Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](OCC)=[O:9].[O-]CC.[Na+:16]>C(OCC)C>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[CH:8][O-:9].[Na+:16]
Reactant: O=C1CCCCC1
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C1CCCCC1=C[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Cyclohexanone (30 ml) and ethyl formate (24 ml) were dissolved in diethyl ether (150 ml), sodium ethoxide (21 g) was added under ice-cooling, and the reaction mixture was stirred at room temperature for 10 hr. Insoluble material was collected by filtration, and washed with diethyl ether to give the object compound (49.2 g) as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[I-:12].[Na+]>C(N(CC)CC)C.C(C(C)=O)C>[I:12][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: [I-]
Reactant: O[C@@H](CCCl)c1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: O[C@@H](CCI)c1ccccc1
Yield: 74.9 %

Procedure:
Commercially available (S)-3-chloro-1-phenyl-1-propanol (6 g) was heated with excess sodium iodide (4 equiv., 18 g) and a few drops of triethylamine in 30 mL of methyl ethyl ketone at 100° C. for 20 h. A sample was taken and monitored by NMR to determine the extent of conversion. The solvent was removed in vacuo and the residue was taken up in dichloromethane and filtered to remove the salts and the iodoalcohol was purified by flash chromatography to yield 6.9 g of product.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C(N(CC)CC)C.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH:34]3[N:38]([CH3:39])[NH:37][C:36](=[O:40])[CH2:35]3)[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCCC1>[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH:34]3[CH2:35][C:36](=[O:40])[N:37]([C:1]([NH:19][CH2:18][C:14]4[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=4)=[O:2])[N:38]3[CH3:39])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: NCc1cccnc1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(C2CC(=O)NN2C)cc1OC1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C2CC(=O)N(C(=O)NCc3cccnc3)N2C)cc1OC1CCCC1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
To a -15° C. solution of phosgene (4.50 mmol, 2.30 mi; 1.9 M solution in toluene) in dry tetrahydrofuran (8 mi) is added neat triethylamine (4.50 mmol, 0.450 g; 0.620 mL) and the resulting suspension is stirred at -15° C. for 10 minutes. To this suspension is added 3-picolylamine (4.50 mmol, 0.490 g; 0.460 mL) and triethylarnine (4.50 mmol, 0.450 g; 0.620 mL) in dry tetrahydrofuran (10 mL) in one portion and the reaction mixture is stirred at -15° C. for 30 minutes. Subsequently, 5-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (3.0 mmol, 0.870 g) in dry tetrahydrofuran (7 mL) is added at -15° C. and the reaction mixture is allowed to warm to room temperature overnight. The reaction is quenched with water (20 mL), the volatiles removed in vacuo, and the residue partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer is dried (Na2SO4) and concentrated in vacuo to give a tan solid. This material is purified by flash chromatography (SiO2 : 1) 50% ethyl acetate/hexane; 2) 100% ethyl acetate; 3) 5% methanol/ethyl acetate) to give a mixture of starting material and product which is triturated with ether. The title compound is isolated as a white solid (0.158 g; 12%). Also isolated is a mixture of starting pyridazone and title compound (0.511 g). 1H-NMR (DMSO-d6,400 MHz) δ 8.45 (m, 3H); 7.65 (dt, 1H, J=8.0, 1.6 Hz); 7.22 (ddd, 1H, J=8.0, 5.0, 0.7 Hz); 6.94 (d, 1H, J=2.0 Hz); 6.88 (d, 1H, J=8.0 Hz); 6.82 (dd, 1H, J=8.0, 2.0 Hz); 4.63 (m, 1H); 4.38 (m, 3H); 3.70 (s, 3H); 3.65 (m, 1H); 2.74 (s, 3H); 2.65 (m, 1H); 1.79 (m, 2H); 1.63 (m, 4H); 1.49 (m, 2H). IR (KBr, cm-1) 3420, 3320, 2950, 1730,1715, 1530,1515, 1235, 1135.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23](O)=[O:24])=[N:11][CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:47][C:48]([CH3:53])([CH3:52])[C:49]([OH:51])=[O:50]>CN(C=O)C>[CH3:26][O:50][C:49](=[O:51])[C:48]([NH:47][C:23]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][N:11]=1)=[O:24])([CH3:53])[CH3:52]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(N)C(=O)O
Reactant: O=C(O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (1.0 g, 2.99 mmol) in DMF (20 mL) at room temperature under N2 is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.925 g, 5.97 mmol) and 1-hydroxybenzotriazole (HOBt) (0.806 g, 5.97 mmol). The mixture is stirred for 15 minutes after which α-aminoisobutyric acid (0.917 g, 5.97 mmol) and diisopropylethyl-amine amine (DIPEA) (1.56 mL, 8.96 mmol) are added. The resulting solution is stirred at room temperature for 16 hours then concentrated under reduced pressure. The resulting brown oil is purified over silica (EtOAc:heptane 1:1) to afford 0.58 g (45% yield) of the desired compound as a colorless solid. 1H NMR (250 MHz, CDCl3) δ ppm 8.13 (1H, s), 8.02 (1 H, d, J=2.3 Hz), 7.31-7.48 (10H, m), 6.90 (1H, d, J=2.3 Hz), 5.19 (2H, s), 5.10 (2H, s), 3.74 (3H, s), 1.58 (6H, s). HPLC-MS: m/z 435 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:31]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:38].[Cl:39][CH2:40][C:41](Cl)=[O:42]>C1(C)C=CC=CC=1>[C:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:12]1[C@@H:11]2[C@H:15]([C@H:7]([CH2:6][C:5]3[CH:30]=[C:31]([O:32][CH2:33][C:34]([F:36])([F:37])[F:35])[C:2]([NH:1][C:41](=[O:42])[CH2:40][Cl:39])=[C:3]([F:38])[CH:4]=3)[CH2:8][S:9](=[O:29])(=[O:28])[CH2:10]2)[O:14][C:13]1=[O:16])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(OCC(F)(F)F)c4)CS(=O)(=O)C[C@@H]32)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(NC(=O)CCl)c(OCC(F)(F)F)c4)CS(=O)(=O)C[C@@H]32)c1

Procedure:
The title compound was prepared in analogous manner as described for example 8p) from (3aR,7S,7aS)-7-[4-amino-3-fluoro-5-(2,2,2-trifluoro-ethoxy)-benzyl]-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (400 mg, 0.716 mmol) and chloroacetylchloride (324 mg, 2.86 mmol) to yield a white foam: TLC Rf=0.40 (toluene-ETA 85:15); ESIMS [M+NH4]+=652, 654, [M−H]−=633, 635; UPLC RtD=1.861 min; 1H NMR (600 MHz, DMSO-d6): δ 9.64 (s, 1H, NH), 7.41 (s, 1H), 7.33 (d, 1H), 7.28 (t, 1H), 7.13 (d, 1H), 6.91 (s, 1H), 6.88 (d, 1H), 4.74 (q, 2H), 4.43 (d, 1H), 4.25-4.18 (m, 4H), 3.78 (d, 1H), 3.65 (t, 1H), 3.50 (t, 1H), 3.17 (t, 1H), 2.99 (m, 2H), 2.56 (m, 2H), 1.25 (s, 9H).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[C:2]#[CH:3].[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:2](=[CH2:3])[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C(=O)OCc1ccccc1)[Sn](CCCC)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 6.42 g (40.1 mmol) of benzyl propiolate from step A above in 25 ml of anhydrous THF was added 0.93 g (0.80 mmol) of tetrakis(triphenylphosphine)palladium(0) followed by a solution of 12.6 g (42.1 mmol) of tributyltin hydride in 25 mL of anhydrous THF over 15 min. After stirring at room temperature overnight the solvent was removed under reduced pressure. The residue was filtered through a pad of Celite® which was then washed with hexanes. The filtrate was concentrated in vacuo and the crude product was purified by silica gel chromatography eluting with a 0-15% ethyl acetate in hexane gradient to afford the title compound as a colorless oil (13 g, 73%). 1H NMR (CDCl3, 500 MHz) δ 7.39 (m, 5H), 6.99 (d, J=2.7 Hz, 1H), 5.98 (d, J=2.7 Hz, 1H), 5.20 (s, 2H), 1.47 (m, 6H), 1.30 (m, 6H), 0.96 (m, 6H), 0.89 (t, J=7.4 Hz, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][N:10]1[CH3:18].[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]3[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[O:36])[N:33]=3)[CH:30]=2)=[C:22]([F:42])[CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:20]([NH:19][C:15]([C:12]5[C:13](=[O:14])[N:9]([C:3]6[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=6[Cl:1])[N:10]([CH3:18])[CH:11]=5)=[O:17])=[CH:21][C:22]=4[F:42])=[CH:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1c(Cl)cccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1c(Cl)cccc1Cl
Yield: 72 %

Procedure:
In the same manner as in Example 46 and using 2-(2,6-dichlorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (370 mg, 1.3 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (250 mg, 0.77 mmol), HATU (490 mg, 1.3 mmol), N,N-diisopropylethylamine (340 mg, 2.6 mmol) and N,N-dimethylformamide (15 mL) as starting materials, the title compound (330 mg, 72%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([N:8]([C:10]([CH3:30])([CH3:29])[CH2:11][CH2:12][C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH2:16])=[O:15])C)C1C=CC=CC=1>CO.C(O)=O.[Pd]>[C:17]1([C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:12][CH2:11][C:10]([CH3:30])([NH:8][CH3:1])[CH3:29])[C:14]([NH2:16])=[O:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1ccccc1)C(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CNC(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10% Palladium-on-carbon was added to a solution of 5-(N-benzyl-N-methylamino)-2,2-diphenyl-5-methylhexanamide (0.6 g--see Example 3) in methanol (19 ml) and formic acid (1 ml). The mixture was stirred at room temperature for 16 hours then filtered and the filtrate concentrated in vacuo to give the title compound as a gum, yield 0.4 g.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2].[CH2:20]([NH2:23])[C:21]#[CH:22]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:23][CH2:20][C:21]#[CH:22])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2]
Reactant: C#CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ncccc1Cl
Solvent: CC#N
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1ncccc1Cl
Reaction time: 16 h

Procedure:
A solution of 1-nitro-2-methylthio-2-{2-[(3-chloro-2-pyridyl)methylthio]ethylamino}ethylene (0.61 g; 1.91 mmoles) [prepared according to the procedure described in U.S. Pat. No. 4,024,260] and propargylamine (1.72 g; 31.2 mmoles) in acetonitrile (15 ml) was stirred and heated to reflux temperature under a positive pressure of nitrogen for 7 hours then allowed to stand at ambient temperature for 16 hours. The reaction mixture was filtered and 346 mg of product collected. Recrystallization from methanol with activated carbon treatment gave the title compound; mp 171°-171.5°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([O:29][CH3:30])[CH2:24]2)[CH:3]=1.[NH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:31])=[O:21])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([O:29][CH3:30])[CH2:24]2)[CH:3]=1
Reactant: N
Reactant: CO[C@H]1CCC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Product: CO[C@H]1CCC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1

Procedure:
Prepared analogously to example 1.4 from 0.15 g racemic racemic 4-[4-Fluoro-2-((trans)-3-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia (7 M in methanol).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:22][CH2:21][N:20]([CH:23]([Cl:26])[CH2:24][CH3:25])[CH2:19][CH2:18]1>>[ClH:26].[O:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:14]2[C:13]([CH3:16])=[CH:12][CH:11]=[C:10]3[C:15]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][NH:9]3)[CH2:24][CH3:25])[CH2:19][CH2:18]1
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: CCC(Cl)N1CCOCC1
Product: CCC(c1c(C)ccc2[nH]nc(-c3ccccc3)c12)N1CCOCC1
Product: Cl
Yield: 55.1 %

Procedure:
By the procedure similar to that described in Example 13, 3-phenyl-5-methylindazole (4.17 g) and 1-morpholinopropyl chloride (3.93 g) were treated to obtain 4.1 g of 1-morpholinopropyl-3-phenyl-5-methylindazole hydrochloride (m.p. 180°-182° C).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[NH2:24][C:25]1([C:30]([OH:32])=[O:31])[CH2:29][CH:28]=[CH:27][CH2:26]1>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][NH:24][C:25]4([C:30]([OH:32])=[O:31])[CH2:29][CH:28]=[CH:27][CH2:26]4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: NC1(C(=O)O)CC=CC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CC=CC1

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with 1-aminocyclopent-3-ene carboxylic acid using an analogous method to that described for the equivalent step in Example 1 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopent-3-ene-1-carboxylic acid; 1H NMR Spectrum: (DMSO-d6) 2.63 (d, 2H); 2.93 (d, 2H); 3.91 (s, 2H); 3.97 (s, 3H); 5.68 (s, 2H); 7.21 (s, 1H); 7.27 (t, 1H); 7.50 (m, 2H); 8.45 (s, 1H); 8.50 (s, 1H); 10.09 (s, 1H); Mass Spectrum: (M+H)+ 443.
Reaction SMILES: [OH-:1].[Na+:2].[C:3]1(=[O:9])[O:8][C:6](=[O:7])[CH:5]=[CH:4]1>O>[C:3]([O-:8])(=[O:9])/[CH:4]=[CH:5]\[C:6]([O-:1])=[O:7].[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
Eight parts by weight of sodium hydroxide and 9.8 parts by weight of maleic anhydride are added to 100 parts by weight of water to obtain a homogeneous solution of disodium maleate. On addition of 10.4 parts by weight of sodium bisulfite to the foregoing solution and stirring, the reaction proceeds exothermically. After the evolution of heat has settled down, the stirring is continued for a further 3 hours at 60°C. A rotary evaporator is then used and the water is removed from the reaction mixture to obtain 26.4 parts by weight of a white powder of trisodium sulfosuccinate.
Reaction SMILES: Br[C:2]1[N:10]=[C:9]2[N:4]([CH:5]=[N:6][C:7]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[C:8]2[CH2:11][CH2:12][CH3:13])[N:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[F:26][C:25]1[C:20]([C:16]2[N:15]([CH2:14][C:7]3[N:6]=[CH:5][N:4]4[N:3]=[C:2]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[N:10]=[C:9]4[C:8]=3[CH2:11][CH2:12][CH3:13])[CH:19]=[CH:18][N:17]=2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: C1CCNC1
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(Br)nc12
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(N3CCCC3)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 175 (77 mg, 0.185 mmol) and pyrrolidine (0.5 ml) is stirred at room temperature for 4 hours. The solvent is removed in vacuo and the residue is partitioned between water (5 ml) and EtOAc (5 ml). The layers are separated and the aqueous layer is extracted with EtOAc (2×5 ml). The combined extracts are washed with brine (5 ml), dried (Na2SO4) and evaporated. PTLC separation of the residue with 5% MeOH in CH2Cl2 gives the title compound 173 as a white solid. H1 NMR (δ, CDCl3): 8.84 (s, 1H), 8.40 (m, 1H), 7.51–7.56 (m, 1H), 7.21–7.31 (m, 2H), 7.18 (s, 1H), 5.76 (s, 2H), 3.53–3.57 (m, 4H), 2.80–2.84 (m, 2H), 1.99–2.02 (m, 4H), 1.58–1.64 (m, 2H), 0.93 (t, 3H). LC-MS (M+1), 407.10.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:15]=1[OH:21].[N:22]1([C:28]2[N:29]=[C:30]([CH2:35][C:36]([O-])=[O:37])[NH:31][C:32](=[O:34])[CH:33]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[Na+]>N1C=CC=CC=1>[Br:20][C:16]1[C:15]([OH:21])=[C:14]([NH:13][C:36](=[O:37])[CH2:35][C:30]2[NH:31][C:32](=[O:34])[CH:33]=[C:28]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:29]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(Br)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.3 %

Procedure:
600 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 550 mg of 2-amino-6-bromophenol are added to a solution of 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 4 ml of pyridine. The reaction mixture is stirred at ambient temperature for 20 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 543 mg of N-(3-bromo-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([CH:20]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:19][CH:18]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccncc1
Reactant: COc1ccccc1
Agent: O=S(=O)(O)O
Product: COc1ccc(C(c2ccncc2)c2ccc(OC)cc2)cc1
Temperature: 70 °C

Procedure:
Anisole, 108.13 g (1.0 mole) was cooled in an ice bath. Concentrated sulfuric acid, 115.3 ml (2.0 mole) was added while stirring the mixture in an ice bath. The temperature rose to 55° C. The reaction was then cooled in the ice bath. To this solution was added 4-pyridine carboxaldehyde, 53.5 g (0.5 mole). The temperature rose to 95° C. and further cooling and stirring brought the temperature down to 20° C. The reaction mixture was heated to 70° C. for 31/2 hr. The red gel was made alkaline with 50% sodium hydroxide-ice mix. The alkaline phase was extracted with toluene and the toluene extracted with a saturated sodium chloride solution. The product crystallized from the toluene solution while standing at room temperature. The white solid can be recrystallized from hot hexane-isopropyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17](O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1C(O)c2ccccc2OC1c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1=Cc2ccccc2OC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 105.4 %

Procedure:
Methyl 2-(3,4-dichlorophenyl)-4-hydroxychroman-3-carboxylate (90 mg) and p-toluenesulfonic acid hydrate (24 mg, 128 μmol) were dissolved in toluene (4.0 mL) and heated to reflux. After 40 min, the solution was cooled to rt, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to provide racemic methyl 2-(3,4-dichlorophenyl)-2H-chromene-3-carboxylate as a white solid (90 mg, 94%). 1H NMR (400 MHz, CDCl3) δ ppm 3.79 (s, 3 H) 6.21 (s, 1 H) 6.81 (d, J=8.1 Hz, 1 H) 6.93 (t, J=7.6 Hz, 1 H) 7.17-7.25 (m, 3 H) 7.35 (d, J=8.6 Hz, 1 H) 7.44 (d, J=2.0 Hz, 1 H) 7.70 (s, 1 H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:13].[Na+].Cl.[NH2:16]O>C(O)C.O>[C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[N:16][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCC1c1ccccc1
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
Scheme IA, step A: 2-Phenyl-cyclopentanone (prepared according to R. Sudha et. al. J. Org. Chem., 61, 1877-1879, 1996) (1.0 g, 6.2 mmol) was dissolved in 20 mL of absolute ethanol. To this solution was added sodium hydroxide (0.5 g, 12.5 mmol) dissolved in 10 mL water followed by hydroxylamine hydrochloride (0.65 g, 9.36 mmol) and stirred overnight at room temperature. The reaction was diluted with water and the precipitate collected by filtration. The white solid was vacuum oven-dried at 35° C. for 30 minutes to give 0.75 g (69%) of the title compound. The NMR was consistent with the assigned structure.
Reaction SMILES: C1(CC[CH2:9][NH2:10])C=CC=CC=1.[CH3:11][CH:12]([CH3:17])[CH2:13][C:14](O)=[O:15].[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][N:19]1[C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=O)=[CH:32][CH:31]=1)=[O:28]>>[CH3:11][CH:12]([CH3:17])[CH2:13][C:14]([NH:10][CH2:9][CH2:34][C:33]1[CH:37]=[CH:38][C:30]([NH:29][C:27]([N:19]2[CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18]2)=[O:28])=[CH:31][CH:32]=1)=[O:15]
Reactant: NCCCc1ccccc1
Reactant: CC(C)CC(=O)O
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: CC(C)CC(=O)NCCc1ccc(NC(=O)N2Cc3ccccc3C2)cc1

Procedure:
The title compound was prepared as described in Example 1C, substituting N-(4-(2-aminoethyl)phenyl)isoindoline-2-carboxamide for 3-phenylpropan-1-amine and 3-methylbutanoic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6, Temp=90° C.) δ 7.50-7.40 (m, 2H), 7.40-7.24 (m, 4H), 7.13-7.02 (m, 2H), 4.76 (s, 4H), 2.68 (t, J=7.3 Hz, 2H), 2.07-1.84 (m, 3H), 0.95-0.76 (m, 6H). MS (ESI (+)) m/e 366 (M+H)+.