Methyl 3,5-diaminobenzoate (260.8 mg, 1.9 mmol) was dissolved in dry tetrahydrofuran (5 mL) in a 100 mL vessel under inert atmosphere. Triethylamine (0.7 mL, 4.99 mmol) was then added and the solution was cooled to 0° C. A solution of 2-decyltetradecanoyl chloride from Step 1 in dry tetrahydrofuran (10 mL) was then added slowly, dropwise. The reaction was then allowed to warm slowly to room temperature. After stirring overnight, the reaction was quenched with water and the tetrahydrofuran was removed by rotary evaporation. The crude product residue was then dissolved in diethyl ether (50 mL) and washed with deionized water (20 mL). The ether layer was separated and concentrated to give methyl 3,5-bis(2′-decyltetradecanamido)benzoate as a pale pink solid (1.17 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=O)=[CH:5][C:4]=1[CH3:16].[CH:17]([Mg]Cl)([CH3:19])[CH3:18]>>[CH:17]([C:10]1[C:11]2[C:6](=[CH:5][C:4]([CH3:16])=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH3:15])([CH3:14])[CH2:8][CH:9]=1)([CH3:19])[CH3:18]
Reactant: CC(C)[Mg]Cl
Reactant: COc1cc2c(cc1C)C(C)(C)CCC2=O
Product: COc1cc2c(cc1C)C(C)(C)CC=C2C(C)C
Yield: 97.9 %

Procedure:
Following General Procedure A, 7-methoxy4,4,6-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 6, 1.0 g, 4.6 mmol) was reacted with a solution of 2 M isopropylmagnesium chloride (12 mL, 22.9 mmol) to give 1.1 g (100%) of the title product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17](O)=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[NH2:26][CH2:27][C@@H:28]([OH:30])[CH3:29]>>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([NH:26][CH2:27][C@@H:28]([OH:30])[CH3:29])=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was reacted with (S)-(+)-1-amino-2-propanol via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)pyridine-3-carboxamide. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)pyridine-3-carboxamide (46 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 7.6 mg of 342. MS (Q1) 516.5. (M)+.