Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>>[CH3:1][C:2]1[C:14]2[N:13]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:14])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2c1[nH]c1cc(O)ccc12
Reactant: CC(C)CCBr
Product: Cc1nccc2c3ccc(OCCC(C)C)cc3n(CCC(C)C)c12
Yield: 69 %

Procedure:
The title compound was synthesized from 1-methyl-7-hydroxy-β-carboline (1.504 g, 4.770 mmol) in presence of 1-bromo-3-methylbutane (1.440 g, 9.520 mmol) as described here above.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCC[C@H]1CC[C@H](C=Cc2ccc(-c3ccc([C@H]4CC[C@H](CCCCC)CC4)cc3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(-c3ccc([C@H]4CC[C@H](CCCCC)CC4)cc3)cc2)CC1

Procedure:
2.20 g of 4-(trans-4-pentylcyclohexyl)-4'-[2-(trans-4-pentylcyclohexyl)vinyl]biphenyl were suspended in toluene/ethanol (3:2) in a sulphonation flask, treated with 200 mg of palladium/carbon (10%) and hydrogenated at normal pressure and 50° C. until the hydrogen uptake came to a standstill. Filtration of the mixture and concentration of the filtrate gave a white semi-crystalline residue which, after recrystallization from 100 ml of hexane, yielded 1.55 g of 4-(trans-4-pentylcyclohexyl)-4'-[2-(trans-4-pentylcyclohexyl)ethyl]biphenyl as colourless needles; transition (presumably S-S) 219.5° C., transition S-N 243.2° C., cl.p. (N-I) 256.1° C. This substance was found to be very strongly super-coolable; upon cooling to room temperature it still did not crystallize. Rf-value (hexane): 0.32.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:11][CH:10]=1.[C:25](Cl)(=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1(C)C=CC=CC=1>[CH2:26]([C:25]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:11][CH:10]=1)=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCC(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
{circle around (1)}: A solvent comprising 1.1 g of triethylamine and 5 g of toluene was added dropwise to a mixture comprising 2.28 g of benzyl 4-hydroxybenzoate, 2.33 g of n-tridecanoic chloride and 15 g of toluene in 30 minutes while cooling it with ice. After finishing adding dropwise, the mixture was stirred at room temperature for 3 hours. After finishing the reaction, deposited salts were filtered off, and the filtrate was neutralized with ½ N hydrochloric acid and washed with water. Then, toluene was distilled off under reduced pressure, and the resultant residue was recrystallized from ethanol, whereby 3.52 g of benzyl 4-n-dodecylcarbonyloxybenzoate was obtained in the form of a colorless crystal.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(N(CC)CC)C.[O:17]=[C:18]1[C:26]([C:27]#[N:28])=[C:25]([N:29]2[CH2:34][CH2:33][N:32]([C:35]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[O:36])[CH2:31][CH2:30]2)[C:24]2[C:20](=[CH:21][S:22][CH:23]=2)[NH:19]1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[O:17]=[C:18]1[C:26]([C:27]#[N:28])=[C:25]([N:29]2[CH2:30][CH2:31][N:32]([C:35]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[O:36])[CH2:33][CH2:34]2)[C:24]2[C:20](=[CH:21][S:22][CH:23]=2)[N:19]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2n(-c2cccnc2)c1=O
Temperature: 25 °C

Procedure:
Cu(OAc)2 (363 mg, 2 mmol), pyridine-3-boronic acid (614 mg, 5 mmol), and triethylamine (560 μL, 4 mmol) were added to a solution of 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile (47) (370 mg, 1 mmol) in wet DMF (DMF:H2O::9:1) stirred at room temperature. The solution was further stirred at room temperature for 24 h. The solution was passed through a bed of celite and the solvent was evaporated. The residue was suspended in water and extracted by CH2Cl2. The combined organic phase was partitioned with 10% aqueous HCl solution. The aqueous phase was separated and the pH was adjusted to 5 by 4 N NaOH solution. Then, a saturated solution of NaHCO3 was added until the pH reached to 8. The solids formed were filtered, washed by water, and dried under vacuum at 70° C. to get 5-oxo-4-pyridine-3-yl-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile as white solids. Yield 243 mg (54%); MP 282° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.99 (m, 8H), 6.42 (d, J=2.8 Hz, 1H), 7.18 (dd, J=4.0, 4.8 Hz, 1H), 7.52 (d, J=2.8 Hz, 1H), 7.64 (dd, J=4.8, 8.0 Hz, 1H), 7.81 (d, J=4.8 Hz, 1H), 7.88 (dm, 1H), 8.47 (d, J=3.2 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.71 (d, J=3.6 Hz, 1H) ppm; MS m/z=448 amu (M++1). Anal. (C22H17N5O2S2) N.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C1(CNOCc2ccccc2)CCCCC1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CN(CC1(C(=O)O)CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold solution of formic acid (15.3 mL, 0.4 mol) in dichloromethane (100 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (5.75 mL, 60 mmol). After 1 h, a solution of 1-(benzyloxyamino-methyl)-cyclohexanecarboxylic acid from Preparation 19 (4.41 mmol theoretical) in dichloromethane (50 mL) was added. The mixture was stirred at room temperature for 18 h and was concentrated in vacuo. Brine (100 mL) was added and the mixture was extracted with dichloromethane (100 mL×2). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale, orange oil (1.77 g, 100%). MH+292.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[CH:16])[CH:5]=[CH:4][C:3]1=2.I[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C#CCc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(O)c1ccc(I)cc1
Product: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
In a similar manner to Example 16(c), by reaction of 8 g (35.3 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne with 8 g (32.1 mmol) of 4-iodobenzoic acid, 10.4 g (94%) of the expected acid are obtained, with a melting point of 167-8° C.
Reaction SMILES: [N:1]1[C:5]2=[C:6]3[CH:14]=[CH:13][CH:12]=[N:11][C:7]3=[N:8][CH2:9][CH2:10][C:4]2=[CH:3][N:2]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:34])=[C:20]([CH:33]=1)[C:21]([NH:23][C:24]1[N:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1)=[O:22]>>[NH:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[N:11][C:7]=3[N:8]([C:30]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[C:20]4[CH:33]=[C:16]([F:15])[CH:17]=[CH:18][C:19]=4[CH3:34])=[N:29][CH:28]=3)=[O:31])[CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1
Reactant: C1=C2CCN=c3ncccc3=C2N=N1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3cccnc32)cn1

Procedure:
As described for Example 13, 4,5-dihydropyrazolo[3,4-d]pyrido[2,3-b]azepine is reacted with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH:49][CH3:50])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:49]([CH2:47][CH3:48])[CH3:50])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCNC
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)CC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-ethyl-N-methylamine (Aldrich) to give the title compound. LC-MS (ES+) 706 [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Li]CCCC.C([O:17][C:18]([C:20]1[N:21]=[N:22][S:23][C:24]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)C>C1COCC1.C1CCCCC1>[N:4]1([CH2:3][CH2:2][NH:1][C:18]([C:20]2[N:21]=[N:22][S:23][C:24]=2[NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:17])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)c1nnsc1Nc1ccccc1
Reactant: NCCN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=C(NCCN1CCOCC1)c1nnsc1Nc1ccccc1
Yield: 60 %

Procedure:
To a solution of N-aminoethylmorpholine (228 mg, 10 mmole) in 2 mL anhydrous THF at −40° C. was added 0.8 mL of 2 M n-BuLi solution in cyclohexane. Some white solid was precipitated instantly. The suspension was stirred for about a half an hour. When the bath temperature reached −10° C., a solution of 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester (60 mg, 0.24 mmole) in anhydrous THF was added to the mixture. After it was stirred at room temperature for an hour, the reaction was quenched with saturated NH4Cl solution. The solution was extracted with EtOAc and residue obtained after the removal of EtOAc was purified by preparative TLC (silica gel, CH2Cl2:MeOH=15:1). The title compound was isolated as a white powder in 60% yield (48 mg). 1H NMR (ppm, in CDCl3): 10.91 (br. s, 1H), 7.77 (br. s, 1H), 7.00-7.60 (m, 5H), 3.70 (m, 4H), 2.60 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>CN(C)C=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: c1ccc2c(c1)CCN2
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1N1CCc2ccccc21

Procedure:
A stirred solution of 38.4 g (0.20 mole) of 1,4-dichloro-2-nitrobenzene and 59.6 g (0.50 mole) of indoline in 400 ml of dimethylformamide (DMF) was heated under nitrogen at 140°-145° C. alignment overnight (23 hours). The DMF solvent was then removed in vacuo and the residue was dissolved in 500 ml of dichloromethane. This solution was extracted with H2O, with dilute hydrochloric acid, with brine, then dried over Na2SO4 and concentrated to an oil. This was adsorbed on a tall chromatography column containing 1.5 kg of silica gel packed in toluene. Elution with toluene brought forth 22.1 g (40% overall yield) of product, which crystallized. A small portion was recrystallized from hexane to afford 1-(4-chloro-2-nitrophenyl)indoline, m.p. 97°-99° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:12][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH:1][C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=1)=[O:24]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CN1CCCCC1CCc1ccccc1N
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2ccccc2CCC2CCCCN2C)cc1

Procedure:
Reaction of 2-(o-aminophenethyl)-1-methylpiperidine (80 g., 0.036 mole) with p-toluoyl chloride (6.2 g., 0.04 mole) in 50 ml. of pyridine according to the method of Example 25 provides 2'-[2-(1-methyl-2-piperidyl)ethyl]p-toluanilide. Crystallization from isopropyl ether and then from isopropyl alcohol provides 3.9 g., (32%) of analytically pure material, m.p. 90.5°-92° C. (corr.).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([CH3:31])[CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)=[C:26]([CH3:31])[CH:25]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Cc1cc(F)ccc1N
Product: Cc1cc(F)ccc1Nc1nc(NCc2ccccn2)nc(C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (4-fluoro-2-methylphenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.01 (s, 3H), 2.07 (s, 3H), 2.15 (s, 3H), 4.30 (bs, 2H), 6.68 (bs, 1H), 6.84-6.89 (m, 1H), 6.98-7.10 (m, 2H), 7.17 (t, J=7.3 Hz, 2H), 7.57-7.67 (m, 2H), 8.43 (d, J=4.2 Hz, 1H); MS (ESI) m/z 338.8 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:18]([NH:22][C:23]([N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1)[CH2:4][CH2:3][N:2]([CH3:1])[CH3:17])=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: COC(=O)c1ccc(CNCCN(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCNC(=O)N(CCN(C)C)Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of methyl 4-[[[2-(dimethylamino)ethyl]amino]methyl]benzoate (compound obtained in Reference Example 36(1), 200 mg) in methylene chloride (4 mL) is added n-butyl isocyanate (143 μL) and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with chloroform (5 mL) and thereto is added a saturated sodium hydrogencarbonate solution (10 mL). After stirring, the organic layer is separated and concentrated. The resultant crude product is purified by column chromatography on silica gel (Solvent; chloroform:methanol=100:0→90:10) to give methyl 4-[[N-(butylcarbamoyl)-N-[2-(dimethylamino)ethyl]amino]methyl]-benzoate (261 mg, yield; 92%) as a pale yellow oil. MS (APCI) m/z: 336 [M+H]+
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40](C#N)=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.Cl.[C:46]([O:49][CH2:50][CH3:51])(=[O:48])C>C(O)C.O>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:42]=[CH:41][C:40]([C:46]([O:49][CH2:50][CH3:51])=[O:48])=[CH:39][CH:38]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C#N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cc1

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and 4-cyanophenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene as colorless powder. APCI-Mass m/Z 657/659 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene (128 mg) was suspended in ethanol (2 ml) and added thereto was a concentrated hydrochloric acid aqueous solution (1 ml). The mixture was heated reflux for 8.5 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-ethoxycarbonylphenyl)-2-thienylmethyl)benzene (39 mg) as pale yellow foam. APCI-Mass m/Z 536/538 (M+NH4).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17]O)=[CH:11][C:10]=2[O:19][CH3:20])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:32])(=O)=O.[NH4+].[Cl-]>ClCCl>[Cl:32][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)=[C:10]([O:19][CH3:20])[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C#CCO)ccc1Oc1cccc(F)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CCCCl)ccc1Oc1cccc(F)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 169.1 %

Procedure:
To a solution of 3-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}prop-2-yn-ol (0.37 mmol; 102 mg) in dry dichloromethane (2 mL), under argon, cooled to −40° C., was added triethylamine (0.41 mmol; 56 μL) then methanesulfonyl chloride (0.39 mmol; 30 μL). The reaction mixture was allowed to stir for 6 hr, with gradual warming to room temperature. The reaction was hydrolysed with saturated NH4Cl, extracted with ethyl acetate. Combined organic phases were dried over Na2SO4, concentrated in vacuo. The title compound (185 mg; 47%) was obtained as a light oil, after purification on preparative TLC (cyclohexane/ethyl acetate: 7/3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[N+:42]([O-])=O)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([OH:38])[CH:30]=4)=[CH:24][CH:23]=3)[CH:19]3[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:21][CH:13]2[CH2:14]4)[CH2:18]3)=[CH:8][CH:7]=1.O.NN>[Pd].C(O)C>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:12]3([C:9]4[CH:10]=[CH:11][C:6]([O:5][C:4]5[CH:39]=[CH:40][C:41]([NH2:42])=[C:2]([OH:1])[CH:3]=5)=[CH:7][CH:8]=4)[CH:13]4[CH2:21][CH:17]5[CH2:16][CH:15]([CH2:20][CH:19]3[CH2:18]5)[CH2:14]4)=[CH:27][CH:26]=2)=[CH:30][C:31]=1[OH:38]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C3(c4ccc(Oc5ccc([N+](=O)[O-])c(O)c5)cc4)C4CC5CC(C4)CC3C5)cc2)cc1O
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccc(C3(c4ccc(Oc5ccc(N)c(O)c5)cc4)C4CC5CC(C4)CC3C5)cc2)cc1O
Reaction time: 24 h
Yield: 67 %

Procedure:
A mixture of 2,2-bis(4-(3-hydroxy-4-nitrophenoxy)phenyl)adamantane (3.00 g, 5.05 mmol), 10% Pd/C (0.06 g) and ethanol (60 mL) were heated to reflux. Then, 20 mL of hydrazine hydrate was added dropwise into the suspension solution over a period of 1 hour. After the mixture was refluexed for another 24 h. The reaction solution was then filtered to remove Pd/C. The crude product was recrystallized from ethanol to give 1.81 g (67.1%) of 2,2-bis(4-(4-amino-3-hydroxyphenoxy)phenyl)adamantane. mp>160° C. (decompose); IR (KBr): 3415, 3298, 2912 cm−1, MS (EI) m/z 534 (M+, 100); Anal. Calcd. for C34H34N2O4: C, 76.40; H, 6.36; N, 5.24. Found: C, 76.21; H, 6.45; N, 5.22.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[CH2:28][NH2:29])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:30](O)(=[O:32])[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:17])([CH3:18])[CH3:16])[CH2:10][C@H:9]1[CH2:28][NH:29][C:30](=[O:32])[CH3:31])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(=O)O
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](CN)N(C(=O)OC(C)(C)C)C2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NC[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To a solution of (2S,4S)-t-BOC-2-(aminomethyl)-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]pyrrolidine (500 mg, 1.21 mmol) prepared in Step A of Example B7 in DMF was added dropwise acetic acid (80 mg, 1.3 mmol), HBTU (490 mg, 1.28 mmol) and DIPEA (0.56 ml, 3.22 mmol) in order. After the reaction mixture was stirred at rt for 5 h, the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with a saturated NaHCO3 aqueous solution, water and 1N HCl. The organic solution was dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc:Hex=1/2) to give the title compound (508 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].[C:10](Cl)(=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:8]([C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][C:10](=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])#[N:9]
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1nsc(N)c1C#N
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1nsc(NC(=O)CC(C)C)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of 5-amino-3-methylisothiazole-4-carbonitrile (method 4) (105.6 g, 0.76 mol) in pyridine (250 ml) at 0° C., isovaleryl chloride (100 g, 0.83 mol) in chloroform (300 ml) was added dropwise. After the completion of the addition the reaction mixture was allowed to warm to r.t. and stirred overnight. The TLC and the MS showed the complete disappearance of the starting material and the reaction mixture was diluted with CHCl3 (600 ml), washed with water (200 ml), 2N HCl (600 ml), satd. NaHCO3 (200 ml), brine (200 ml) and dried over Na2SO4Concentration of the CHCl3 layer provided the crude product which was triturated from DCM/hexanes ( 1/10) and filtered off to isolate N-(4-cyano-3-methyl-isothiazol-5-yl)-3-methyl-butyramide (149.7 g, 88%) as an off-white crystalline solid. 1H NMR (300 MHz) δ 1.04 (d, 6H), 2.18-2.32 (m, 1H), 2.46 (d, 2H), 2.53 (s, 3H), 9.87 (bs, 1H).