Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)[NH:3]1.[CH2:24]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:32]([N:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]1)=[CH:5][CH2:6]3)=[O:23])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)N(Cc1ccccc1)Cc1ccccc1
Yield: 71 %

Procedure:
The title compound was prepared in a yield of 71% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and N,N-dibenzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[SH:20][CH2:21][C:22]([OH:24])=[O:23]>CN(C)C=O>[C:22]([CH2:21][S:20][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([Cl:1])[CH:12]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SCC(=O)O)cc1Cl
Temperature: 80 °C

Procedure:
A mixture containing ethyl 2,4-dichlorobenzoate (10.0 g), potassium carbonate (9.44 g), dimethylformamide (50 ml), and mercaptoacetic acid (3.8 ml) was allowed to react with heat at 80° C. for 4 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[P:9]([O-:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH2:11]([O:10][P:9]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: CCOP([O-])OCC
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1ccc(F)cc1
Temperature: 90 °C
Yield: 61.7 %

Procedure:
4-Bromo-fluorobenzene (10.95 g, 62.57 mmol) was added to diethyl phosphite (8.86 mL, 68.8 mmol) at ambient temperature, followed by the addition of triethylamine (9.6 mL, 68.8 mmol). The resulting solution was degassed with nitrogen followed by the addition of tetrakis(triphenylphosphine)-palladium (3.0 g, 2.6 mmol). The resulting mixture was heated at 90° C. overnight. The reaction mixture was allowed to cool to ambient temperature and then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) and then with saturated brine (2×350 mL). The crude product was purified by vacuum distillation (ca. 98° C., 0.6 Torr) to yield 8.956 g of 4-fluorophenyl-phosphonic acid diethyl ester (38.6 mmol, 94% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.88-7.80 (m, 2H); 7.20-7.14 (m 2H); 4.22-4.04 (m, 4H); 1.36-1.32 (t, 6H); ESMS (m/z): M+1)+ found, 233.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=1>>[C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)(=[O:11])=[O:10])#[N:33]
Reactant: N#Cc1ccccc1CBr
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(Cc2ccccc2C#N)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)-benzoate (Example 5-10b) and alpha-bromo-o-tolunitrile. MS(M−H, 435.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.664 (s, 2H), 4.348 (s, 2H), 4.498 (s, 2H), 6.728 (d, 2H, J=8.4 Hz), 7.036 (d, 2H, j=8.4 Hz), 7.352 (t, 2H, J=9.2 Hz), 7.548 (t, 1H, J=7.6 Hz), 7.640 (d, 1H, J=7.6 Hz), 8.003 (d, 2H, J=8 Hz), 8.139 (d, 2H, J=8.4 Hz), 13.559 (s, broad, 1H).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[CH3:5][O:6][C:7]1[C:8]([OH:22])=[C:9]([C:14]([N+:19]([O-:21])=[O:20])=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:5][O:6][C:7]1[C:8]([O:22][CH:2]([CH3:4])[CH3:3])=[C:9]([C:14]([N+:19]([O-:21])=[O:20])=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1OC(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
2-Iodopropane (0.5 ml, 0.005 mol) was added to a suspension of methyl 3,4-dimethoxy-2-hydroxy-6-nitrobenzoate (1 g, 0.0039 mol) and sodium carbonate (1.6 g, 0.015 mol) in dimethylformamide (15 ml) and the reaction stirred at 60° C. for 2 hours. On cooling, the reaction was concentrated under reduced pressure and the residue partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was further extracted with ethyl acetate (2×25 ml), the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure to give the subtitle compound as a crystalline solid (1.1 g, 74%). 1H-NMR (CDCl3): Γ=1.28 (6H, d), 3.94 (9H, m), 4.72 (1H, m), 7.49 (1H, s).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[CH3:23]>N1C=CC=CC=1>[CH3:23][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[CH2:16][CH2:15][C:14]1[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=1[NH:12][C:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCCCC1CCc1ccccc1N
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Product: CN1CCCCC1CCc1ccccc1NC(=O)C=Cc1ccccc1
Reaction time: 3 h
Yield: 70 %

Procedure:
Cinnamoyl chloride (6.0 g., 0.036 mole) is added to a solution of 2-(o-aminophenethyl)-1-methylpiperidine (7.8 g., 0.036 mole) in 100 ml. of pyridine in one portion with vigorous stirring. Stirring is continued for 3 hours and the pyridine solution is then concentrated in vacuo. The resulting residue is taken up in 150 ml. of water and made basic with 40% sodium hydroxide. The basified solution is extracted with several 200 ml. portions of ether, which are combined, washed with water, dried over magnesium sulfate and the ether solvent evaporated. The residue thus obtained crystallizes and is further purified by crystallizing from isopropyl ether providing 8.7 g. (70% yield) of analytically pure 2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide melting at 101.5° -103.5° C. (corr.).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][CH:6]=1)(=O)[CH3:2].B#B>>[CH2:1]([NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][CH:6]=1)[CH3:2]
Reactant: CC(=O)Nc1cccc(C)n1
Agent: B#B
Product: CCNc1cccc(C)n1

Procedure:
The process for producing 6-ethylamino-2-picoline which comprises reacting 6-acetamido-2-picoline with diborane in an inert non-polar solvent at about 0° to 70° C. to produce 6-ethylamino-2-picoline and using a low boiling petroleum solvent to separate the soluble 6-ethylamino-2-picoline from the insoluble 6-acetamido-2-picoline.
Reaction SMILES: [CH3:1][N:2]([O:23][CH3:24])[C:3](=[O:22])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]([O:23][CH3:24])[C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH3:27])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CON(C)C(=O)c1cc(O)ccc1NC(=O)OCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(NC(=O)OCc2ccccc2)c(C(=O)N(C)OC)c1
Temperature: 0 °C

Procedure:
An N,N-dimethylformamide (8 ml) solution of N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-hydroxybenzamide (0.8 g), methyl iodide (0.2 g) and potassium carbonate (0.5 g) was stirred for 3 hours at 60° C. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The organic layer was washed with water, which was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give N-methyl-N-methyloxy 2-benzyloxycarbonylamino-5-methyloxy-benzamide as a yellow oily product (0.55 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:51])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:38][CH:39]=[C:40]([CH2:42][O:43]C3CCCCO3)[N:41]=2)[CH:32]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[O:38][CH:39]=[C:40]([CH2:42][OH:43])[N:41]=4)[CH:32]=3)[CH2:29][C:28](=[O:51])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.23 g) (Example J27) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.31 g) (Example K11) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.18 g).
Reaction SMILES: [Na].[NH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[NH2:3].[C:10](#[N:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[NH2:19][C:10]1[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[N:3]=1
Reactant: N#CC=Cc1ccccc1
Reactant: NNc1ccccn1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccccn2)C(c2ccccc2)C1

Procedure:
A 1.02 g. amount of sodium metal is dissolved in 250 ml. of absolute ethanol, then 21.82 g. of 2-hydrazinopyridine is added, followed by 25.8 g. of cinnamonitrile. The reaction mixture is refluxed for 16 hours, then the solvent is removed in vacuo. Water is added and the solid is collected by filtration. The solid is recrystallized from 3A ethanol to yield 20.32 g. of the desired product as yellow crystals, m.p. 203°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([OH:21])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[O:28][N:27]=[C:26]([CH2:29][NH2:30])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[N:12][CH:11]=[C:10]([CH:9]=2)[C:19]([NH:30][CH2:29][C:26]2[CH:25]=[C:24]([C:23]([F:32])([F:31])[F:22])[O:28][N:27]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: NCc1cc(C(F)(F)F)on1
Product: O=C(NCc1cc(C(F)(F)F)on1)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CAN 1018782-76-7) and 5-trifluoromethyl-isoxazol-3-methanamine (example BF) as starting materials; LC-MS (UV peak area/ESI) 98%, 452.0975 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([OH:13])[CH:4]=1.[CH2:14]([C:23]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(O)[C:24]#[CH:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C1(C)C=CC=CC=1>CCCCCC>[CH2:14]([C:23]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[O:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:12]3[C:7]([C:6]=2[CH:25]=[CH:24]1)=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1
Reactant: C#CC(O)(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reactant: COc1cc(O)cc2ccccc12
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(CC2(Cc3ccc(OC)cc3)C=Cc3c(cc(OC)c4ccccc34)O2)cc1
Reaction time: 1.5 h

Procedure:
A mixture of 4-methoxy-2-naphthol (0.26 g; 0.015 mol). 1,1-dianisylprop-2-yn-1-ol (0.40 g g;0.0015 mol), acidic alumina Brockmann 1 (3.5 g) and toluene (40.0 ml) was heated and stirred for 1.5 h, cooled, filtered. The filtrate was washed with 2M NaOH then water, dried and evaporated to give an orange gum. Trituration with hexane yielded 3,3-dianisyl-6-methoxy-3H-naphtho[2,1-b]pyran of formula (1) below as an off-white solid (41%). Crystallisation from hexane and ethylacetate gave the pyran as white micro-platelets, m.pt. 158°-160° C. ##STR8##
Reaction SMILES: F[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([NH2:22])(C)(C)C.O>O1CCOCC1>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:3]([N+:15]([O-:17])=[O:16])=[C:2]([NH2:22])[CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1-c1ncccn1
Reactant: CC(C)(C)N
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(F)cc(-c2ncccn2)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of 2-(3,5-difluoro-2-nitro-phenyl)-pyrimidine (1.5 g, 6.32 mmoles) in dioxane (10 mL) was added tBuNH2 (6.6 mL, 63.24 mmoles) at room temperature. The mixture was heated to 100° C. in a sealed tube for 10 hours. The mixture was then cooled to room temperature, poured into water, and the solids stirred for 1 hour. The mixture was filtered, solids washed with water until filtrate was clear. The crude product was then diluted in MeOH, 6NHCl added, and the resulting mixture heated at reflux for 3 hours. The reaction was cooled to room temperature and poured into ice. The resulting heterogeneous mixture was warmed to room temperature, filtered, solids washed with water until filtrate ran clear, and dried in vacuo to afford the title compound (1.33 g, 90%) as an orange powder. 1H NMR (dmso-d6, 500 MHz): 8.87 (d, 2H); 7.52 (dd, 1H); 7.08 (dd, 1H); 6.86 (dd, 1H); 6.60 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]([OH:14])=[O:13].S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]([O:14][CH3:19])=[O:13]
Reactant: CO
Reactant: O=C(O)c1cccc2cc(Cl)ncc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2cc(Cl)ncc12
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A 20 mL microwave vial was charged with 3-chloroisoquinoline-8-carboxylic acid (1 g, 4.82 mmol) in 5 mL of MeOH and then was added with thionyl chloride (0.703 mL, 9.63 mmol). Stirred at 65° C. overnight and then concentrated in vacuo. Purified by silica gel chromatography (0-50% EtOAc in hexane) yielded Methyl 3-chloroisoquinoline-8-carboxylate (27-1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2Cl)[CH:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[N:3]=1>CO.[Pd]>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[CH:5]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CN1CCN(c2cc(-c3sccc3Cl)nc(Cl)n2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2cc(-c3cccs3)nc(Cl)n2)CC1
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-4-(3-chloro-thiophen-2-yl)-6-(4-methyl-piperazin-1-yl)-pyrimidine (30 mg, 0.1 mmol) in methanol (2 mL) was added 10% Pd/C (15 mg). The resulting mixture was stirred under hydrogen balloon overnight. Palladium on carbon was removed through Celite® filtration. The filtrate was dried and purified by TLC plate to yield the title compound as a solid.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.CN(C)C=O>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][C:4]([S:7][CH2:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Sc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CSc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a solution of 4-biphenylthiol (2.79 g., 0.015 mole) in dry tetrahydrofuran (30 ml) and dimethylformamide (6 ml) was added portionwise sodium hydride (0.37 g., 0.015 mole) with stirring under a nitrogen atmosphere. The resulting solution was added dropwise over 45 min. to ethyl bromopyruvate (3.0 g, 0.015 mole) in dry tetrahydrofuran (30 ml) with stirring under nitrogen at -7° to -10° C. After 1 hr. at 25° C. ice-water (250 ml) was added. Extraction with methylene chloride (3×50 ml) followed by evaporation of the extract, and recrystallization of the residue from carbon tetrachloride gave 1.56 g (35%) of ethyl 3-(4-biphenylylthio)-2-oxopropionate, m.p. 154.5°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(2-methoxyphenyl)benzoate (1.34 g, 2.8755 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (20 ml) and 1,4-dioxane (40 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (200 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (1.21 g, 2.6769 mmol, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32]CC)=[O:31])=[CH:26][CH:25]=2)=[O:22])[CH2:17][CH2:16]1.O.[OH-].[Li+].O>O1CCOCC1>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:22])=[CH:25][CH:26]=1)([OH:32])=[O:31]
Reactant: CCOC(=O)c1ccc(NC(=O)N2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(C(=O)O)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100 %

Procedure:
To a solution of 390 mg (0.84 mmol) of 4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-ethoxycarbonylphenyl)-1-piperazinecarboxamide obtained in Example 89 in 10 ml of 1,4-dioxane were added 70.4 mg (1.68 mmol) of lithium hydroxide monohydrate and 1 ml of water, followed by stirring at room temperature for 4.5 hours. To the resulting mixture was further added 70.4 mg (1.68 mmol) of lithium hydroxide monohydrate, followed by overnight stirring at room temperature. After the solvent was evaporated, water was added to the residue, and the resulting mixture was adjusted to pH 4 with 4 N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel column chromatography to give the desired compound as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[CH3:14][O:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[C:3]1[N:15]=[C:16]([NH2:18])[S:17][CH:2]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Solvent: CCO
Product: COc1ccc(-c2csc(N)n2)c(OC)c1
Yield: 82.7 %

Procedure:
A mixture of 2-bromo-1-(2,4-dimethoxyphenyl)ethanone (14.5 g, 55.8 mmol) and thiourea (4.32 g, 56.7 mmol) in 95% EtOH (110 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,4-dimethoxyphenyl)thiazol-2-amine (10.9 g) as yellow solids in 62% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 2 H), 7.53 (s, 1 H), 6.97 (s, 1 H), 6.69 (s, 1 H), 6.67-6.63 (m, 1 H), 3.86 (s, 3 H), 3.80 (s, 3 H).
Reaction SMILES: [O:1]=[C:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[OH:1][CH:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1
Reactant: O=C1CCC2=C(C1)c1ccccc1Oc1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OC1CCC2=C(C1)c1ccccc1Oc1ccccc12

Procedure:
6.2 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are added to a suspension of 3.7 g of lithiumaluminiumhydride in 300 ml of dry ether. After refluxing for 2 hours 14.8 ml of water are added carefully. The suspension obtained is filtered off and after that the filtrate is dried and evaporated to dryness.
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[N:24]1C(=O)C(=CC2C=CC=CC=2)S[C:25]1=[S:37])(=O)C.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CO>[C@@H:6]1([NH:24][C:25]([N:42]2[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)=[S:37])[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: CN1CCNCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](N2C(=O)C(=Cc3ccccc3)SC2=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Product: CN1CCN(C(=S)N[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-5-benzylidenerhodanine(1.102 g., 0.002 mole) was added to a solution of N-methylpiperazine(2.40 g., 0.024 mole) in 50 ml. of methanol in a pressure bottle. The reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered and the filtrate was evaporated to a brownish heavy syrup below 30° in vacuo. The residual syrup was dissolved in the minimum amount of acetone, and anhydrous ether was added to the solution to give a sticky precipitate. The supernatant was decanted, and the residual solid was dissolved in the minimum amount of methanol. Anhydrous ether was added to the solution to give a yellow precipitate. The solid was filtered, partially dissolved in ethyl acetate, and then chromatographed on a column of silica gel(1×20 cm) using ethyl acetate as the first solvent(50 ml.) and methanol as the second solvent(200 ml.). The 200 ml. of methanol effluent was reduced to ca. 20 ml. and was set aside at 5° for 24 hours. The white precipitate was filtered, washed with methanol, and dried at room temperature in vacuo, yielding 0.325 g.(50.6%); m.p. 175°-177°(dec.).