Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[N:15]=[CH:14][C:13]2[O:16][C:17]3[C:22]([C@@:23]4([CH2:28][CH2:27][O:26][C:25]([NH2:29])=[N:24]4)[C:12]=2[CH:11]=1)=[CH:21][C:20]([NH2:30])=[CH:19][CH:18]=3.[O:31]1[CH2:36][CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32]1>O1CCOCC1.O>[O:31]1[CH2:36][CH2:35][CH:34]=[C:33]([C:10]2[N:15]=[CH:14][C:13]3[O:16][C:17]4[C:22]([C@@:23]5([CH2:28][CH2:27][O:26][C:25]([NH2:29])=[N:24]5)[C:12]=3[CH:11]=2)=[CH:21][C:20]([NH2:30])=[CH:19][CH:18]=4)[CH2:32]1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1cnc(Cl)cc12
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1cnc(C3=CCCOC3)cc12
Temperature: 120 °C
Yield: 74.8 %

Procedure:
A microwave reaction vessel was charged with potassium phosphate (tribasic) (0.670 g, 3.16 mmol), (S)-3-chloro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.2 g, 0.631 mmol), and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.398 g, 1.894 mmol) in dioxane (4 ml) and water (2 ml). The vessel was capped and the solution was purged with nitrogen for 10 minutes. Next, bis[di-tert-butyl(4 dimethylaminophenyl)phosphine]dichloropalladium(II) (0.022 g, 0.032 mmol) was added and the vessel was sealed. The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 35 minutes. The reaction was poured into water and the mixture was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 20:1 solution of DCM to a 2M solution of NH3 in MeOH, to provide (S)-3-(5,6-dihydro-2H-pyran-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.172 g, 0.472 mmol, 74.8% yield) as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[CH3:2].C([N:23]=[C:24]=[S:25])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH2:1]([C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:24]([NH2:23])=[S:25])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[CH3:2]
Reactant: CCc1ncc(-c2ccc(N)cc2)o1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ncc(-c2ccc(NC(N)=S)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 4-(2-ethyl-oxazol-5-yl)-phenylamine (470 mg, 2.5 mmol, CAS 73286-36-9) in tetrahydrofurane (20 mL) was added benzoyl isothiocyanate (449 mg, 2.8 mmol). The reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was suspended in methanol (30 mL). Potassium carbonate (1036 mg, 7.5 mmol) dissolved in water (15 mL) was added drop wise to the suspension. The reaction was stirred at room temperature over night. The resulting solution was evaporated and the residue was stirred with water. The precipitate was filtered off, washed twice with water and twice with diethyl ether. The residue was dissolved in tetrahydrofurane and the solvent was removed under reduced pressure to yield the title compound as a light yellow solid (270 mg, 44%). MS ISP (m/e): 248.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ=9.80 (s, 1H, NH), 7.61 (d, 2H), 7.52 (d, 2H), 7.46 (s, 1H), 3.80 (q, 2H), 1.28 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][O:22][CH3:23])=[C:19]([C:24](O)=[O:25])[C:18]([CH2:27][O:28][CH3:29])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[N:30]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][O:22][CH3:23])=[C:19]([C:24]([N:33]4[CH2:34][CH2:35][CH2:36][N:30]([CH2:37][CH2:38][OH:39])[CH2:31][CH2:32]4)=[O:25])[C:18]([CH2:27][O:28][CH3:29])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: COCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(COC)c1C(=O)O
Reactant: OCCN1CCCNCC1
Product: COCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(COC)c1C(=O)N1CCCN(CCO)CC1

Procedure:
In analogy to the procedure described for example 1, 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 2-[1,4]diazepan-1-yl-ethanol gave the title compound as brown oil. MS: 539.3 (MH+, 1 Cl).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(OC(OCC)C[Mg]Br)C.[BH4-].[Na+].[CH2:30]([OH:32])[CH3:31]>>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])([CH3:2])[CH2:31][CH2:30][OH:32])=[CH:5][CH:6]=1
Reactant: CCO
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: CCOC(C[Mg]Br)OCC
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 2 h

Procedure:
A solution of 2.76 g. of 3 hydroxy-3-(2',4'-difluoro-4-biphenylyl)-butanol, obtained by reacting 4-acetyl-2',4'-difluorobiphenyl with 2,2-diethoxyethyl magnesium bromide and subsequently hydrolyzing the reaction product, in 12 ml. of ethanol is added dropwise to a solution of 0.6 g. of NaBH4 in 15 ml. of ethanol. The mixture is stirred for 2 hours at 20° and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.
Reaction SMILES: Br[C:2]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1.C(=[NH:57])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>[Cl-].[Na+].O>[NH2:57][C:2]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)cc2Br)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)cc2N)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
The mixture of 0.800 g of tert-butyl 3-(2-bromo-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate, 0.250 ml of benzophenone imine, 0.0037 g of dipalladiumtris(dibenzylidenacetone)-chloroform complex, 0.0051 g of (R)-(+)-2,2′-bis(diphenylphosphine)-1,1′-binaphthyl and 0.168 g of sodium tert-butoxide is admixed with 6.0 ml of toluene and stirred under argon at 80° C. over 72 hours. The reaction mixture is cooled, admixed with brine (20 ml) and extracted with ethyl acetate (2×80 ml). The organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The residue is dissolved in 6.0 ml of methanol, admixed with 0.090 g of 5% Pd/C and 1.15 g of ammonium formate, and stirred at 60° C. over 72 hours. The reaction mixture is diluted with methanol (20 ml) and clarified by filtration, and the filtrate is concentrated by evaporation. The residue is admixed with 0.1M NaOH (100 ml) and extracted with ethyl acetate (2×100 ml). The organic phases are washed successively with 0.1M NaOH (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.30 (1:2 EtOAc-heptane); Rt=5.32.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Cl.[Cl:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[ClH:12].[N:20]1([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][N:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[NH2:10])=[CH:15][CH:16]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: NNc1ccc(F)cc1
Reactant: ClCc1ccc(-n2ccnc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NN(Cc1ccc(-n2ccnc2)cc1)c1ccc(F)cc1

Procedure:
The 1-[4-1H-imidazol-1-yl)benzyl]-1-(4-fluorophenyl)hydrazine hydrochloride used above is prepared as follows: a mixture of 1-(4-fluorophenyl)hydrazine hydrochloride (3.3 g), 1-[4-(chloromethyl)phenyl]-1H-imidazole hydrochloride (3.1 g), triethylamine (6.6 ml) and toluene (200 ml) is refluxed under nitrogen for 13 hours. After cooling the mixture is filtered and the solution is evaporated to dryness. The residue is purified through a silica gel column eluiting with methylene chloride/methanol (100/5) to give 2.0 g of 1-[(4-1H-imidazol-1-yl)benzyl]-1-(4-fluorophenyl)hydrazine hydrochloride, ms: m/e 282 (M+), 158,157.
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[CH:10]([CH2:20][Cl:21])[CH2:9]1)=[O:7])(C)(C)C.C([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([C:34]([NH:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)=[O:35])[CH:28]=2)(O)=O>>[Cl:21][CH2:20][CH:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[N:8]([C:6]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([C:34]([NH:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:35])[CH:28]=3)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2ccc([N+](=O)[O-])cc21
Reactant: O=C(NCCN1CCOCC1)c1ccc2cc(C(=O)O)[nH]c2c1
Product: O=C(NCCN1CCOCC1)c1ccc2cc(C(=O)N3CC(CCl)c4ccc([N+](=O)[O-])cc43)[nH]c2c1
Yield: 50 %

Procedure:
1-(t-Butoxycarbonyl)-3-(chloromethyl)-6-nitroindoline was coupled with 2-carboxy-N-[2-(4-morpholinyl)ethyl]indole-6-carboxamide by the method described above and triturated with hot MeOH to give 2-[[3-(chloromethyl)-6-nitroindolin-1-yl]carbonyl]-N-[2-(4-morpholinyl)ethyl]indole-6-carboxamide as a yellow solid (50%), mp 227-228° C. (dec.). 1H NMR [(CD3)2SO] δ12.15 (s, 1H, indole NH), 8.98 (d, J=2.0 Hz, 1H, H-7), 8.41 (t, J=5.5 Hz, 1H, amide NH), 8.04 (dd, J=8.3, 2.2 Hz, 1H, H-5), 8.01 (s, 1 H, H-3' or H-7'), 7.76 (d, J=8.2 Hz, 1H, H-4 or H-4'), 7.74 (d, J=8.0 Hz, 1H, H-4 or H-4'), 7.57 (dd, J=8.5, 1.1 Hz, 1H, H-5'), 7.28 (d, J=1.4 Hz, 1H, H-3' or H-7'), 4.86 (t, J=10.1 Hz, 1H, H-2), 4.51 (dd, J=10.7, 5.2 Hz, 1H, H-2), 4.19-4.06 (m, 3H, H-3 and CH2Cl), 3.59 (t, J=4.5 Hz, 4H, CH2O), 3.42 (q, J=6.5 Hz, 2H, CONHCH2), 2.50 (t, J=6.9 Hz, 2H, CONHCH2CH2), 2.46-2.41 (m, 4H, NCH2CH2O); 13C NMR δ166.7 (CONH), 160.4 (CON), 147.6, 144.6, 144.0, 135.7, 131.8, 130.8, 129.0 (C-6,8,9,2',6',8',9'), 125.5, 121.6, 119.5, 118.9, 112.0, 111.2, 106.1 (C-4,5,7,3',4',5',7'), 66.2 (CH2O), 57.4 (CONHCH2CH2), 54.0 (C-2), 53.3 (NCH2CH2O), 47.0 (CH2Cl), 42.0 (C-3), 36.6 (CONHCH2). A sample was converted to the hydrochloride salt and triturated with hot EtOH to give 2-[[3-(chloromethyl)-6-nitroindolin-1-yl]carbonyl]-N-[2-(4-morpholinyl)ethyl]indole-6-carboxamide hydrochloride as a pale yellow powder, mp 280-285° C. (dec.). Anal. (C25H26ClN5O5.HCl.H2O) C,H,N.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:10]([OH:22])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](Cl)=[O:41]>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[C:10]([O:22][C:40](=[O:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=2)[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccn1
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)C)cc2O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)C)cc2OC(=O)c2ccccn2)cc1

Procedure:
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(p-toluyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with picolinoyl chloride, there is obtained 3-(picolinoyloxy)-4-(p-toluyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, usign a procedure similar to that described above in Example 2B, there is obtained 3-(picolinoyloxy)-4-(p-toluyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.[C:17]([C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][CH:25]=[CH:26][CH2:27]Cl)=[CH:21][CH:20]=1)#[N:18]>CC#N>[C:17]([C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][CH:25]=[CH:26][CH2:27][N:7]2[CH2:8][CH:1]3[CH2:9][CH:5]([CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]3)[CH2:6]2)=[CH:21][CH:20]=1)#[N:18]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: N#Cc1ccc(OCC=CCCl)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC=CCOc3ccc(C#N)cc3)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.13 g; 5 mmol; see Example F above) was added to a stirred solution of 4-(4-cyanophenoxy)-1-chloro-2-butene (1.04 g; 5 mmol; from step (a) above) in MeCN (25 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between diethyl ether and KHS04 (0.3 M). The aqueous layer was treated with NaOH (2M) and subsequently extracted with CH2Cl2. The organic layer was washed with water, dried, concentrated and purified using column chromatography (CH2Cl2:MeOH; 95:5) to give the title compound (0.84 g; 2.1 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH:27]([CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC(C)([O-])C.[K+]>CC(N(C)C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH:27]([CH2:31][O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1cccc(CCc2ccccc2O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2OCC2CN(C(=O)OC(C)(C)C)CCO2)c1
Yield: 99.9 %

Procedure:
Following a procedure similar to that described in Example 40, 1.00 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 1.63 g of 4-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)morpholine and 0.490 g of potassium t-butoxide were reacted in 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40, and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.87 g (yield 94.5%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH3:37])=[C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:29]3[CH:30]=[C:25]([O:24][CH3:23])[CH:26]=[CH:27][C:28]=3[CH3:37])[CH2:36][CH2:35]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc(C)c(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1ccc(C)c(N2CCN(C(=O)Nc3cc4ccccc4nc3OC)CC2)c1
Yield: 82 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(5-methoxy-2-methylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]([CH2:37][CH:38]=O)[C:34](=[O:40])[CH:33]=[CH:32]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:38][CH2:37][N:35]4[C:36]5[C:31](=[CH:30][CH:29]=[CH:28][C:27]=5[CH3:26])[CH:32]=[CH:33][C:34]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: Cc1cccc2ccc(=O)n(CC=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To 2 mL of a chloroform solution containing 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.14 g of (8-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 20 μL of acetic acid and 0.22 g of sodium triacetoxyborohydride were added, and stirred at room temperature overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; hexane:ethyl acetate=1:1], to give 0.13 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(8-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: [F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][OH:4].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:4][CH2:3][CH:2]([F:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCC(F)CO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 5 h
Yield: 66.7 %

Procedure:
In a vessel sufficiently replaced with nitrogen, 0.40 g (3.0 mmol) of (-)-2-fluoroheptanol and 1.00 g (13 mmol) of dry pyridine were placed and dried for 30 min. under cooling on an ice bath. Into the solution, 0.69 g (3.6 mmol) of p-toluenesulfonyl chloride was added, and the mixture was stirred for 5 hours. After the reaction, 10 ml of 1N-HCl was added, and the resultant mixture was subjected to two times of extraction with 10 ml of methylene chloride. The extract liquid was washed once with 10 ml of distilled water and dried with an appropriate amount of anhydrous sodium sulfate, followed by distilling-off of the solvent to obtain 0.59 g (2.0 mmol) of (+)-2-fluoroheptyl p-toluenesulfonate.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([O:22]C)[CH:19]=[C:18]([O:24]C)[CH:17]=1)=[O:15]>>[OH:22][C:20]1[CH:21]=[C:16]([C:14]2[O:15][C:5]3[C:6](=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=3)[CH:13]=2)[CH:17]=[C:18]([OH:24])[CH:19]=1
Reactant: COc1cc(OC)cc(C(=O)CBr)c1
Reactant: COc1cc(O)cc(OC)c1
Product: Oc1cc(O)cc(-c2cc3c(O)cc(O)cc3o2)c1
Yield: 74 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(3,5-dimethoxyphenyl)ethanone: Yield 74% following procedures A.2 and A.5; m.p. 244° C. (dec.); IR 3349, 2920, 1610, 1442, 1252, 1134 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.78 (s, 1H), 9.33 (s, 2H), 9.32 (s, 1H), 7.01 (s, 1H), 6.62 (d, J=2.0, 2H), 6.39 (s, 1H), 6.19-6.15 (m, 2H); 13C-NMR (126 MHz, δ ppm, CD3OD) 160.0, 158.6, 157.9, 154.5, 152.4, 134.1, 112.9, 103.9, 103.4, 99.8, 98.8, 90.8.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2O.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:24]>ClC(Cl)C>[Cl:24][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: Oc1ncnc2ccc(I)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2ccc(I)cc12
Temperature: 90 °C
Yield: 71.4 %

Procedure:
To a cooled (0° C.) suspension of 6-iodoquinazolin-4-ol (107.6 g, 396 mmol) and DIEA (138 mL, 791 mmol) in dichloroethane (600 mL) was added POCl3 (44.25 mL, 475 mmol). After heating to 90° C. for 16 hours, the reaction mixture was cooled to room temperature and the crystals (73.8 g) collected by filtration. The filtrate was concentrated under reduced pressure and azeotroped twice with toluene. The solids (8.3 g) were triturated with isopropanol (450 mL) and cooled in an ice bath before collecting by filtration and drying under high vacuum. The two solids were combined to provide the product (82.1 g, 71%) as white solid.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30].CCOCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([NH:30][CH2:29][C:28]([O:27][CH3:26])=[O:31])=[O:24]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1cc2ccccc2n1C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
DMAP (1.222 g, 0.01 mol) and EDAC (2.680 g, 0.014 mol) were added as solids to a solution of 1-methylindole-2-carboxylic acid (1.752 g, 0.01 mol) and glycine methyl ester hydrochloride (1.256 g, 0.01 mol) in methylene chloride (30 mL) and DMP (5 mL) under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and then for 3 hours at room temperature. The reaction mixture was partitioned with ethyl acetate and 5% KHSO4 solution and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solution was washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) solution and brine, dried over sodium sulfate, and concentrated to give a purple powder as crude product. Trituration of the powder with ether afforded the title product (1.734 mg, 70%). TLC: (methanol/methylene chloride 1:9): Rf=0.61; 1H NMR (CDCl3): δ7.65 (dt, J=8.0, 1.1, 1H), 7.41-7.31 (m, 2H), 7.16 (dd, J=6.6, 1.4, 1H) 6.96 (d, J=0.5, 1H), 6.67 (bs, 1H), 4.25 (d, J=5.2, 2H), 4.05 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:11]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1ccccc1
Temperature: -10 °C
Yield: 84.9 %

Procedure:
A solution of 10.9 grams (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 14.1 grams (0.1 mole) benzoyl chloride in 200 milliliters xylene was refluxed at about 140° C. for 20 hours. Upon cooling the reaction mixture to -10° C., 13.7 grams (85% yield) pure product precipitated; m.p. 190.5° C.