Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:32]1[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:34][CH2:33]1)=[O:20])=[N:5]2
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(Cl)c(Cl)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 65.6 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate (28 mg, 0.089 mmol) and 1-(3-methoxy phenyl)piperazine (35 mg, 0.18 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (27 mg, 0.18 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (1:1) mixture and concentration gave 27 mg of the titled compound (yield, 66%). 1H NMR (300 MHz, CDCl3) δ 3.28-3.30 (m, 4H), 3.74-3.76 (m, 4H), 3.81 (s, 3H), 4.19 (s, 3H), 6.47-6.49 (m, 3H), 6.53-6.57 (m, 1H), 7.30 (br s, 1H), 7.85 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14](OC)=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:18])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:19][NH2:20].Cl>O>[CH:1]1([C:5]2[C:13]([C:14](=[O:15])[NH:20][CH3:19])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:18])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: COC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Agent: Cl
Solvent: O
Product: CNC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Into a 20-mL sealed tube, was placed 4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid (compound 62.2, 1.0 g, 4.0 mmol) and methylamine (30% in ethanol) (8 mL). The resulting solution was stirred overnight at 120° C. behind a blast shield, then cooled and diluted with H2O (20 mL). The pH of the solution was adjusted to 4-5 with hydrogen chloride (1 M) and the solids were collected by filtration. The crude product was re-crystallized from ethyl acetate/petroleum ether in the ratio of 1:10 to yield the title compound as an off-white solid (500 mg, 50%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:25]([F:28])([F:27])[F:26])([C:5]1[N:6]([CH3:24])[C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)[NH2:4].[CH:31]1(C(Cl)=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[CH:31]1([C:24]2[N:6]3[C:7]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:8]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)[N:9]=[C:5]3[C:3]([C:2]([F:29])([F:1])[F:30])([C:25]([F:26])([F:27])[F:28])[N:4]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cn1c(C(N)(C(F)(F)F)C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Solvent: c1ccncc1
Product: Fc1ccc(-c2nc3n(c2-c2ccc(F)cc2)C(C2CCCCC2)=NC3(C(F)(F)F)C(F)(F)F)cc1
Temperature: 130 °C
Yield: 46.9 %

Procedure:
To a solution of α,α-bis(trifluoromethyl)-4,5-bis(4-fluorophenyl)-1-methyl-1H-imidazole-2-methanamine (3.38 gr, 7.8 mmole) in pyridine (1.7 gr) was added cyclohexane carbonyl chloride (3.5 gr, 23.9 mmole). The reaction mixture was heated at 130° C. for 4 hours. The mixture was purified by column chromatography, eluting with hexane, then mixture of hexane-ethylacetate (9:1) to give 5-cyclohexyl-2,3-bis(4-fluorophenyl)-7,7-bis(trifluoromethyl)-7H-imidazo[1,5-A]-imidazole (1.88 gr, 37%) as a white solid: mp 162.2-162.6. Anal. Calcd for C25H19F8N3 :C,58.60;H,3.54;N,8.20. Found: C,58.43;H,3.79;N,8.16.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[S:6][C:7]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:8]=3[C:9]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[CH:3]=1.[BH4-].[Na+].C(O)(=O)C(O)=O>COCCOCCOC>[CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[S:6][C:7]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: CSc1ccc2c(c1)C(N1CCN(C)CC1)=Cc1cc(C)ccc1S2
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CSc1ccc2c(c1)C(N1CCN(C)CC1)Cc1cc(C)ccc1S2
Reaction time: 0.5 h

Procedure:
16 G. of 1-{2-methyl-8-(methylthio)-dibenzo[b,f]thiepin-10-yl}-4-methylpiperazine are dissolved in 200 ml. of diglyme and, at room temperature under an atmosphere of nitrogen, treated with 11.5 g. of sodium borohydride. The reaction mixture is stirred for 30 minutes and the within 45 minutes treated with a solution of 60 g. of oxalic acid in 300 ml. of diglyme. Subsequently, the mixture is heated for 2 hours at 100°, evaporated under reduced pressure and equilibrated between 2N aqueous sodium hydroxide and chloroform. The chloroform extracts are washed with water, dried and purified on a column containing 300 g. of aluminum oxide (activity grade II). 1-{10,11-dihydro-2-methyl-8-(methylthio)dibenzo[b,f]thiepin-10-yl}-4-methylpiperazine is obtained as a light oil. The corresponding maleate is precipitated from acetone and melts at 193°-194°.
Reaction SMILES: [S:1]1[C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.[C:26]1([Li])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.C1CCCCC1.C(OCC)C>[C:16]1([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:5]3[S:1][C:2]4[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=4[CH:4]=3)[OH:7])[CH2:9][CH2:10]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1cc2ccccc2s1)C1CCN(CCc2ccccc2)CC1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: OC(c1ccccc1)(c1cc2ccccc2s1)C1CCN(CCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Dissolve [benzo[b]thiophene-2-yl][1-(2-phenylethyl)-4piperidinyl]methanone (3.5 g, 10.01 mmol) in anhydrous tetrahydrofuran (100 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, phenyllithium (6 mL of a 2.0M solution in cyclohexane/ethyl ether, 12.0 mmol) and stir at -78° C. for 5 hours. Remove the ice bath and allow to warm to room temperature. Pour into saturated ammonium chloride (100 mL) and stir for 20 minutes. Separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, wash with water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (50% ethyl acetate/hexane) and recrystallize (isopropanol) to give the title compound as a white solid; mp 144°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([CH:16]=O)=[CH:13][S:14][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[C:24]([CH2:16][C:12]2[C:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])=[CH:15][S:14][CH:13]=2)=[C:23]1[CH3:32]
Reactant: O=Cc1cscc1S(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2cscc2S(=O)(=O)c2ccc(Cl)cc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 4-(4-chloro-benzenesulfonyl)thiophene-3-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C@@H:12]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][N:28]2[C:32](=[O:33])[C:31]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]3[C:29]2=[O:38])[O:15][C@H:13]1[SH:14])(=[O:10])[CH3:9].[CH3:39][CH:40]([CH2:42][CH2:43][CH2:44][C@H:45]([C@@H:47]1[C@:64]2([CH3:65])[C@H:50]([C@H:51]3[C@H:61]([CH2:62][CH2:63]2)[C@:59]2([CH3:60])[C:54]([CH2:55][C@@H:56]([O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]I)[CH2:57][CH2:58]2)=[CH:53][CH2:52]3)[CH2:49][CH2:48]1)[CH3:46])[CH3:41]>ClCCl>[C:8]([O:11][C@@H:12]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][N:28]2[C:32](=[O:33])[C:31]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]3[C:29]2=[O:38])[O:15][C@H:13]1[S:14][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][O:66][C@H:56]1[CH2:57][CH2:58][C@@:59]2([CH3:60])[C:54](=[CH:53][CH2:52][C@@H:51]3[C@@H:61]2[CH2:62][CH2:63][C@@:64]2([CH3:65])[C@H:50]3[CH2:49][CH2:48][C@@H:47]2[C@H:45]([CH3:46])[CH2:44][CH2:43][CH2:42][CH:40]([CH3:41])[CH3:39])[CH2:55]1)(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](S)O[C@H](CN2C(=O)c3ccccc3C2=O)[C@@H]1OC(C)=O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Triethylamine (0.8 ml.) is added to a solution of 2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-1-thio-β-D-galactopyranose (2.5 g.) and 6-(5-cholesten-3β-yloxy)hexyl iodide (3.3 g.) in dichloromethane (20 ml.). The solution is kept at room temperature under nitrogen overnight, and washed with water, dried, and evaporated in vacuo to a syrup (4.71 g.). This material is put on a column of silica gel and eluted with chloroform followed by 2% ethyl acetate in chloroform. The desired fractions are combined and evaporated in vacuo to give the title compound (4.0 g., 78%); Rf 0.2 (CHCl3 -EtOAc. 95:5), [α]D27 -93° C. (C 1.18, chloroform); n.m.r. (chloroform-d); δ 7.60-7.91 (4 aromatic), 1.93, 2.03, and 2.24 (3 OAc) 0.68 (CH3 -18).
Reaction SMILES: N1(C([O-])=O)CCCCC1.[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][N:18]2[C:21]([C:24]3[CH:33]=[C:32]([C:34]4[O:38][CH:37]=[N:36][CH:35]=4)[C:31]4[C:26](=[C:27]([OH:39])[CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:22][N:23]=[C:17]2[CH:16]=1.[F:40][C@H:41]1[C@@H:46](OS(C)(=O)=O)[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[F:40][C@H:41]1[C@H:46]([O:39][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:26]=2[N:25]=[C:24]([C:21]2[N:18]4[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][CH3:10])=[CH:16][C:17]4=[N:23][CH:22]=2)[CH:33]=[C:32]3[C:34]2[O:38][CH:37]=[N:36][CH:35]=2)[CH2:45][CH2:44][NH:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H](F)C1
Reactant: COCCOc1ccn2c(-c3cc(-c4cnco4)c4cccc(O)c4n3)cnc2c1
Agent: O=C([O-])N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCOc1ccn2c(-c3cc(-c4cnco4)c4cccc(O[C@@H]5CCNC[C@H]5F)c4n3)cnc2c1
Temperature: 106 °C
Yield: 3 %

Procedure:
Preparation of (trans)tert-butyl 3-fluoro-4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)-4-oxazol-5-yl)quinolin-8-yloxy)piperidine-1-carboxylate: To 2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)-4-(oxazol-5-yl)quinolin-8-ol (9 mg, 0.02 mmol) in DMA (2 mL) was added (cis)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (13 mg, 0.04 mmol) and Cs2CO3 (22 mg, 0.07 mmol). The reaction vial was sealed and heated to 106° C. for 4 hours. The reaction was cooled to ambient temperature and concentrated. The crude residue was purified by flash column chromatography (DCM/MeOH 10:1) providing the desired product (3%).
Reaction SMILES: CO[C:3]([C:5]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])=[O:4].[OH-].[Na+].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:49]([O:51][CH2:52][CH2:53][O:54][NH2:55])=[CH2:50].CCN(C(C)C)C(C)C>C1COCC1.CO>[CH:49]([O:51][CH2:52][CH2:53][O:54][NH:55][C:3]([C:5]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])=[O:4])=[CH2:50]
Reactant: C=COCCON
Reactant: COC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a stirred solution of 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (150.0 mg, 0.33 mmol) in anhydrous THF (3.5 mL) and anhydrous methanol (1.0 mL) under N2 was added freshly prepared 1N aqueous sodium hydroxide (0.66 ml, 2.0 eq). The reaction mixture was stirred at 65° C. for 1 h. The resultant reaction mixture was evaporated in vacuo and azeotroped with toluene (3×5 ml) to give a yellow solid. The yellow solid was redissolved in anhydrous THF (6.6 ml). EDCI (127.0 mg, 0.66 mmol, 2.0 eq) and HOBT (89.7 mg, 0.66 mmol, 2.0 eq) were added. The reaction mixture was stirred at room temperature. After 5 minutes O-(2-vinyloxy-ethyl)-hydroxylamine (68.5 mg, 0.66 mmol, 2.0 eq) and DIPEA (0.12 mL, 0.66 mmol, 2.0 eq) were added, and the reaction mixture was stirred at ambient temperature under N2 for 16 h. The reaction mixture was absorbed onto silica and purified by flash column chromatography (silica, ISCO, 45 mL/min, 0 to 20% EtOH in DCM) to give the desired product as a pale yellow solid (57.5 mg, 33.1%). 1H-NMR (400 MHz, CD3OD) δ ppm 8.72 (s, 1H), 8.24 (d, J=6.0 Hz, 1H), 7.54-7.32 (m, 2H), 7.21 (ddd, J=8.5, 1.1 Hz, 1H), 6.61-6.39 (m, 1H), 3.86-3.70 (m, 2H), 3.62 (t, J=6.0 Hz, 2H), 3.35-3.24 (m, 1H), 3.34-3.32 (m, 1H), 3.14-3.00 (m, 2H), 1.42-1.27 (m, 2H), 0.94-0.78 (m, 2H); LC-MS (method D): [M+H]+=523.2, RT=2.21 min.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][N:18]([CH2:23][CH2:24][C:25]#[N:26])[CH2:19][CH2:20][C:21]#[N:22])[CH2:12]1)[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([CH2:10][N:5]([CH2:4][CH2:3][CH2:1][NH2:2])[CH2:6][CH2:7][CH2:8][NH2:9])[CH2:12]1)[CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: [H][H]
Reactant: N#CCCN(CCC#N)CC1CCCC(CN(CCC#N)CCC#N)C1
Solvent: C1COCCO1
Product: NCCCN(CCCN)CC1CCCC(CN(CCCN)CCCN)C1
Yield: 97.6 %

Procedure:
5.00 g of N,N,N′,N′-tetrakis(2-cyanoethyl)-1,3-bis(aminomethyl)cyclohexane, 0.50 g of Raney Co and 50 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 8.0 MPa at 180° C. for 2 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 5.10 g of the title compound as a pale red oil.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C@H:8](N)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.N([O-])=[O:14].[Na+]>OS(O)(=O)=O>[OH:14][C@@H:8]([CH2:7][CH:4]1[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1)[C:9]([OH:11])=[O:10]
Reactant: O=N[O-]
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)[C@@H](O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a stirring suspension of L-cyclohexylalanine (4.00 g, 23.4 mmol) in 0.5M H2SO4 (120 mL) at 0° C. is slowly added dropwise an aqueous solution of NaNO2 (12.1 g in 40 mL H2O). Addition is complete after approximately 1 hour, at which point the solution is allowed to warm to room temperature. After 16 hours, the reaction mixture is extracted with ether (3×100 mL), and the combined organic extracts are washed with 1M NaHSO4 (1×200 mL) and brine (1×100 mL) and then dried over anhydrous Na2SO4. The solvent is removed in vacuo, and the crude product is recrystallized from Et2O/pentane (10 mL/100 mL) to afford 2.1 g (52% yield) of (S)-2-hydroxy-3-cyclohexylpropionic acid as fine white needles.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([CH3:23])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:36]1[CH2:40][CH2:39][N:38]=[C:37]1[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][NH:49][CH3:50])=[CH:43][CH:42]=1.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([N:49]([CH2:48][CH2:47][C:44]3[CH:43]=[CH:42][C:41]([C:37]4[NH:38][CH2:39][CH2:40][N:36]=4)=[CH:46][CH:45]=3)[CH3:50])=[O:22])[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([CH3:23])[CH:3]=1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Reactant: Cc1cc(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)cc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)co2)c(C)cc1Cl

Procedure:
5-({[(4-chloro-2,5-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (30 mg, 0.08 mmol) was dissolved in DMF (1 mL) and CDI (20 mg, 0.12 mmol) was added. The mixture was stirred until acid activation was complete. 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine.HCl (19 mg, 0.08 mmol) and DIPEA (0.042 mL, 0.24 mmol) were sonicated in DMF (1 mL) for 15 min, 0.5 mL of activated acid solution was added to 0.25 mL of amine solution and the reaction was microwaved (120° C., 200 W) for 20 min, then 2×60 min. A portion of the reaction was concentrated and purified using prep method A.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1(=[O:26])[N:11]([C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[C:13]([OH:15])=[O:14])[C:10](=[O:21])[C:9]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:8]12.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:10]1(=[O:21])[N:11]([C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[C:13]([O:15][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:14])[C:7](=[O:26])[C:8]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:9]12
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of cesium carbonate (3.819 g, 11.7 mmol.) and (S)-2-phthalimido-6-hydroxyhexanoic acid (6.00 g, 21.6 mmol.) in dimethylformamide (60 ml.) was treated with benzyl bromide (3.30 ml., 4.75 g., 27.7 mmol.). After stirring at room temperature for 2 hours, the mixture was partitioned between ethyl acetate and water. The organic extract was washed with water (twice) and brine, then dried (sodium sulfate), filtered and stripped to give an oil. The oil was flash chromatographed (Merck silica gel, 6/4-ethyl acetate/hexane) to give essentially pure product as a solid. Recrystallization from ethyl acetate/hexane gave 7.173 g. (1st crop) and 394 mg. (2nd crop) for a total of 7.567 g. of pure title product; m.p. 106°-108.5° C.; [α]D =-27.5° (c=1.5, methanol). TLC (75/25 ethyl acetate/hexanes) Rf =0.43.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)=[O:4].[Li+].[CH3:18][CH:19]([N-]C(C)C)[CH3:20].C(Br)C#C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:20][C:19]#[CH:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: C#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: C#CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 1 (6 mmol) was dissolved in THF (20 mL) and cooled down to −78° C. in a dry ice-acetone bath. LDA (5 mL, 2.0 M, 10 mmol) was then added dropwise. The mixture was stirred at −78° C. for 1 hr. Propargyl bromide (1.5 mL) was added in neat. The reaction was allowed to warm to rt naturally and stirred for 24 hrs. It was then quenched with sat. NH4Cl solution, extracted with ethyl acetate 2×50 mL. The organic layer was washed with brine, dried (MgSO4) and concentrated. The crude was purified on silica gel column using 4:1 hexanes/ethyl acetate to get the title compound (0.65 g) as an off-white gum. MS (267, M+H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].Cl[C:11]1[N:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH:2]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1Oc1cccnc1
Temperature: 120 °C
Yield: 55.8 %

Procedure:
To a solution of pyridin-3-ol (1.3 g, 10 mmol) in N,N-dimethyl formamide (25 ml) was added 60 % NaH in mineral oil (0.3 g, 15 mmol) and 2-chloronicotinonitrile (1.38 g, 10 mmol) and heated at 120° C. for overnight. The reaction mixture was quenched with 1M NaHCO3 and extracted with ethyl acetate (3×30 ml). The combined organic extracts were washed with saturated NaCl (50 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography using dichloromethane to yield 1.1 g (50%) of product. MS (ESI+) m/z 198 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[NH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: CN1CCN(N)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(Nc2ncnc(Nc3ccc(P(C)(C)=O)cc3)n2)CC1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 1-Amino-4-methyl-piperazine (13 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].ClCCl.S(Cl)(Cl)=O.[CH3:26][NH:27][CH3:28]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([N:27]([CH3:28])[CH3:26])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 3 h

Procedure:
To a stirred solution of 25 g. (0.1 mole) of 3,5-di(t-butyl)-4-hydroxybenzoic acid in 200 ml. of dichloromethane is added 1 ml. of N,N-dimethylformamide and 0.11 mole of thionyl chloride. The mixture is heated at its reflux temperature for 40 minutes, then 0.1 mole of aqueous dimethylamine is added dropwise. The mixture is stirred for three hours and extracted twice with dichloromethane. The dichloromethane extracts are dried then evaporated to provide a residue which is recrystallized from a benzene-hexane mixture. The while solid is dissolved in dichloromethane, washed twice with 10 percent sodium hydroxide solution, then the dichloromethane layer is evaporated under vacuum. The product is recrystallized twice from a benzene-hexane mixture to provide 3,5-di(t-butyl)-4-hydroxy-N,N-dimethylbenzamide, m.p. 173°-174.5° C.