Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[N:34]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[C:44](O)=[O:45].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C@@H:2]([NH:1][C:44]([C@@H:35]2[CH2:36][C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:43][N:34]2[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:45])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH2:22][CH:23]3[CH2:24][CH2:25]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}-piperazinyl) propan-1-one (Example 58, Step 3) (224 mg, 0.457 mmol), according to the procedure for Preparation XIX using Boc-L-Tic-OH (135 mg, 0.487 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (285 mg, 0.959 mmol), HOAT (68 mg, 0.50 mmol), and DMF (7 mL). The compound was isolated (339 mg). MS (ESI, pos. ion) m/z: 750 (M+H), (ESI, neg. ion) m/z: 748 (M−H). Calc'd for C39H48ClN5O6S: 750.35.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19](C)[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.FC1C=CC(CN[C:40](C2N=C(C(NC(C3OC(C)=NN=3)=O)(C)C)NC(=O)C=2O)=[O:41])=CC=1>>[CH3:40][O:41][C:22]([C:15]1[N:14]=[C:13]([C:10]([NH:9][C:7]([C:5]2[O:6][C:2]([CH3:1])=[N:3][N:4]=2)=[O:8])([CH3:12])[CH3:11])[NH:19][C:17](=[O:18])[C:16]=1[OH:21])=[O:23].[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH2:24])=[CH:27][CH:28]=1
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)[nH]2)o1
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Product: COC(=O)c1nc(C(C)(C)NC(=O)c2nnc(C)o2)[nH]c(=O)c1O
Product: NCc1ccc(F)cc1

Procedure:
Among the advantages of the novel route of synthesis of raltegravir is the regioselective methylation of N-(4-fluorobenzyl)-2-(2-(5-methyl-1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-1,6-dihydro-5-hydroxy-6-oxopyrimidine-4-carboxamide (VI) obtained by amidation of methyl-2-(2-(5-methyl-1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-1,6-dihydro-5-hydroxy-6-oxopyrimidine-4-carboxylate (Va) with p-fluorobenzyl amine. The methylation reaction provides regioselectivity of more than 99% as against methylation of oxygen at 6th position, thereby resulting in a higher yield of more than 90%. The yield for the methylation reaction is in the range of 88 to 90%.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CN1CCOCC1.[Cl:17][C:18]1[CH:19]=[C:20]([C:41](Cl)=[O:42])[C:21]2[O:26][CH:25]([CH3:27])[C:24](=[O:28])[N:23]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[C:22]=2[CH:40]=1>C(Cl)(Cl)Cl>[ClH:17].[Cl:17][C:18]1[CH:19]=[C:20]([C:41]([NH:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[O:42])[C:21]2[O:26][CH:25]([CH3:27])[C:24](=[O:28])[N:23]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=3)[C:22]=2[CH:40]=1
Reactant: CC1Oc2c(C(=O)Cl)cc(Cl)cc2N(Cc2cccc(C(F)(F)F)c2)C1=O
Reactant: NC1CN2CCC1CC2
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CC1Oc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc2N(Cc2cccc(C(F)(F)F)c2)C1=O
Product: Cl

Procedure:
To a solution of 1.35 g of 3-aminoquinuclidine and 1.14 g of N-methylmorpholine in 30 ml of chloroform is added a solution of 4.5 g of 6-chloro-4-(3-trifluoromethylbenzyl)-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid chloride in 20 ml of chloroform under cooling and stirring followed by stirring for 4 hours. The resultant solution is washed with water, aqueous sodium hydrogen carbonate and then water, and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanol and treated with ethanolic hydrochloric acid to give 6-chloro-4-(3-trifluoromethylbenzyl)-3,4-dihydro-2-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 271°-274° C. with decomposition.
Reaction SMILES: [OH-].[K+].O.[I-].[CH3:5][S+](C)C.[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH:19]=[O:20].[C:21](#[N:23])C>CCOCC>[CH3:5][NH:23][CH2:21][CH:19]([C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1)[OH:20]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CC#N
Reactant: C[S+](C)C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CNCC(O)c1ccc2ccccc2n1
Temperature: 60 °C

Procedure:
Potassium hydroxide (3.21 g) and H2O (0.13 mL) are added to acetonitrile (50 mL). Trimethylsulfonium iodide (5.84 g) and 2-quinoline carboxaldehyde (4.50 g) are then added. The reaction mixture is heated to 60° C. for 4 h. The reaction mixture is allowed to cool to room temperature and is diluted with Et2O (25 mL) The precipitate is filtered off. 1H NMR of an aliquot of the filtrate showed mostly starting material and a small amount of the desired epoxide. The filtrate is concentrated in vacuo and the residue is re-subjected to the reaction conditions above and heated to 60° C. for 1 h. The reaction mixture is allowed to cool to room temperature and is diluted with Et2O (25 mL). The precipitate is filtered off and the filtrate is concentrated in vacuo. The resulting crude epoxide (5.5 g) is dissolved in methanol (20 mL) and added to a 2.0 M solution of methylamine in methanol (100 mL). The reaction mixture is heated to reflux for 1 h. The reaction mixture is allowed to cool to room temperature and concentrated in vacuo. The resulting brown oil is purified via column chromatography (CHCl3/methanol, 95/5, 90/10; CHCl3/methanol/NH4OH, 90/10/1) to yield 1.191 g of the title compound as a yellow-green oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[N:9]2[C:10](=[O:19])[CH:11](I)[CH2:12][CH2:13]3)[CH:5]=[CH:6][CH:7]=1.[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:17][CH2:16][CH2:15][C@H:14]3[N:9]2[C:10](=[O:19])[CH:11]([P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[CH2:12][CH2:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C1C(I)CC[C@@H]2CCC[C@H](c3cccc(F)c3)N12
Product: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3cccc(F)c3)N2C1=O
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of (6R*,9aS*)-6-(3-fluorophenyl)-3-iodooctahydroquinolizin-4-one (597 mg) with triethyl phosphite (6 mL) was stirred at 120° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 670 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([N+]([O-])=O)=[CH:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]1=2)#[N:2].C([O:23]CCO)C>Cl.[Fe]>[C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:23])[CH2:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]1=2)#[N:2]
Reactant: N#CN1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Reactant: CCOCCO
Agent: [Fe]
Agent: Cl
Product: N#CN1c2ccccc2CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
26.3 g (0.1 mole) of 5-cyano-10-nitro-5H-dibenz[b,f]azepine are suspended in a mixture of 265 ml of ethylene glycol monoethyl ether and 75 ml of concentrated hydrochloric acid. 40 g of iron powder are added in small portions at 40° in the course of 40 minutes and the temperature is maintained at 40° by external cooling. The mixture is stirred for a further 2 hours at room temperature, is then heated to 80°, the precipitated product dissolving again, and is filtered through a heated suction filter, which is subsequently washed with ethylene glycol monoethyl ether. The crystallisation which commences in the filtrate is completed by adding 200 ml of water. After cooling for one hour in an ice-bath, filtration is carried out followed by washing with a mixture of ethylene glycol monoethyl ether and water in a ratio of 1:1. 5-cyano-10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine is obtained which is identified, by comparing the IR spectra, with material from Example 27.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C@H:7]([OH:21])[CH2:8][NH:9][C@H:10]([CH3:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)[CH:27]=[O:28]>>[Si:13]([O:12][CH2:11][C@H:10]([N:9]1[CH2:8][C@H:7]([CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([Cl:1])[CH:3]=2)[O:21][C:27]1=[O:28])[CH3:20])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)NC[C@@H](O)COc1cccc(Cl)c1
Reactant: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)N1C[C@H](COc2cccc(Cl)c2)OC1=O

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 3.45 g of 1(R)-(3-chlorophenoxymethyl)-2-(2-t-butyldimethylsilyloxy-1(R)-methylethylamino)ethanol (prepared as described in Preparation 42), 1.78 g of N,N'-carbonyldiimidazole and 30 ml of anhydrous dimethylformamide were used, to give 3.52 g of the title compound having an Rf value of 0.74 (on silica gel thin layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =-53.3° (methanol, c=1.020).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[C:15]1([C:21]2[O:22][CH:23]=[C:24]([C:26]([N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])[N:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[ClH:1].[ClH:1].[C:15]1([C:21]2[O:22][CH:23]=[C:24]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])[N:25]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(-c3ccccc3)n2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1coc(-c2ccccc2)n1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 67 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-phenyloxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (44.8 mg, 0.077 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 22.6 mg (67%) of the desired product as a white solid. LC-MS: RT=4.36 min, [M+H]+=365.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[CH:25][C:24]=2[O:34][CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([C:36]([F:39])([F:38])[F:37])[NH:17]2)(=[O:11])=[O:10].O[Li].O>C1COCC1.CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=2[O:34][CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([C:36]([F:38])([F:39])[F:37])[NH:17]2)(=[O:11])=[O:10]
Reactant: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C(F)(F)F)cc3c2NS(=O)(=O)c2ccc(C)cc2C)c(OC)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C(F)(F)F)cc2c1NS(=O)(=O)c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 14.6 (0.020 g, 0.047 mmol) in a mixture of THF/CH3OH/H2O (0.5 mL, ratio=2/2/1), was added LiOH.H2O (0.010 g, 0.220 mmol). The mixture was stirred at room temperature for 1 h. The solution was chromatographed using HPLC to give 14 as a white solid. MS ESI (pos.) m/z: 549.2 (M+H)+. 1H NMR (400 MHz) (CDCl3) δ 8.32 (s, 1H); 7.57 (d, J=7.2 Hz, 1H); 7.20 (s, 1H); 7.11 (d, J=7.2 Hz, 1H); 6.86 (m, 3H); 6.71 (d, J=9.2 Hz, 1H): 6.64 (d, J=8 Hz, 1H); 6.34 (d, J=8 Hz, 1H); 3.80 (s, 3H); 3.62 (s, 2H); 2.53 (s, 3H); 2.33 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:15]/[O:16][CH2:17][CH:18]=[CH2:19])/[C:12](O)=[O:13])[N:10]=1)=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:21].CCCCCC>C(Cl)Cl>[ClH:1].[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:15]/[O:16][CH2:17][CH:18]=[CH2:19])/[C:12]([Cl:21])=[O:13])[N:10]=1)=[O:4]
Reactant: C=CCO/N=C(\C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: C=CCO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 13 ml of methylene chloride is suspended 610 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-allyloxyiminoacetic acid and under ice-cooling and stirring 502.4 mg of phosphorus pentachloride is added. The mixture is stirred at room temperature for 30 minutes, after which 100 ml of hexane is added to the reaction mixture. The resulting crystals are recovered by filtration and washed with hexane to give 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-allyloxyiminoacetyl chloride hydrochloride, m.p. 67°-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)[C:7]=2[CH:25]=1.Cl.Cl.Cl.[N:29]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([CH2:36][CH2:37][N:38]2[CH2:39][CH2:40][CH:41]([NH:44][C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[C:13]([O:12][CH2:11][C:8]3[C:7]5[CH:25]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[O:10][CH:9]=3)[CH:21]=[CH:20][CH:19]=4)=[O:24])[CH2:42][CH2:43]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: COc1ccc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c2c1
Agent: Cl
Product: COc1ccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCCCCC6)CC5)cc34)c2c1

Procedure:
This compound is synthesized from 4-(5-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (121) (preparation see below) and amine 5 analogously to the method described in example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[C:33]([C:35]1[CH:36]=[C:37]([NH:41][C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[C:49]([NH2:52])[CH:50]=3)[N:45]=[CH:44][N:43]=2)[CH:38]=[CH:39][CH:40]=1)#[CH:34]>N1C=CC=CC=1.C1COCC1>[C:33]([C:35]1[CH:36]=[C:37]([NH:41][C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[C:49]([NH:52][C:15]([CH:14]=[C:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]4)=[O:17])[CH:50]=3)[N:45]=[CH:44][N:43]=2)[CH:38]=[CH:39][CH:40]=1)#[CH:34]
Reactant: C#Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C#Cc1cccc(Nc2ncnc3ccc(NC(=O)C=C4CCN(C(=O)OC(C)(C)C)CC4)cc23)c1

Procedure:
1 g of 2-(1-(tert-butyloxycarbonyl)piperidine-4-ylidene)acetic acid was added to 20 mL of anhydrous THF in a one-neck flask (100 mL). The solution was stirred and cooled on salt-ice bath. Then, 0.6 mL of isobutyl chloroformate and 0.5 mL of N-methylmorpholine were added, and the reaction mixture was let stir for 20 min 1.046 g of N4-(3-ethynylphenyl)quinazoline-4,6-diamine dissolved in 10 mL of pyridine (dried over molecular sieves) and 0.4 mL of N-methylmorpholine were added to the reaction mixture on an ice bath with stirring. After reaction completion, the solvent was evaporated in vacuo and the remaining residue was partitioned with chloroform and water. The chloroform layer was washed once with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product. The crude product was recrystallized from isopropanol. MS (EI) 482 M+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[C:17]([F:26])[CH:16]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].IC.[C:30](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:11]([O:10][C:8](=[O:9])[C:7]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[C:17]([F:26])[CH:16]=1)([CH3:30])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:27])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C2OCCO2)c(F)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(C2OCCO2)c(F)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Di-tert-butyl[4-(1,3-dioxolan-2-yl)-3-fluorophenyl]malonate (2.45 g, 6.41 mmol), iodomethane (0.80 mL, 12.85 mmol) and potassium carbonate (1.78 g, 12.9 mmol) were suspended in DMF (10 mL) and heated at 70° C. for 3 hours in a sealed tube. A further portion of iodomethane was added (0.60 mL, 9.64 mmol) and heating continued at 75° C. for 3 hours. Room temperature was attained, H2O (150 mL) was added and the products extracted into Et2O (2×100 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC gave the clean product (orange oil). 1H NMR (CDCl3) δ 7.47 (t, J=8.1 Hz, 1H), 7.19 (dd, J=8.1, 1.8 Hz, 1H), 7.17 (dd, J=12.0, 1.8 Hz, 1H), 6.07 (s, 1H), 4.13 (m, 2H), 4.03 (m, 2H), 1.74 (s, 3H), 1.45 (s, 18H).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[CH2:21]([NH:24][CH:25]1[CH2:33][CH2:32][C:28]2[N:29]=[CH:30][S:31][C:27]=2[CH2:26]1)[CH2:22][CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:15]1([CH:12]2[CH2:13][CH2:14][N:9]([C:7]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH2:21][CH2:22][CH3:23])[CH:25]3[CH2:33][CH2:32][C:28]4[N:29]=[CH:30][S:31][C:27]=4[CH2:26]3)=[O:8])[CH2:10][CH2:11]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCNC1CCc2ncsc2C1
Reactant: O=CCCCNC(=O)N1CCC(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN(CCCCNC(=O)N1CCC(c2ccccc2)CC1)C1CCc2ncsc2C1
Reaction time: 8 h
Yield: 34 %

Procedure:
A solution of 713 mg (2.6 mmol) N-(4-oxobutyl)-4-phenylpiperidine-1-carboxamide and 395 mg (2 mmol) propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amine in 1,2-dichloroethane (20 mL) is stirred for about 30 minutes. Then 0.75 g (3 mmol) of sodium triacetoxyborohydride is added and the mixture is stirred overnight. After hydrolysation with 30 mL of 1N aqueous NaOH solution the organic phase is separated, dried over sodium sulfate and concentrated in vacuum. The crude product obtained is purified via column chromatography on silica gel.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].N[C:29]1C=[C:33](C(O)=O)[C:32]([OH:38])=[CH:31]C=1.CN(C=O)C>C1COCC1>[CH3:29][CH2:21][O:23][CH2:24][CH3:27].[CH:2]([O:38][CH:32]([CH3:31])[CH3:33])([CH3:18])[CH3:3].[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)OC(C)C
Product: CCOCC
Reaction time: 18 h

Procedure:
70.4 g (0.14 mole) of BOC-L-Lys(Z)-SDP (m.w. 502.6) was dissolved in 200 ml of THF, which was then added dropwise to a solution of 21.4 g (0.14 mole) of 5-aminosalicyclic acid (m.w. 153.14) in 187 ml of 1.5 N NEM/DMF solution at 0°-5° C., and the reaction was effected at normal temperature for 18 hours, after which the reaction mixture was concentrated to 100-200 ml, 1600 ml of ether/ethyl acetate (50 v/50 v) was added, the mixture was washed with 1000 ml of cold 5% HCl three times and then with 1000 ml of saturated aqueous NaCl twice, active carbon was added, dried on magnesium sulfate, and the solvent was distilled off, to obtain, by recystallization from ether/isopropyl ether, 8.9 g (yield 55%) of crystalline BOC-L-Lys(Z)-CHA (m.w. 515.6) of m.p. 102°-105° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=1.Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.[Cl-].[Na+]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:16][CH2:15][C:14]2[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[F:3])=[N:11][O:12][C:13]=2[CH3:17])=[N:20][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1onc(-c2ccccc2F)c1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 1.16 g, 26.5 mmol) in THF (30 mL) was added a solution of [3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (5.0 g, 24.1 mmol) in THF (60 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (4.65 g, 26.5 mmol) in THF (60 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=4:1 to 2:1) afforded the title compound (4.0 g, 49%) which was obtained as a white solid. MS: m/e=343.0 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:8]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@@H:9]1[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:24]([Mg]Br)[CH3:25].[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[CH2:1]([C@H:8]1[O:12][C:11]([CH3:13])([CH3:14])[O:10][C@@H:9]1[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[CH2:24][CH3:25])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1ccc(C=O)cc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1ccc(C(O)CC)cc1
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 4-(((4R,5R)-5-heptyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)benzaldehyde (N) (16 mg, 0.05 mmol) in THF (0.2 mL) at 0° C. was added ethylmagnesium bromide (20 μL, 3M in THF) dropwise. After one hour, the reaction mixture was heated to refluxing temperature for an additional hour until TLC indicated completion of the reaction. Upon completion, saturated aqueous NH4Cl was added, and the mixture extracted with ether. The collected organic layers were washed with brine, dried with MgSO4, filtered and concentrated. Preparative thin layer chromatography (25% EtOAc/Hex, 250 μm, silica) yielded the title compound (6 mg, 0.017 mmol, 35%). 1H NMR (CDCl3, 300 MHz) δ 7.27 (2H, d, J=7.2 Hz), 7.21 (2H, d, J=8.1 Hz), 4.58 (1H, t, J=6.6 Hz), 3.88-3.81 (1H, m), 3.71-3.65 (1H, m), 2.92 (1H, dd, J=0.02, 18.6 Hz), 2.82 (1H, dd, J=0.02, 18.6 Hz), 1.86-1.68 (2H, m), 1.51-1.29 (12H, m), 1.37 (3H, s), 1.35 (3H, s), 0.92-0.85 (6H, m); HRMS (FAB+) calcd for C22H35O3 [M−H]: 347.2586; found 347.2575, C22H35O3.