Azzindani/Open_Reaction_Data huggingface dataset:
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: C#CC(=O)OCc1ccccc1
Reactant: CCCC[SnH](CCCC)CCCC
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 in 25 ml of anhydrous TI-IF 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: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:14])[C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].[H-].[Na+].C1C=CC=CC=1.Cl[N:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[NH:25]1>O>[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:14][N:24]2[N:25]=[C:26]([O:32][CH3:33])[CH:27]=[C:28]([O:30][CH3:31])[NH:29]2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)c1c(O)cccc1C(C)=O
Reactant: COC1=CC(OC)=NN(Cl)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1c(ON2N=C(OC)C=C(OC)N2)cccc1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.6 %

Procedure:
1.0 g of methyl 6-acetylsalicylate was added to a suspension solution of 0.23 g of sodium hydride and 30 ml of benzene, and the resultant mixture was stirred for 10 minutes at room temperature. 0.95 g of 2-chloro-4,6-dimethoxytriazine was added to the resultant mixture, and the mixture was stirred for one day and one night at room temperature. After completing the reaction, the reaction liquor was poured into water, and was extracted with ethyl acetate. The extracted product was washed with water, dried and concentrated to obtain a crystal. The product thus obtained was purified by column chromatography to obtain 1.15 g of the aimed compound (melting point=151° to 156° C.) at a yield of 67%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])/[C:8]([O:10]CC)=[O:9])[N:6]=1.O.[OH-].[Na+]>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCC(=O)N1CCCCC1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1nc(/C(=N/OCC(=O)N2CCCCC2)C(=O)O)cs1
Reaction time: 48 h
Yield: 78.1 %

Procedure:
77.2 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[(1-piperidinecarbonyl)methoxy]imino]-acetate are dissolved in 3 l of methanol and 265 ml of water and the solution is treated with 250 ml of 1N aqueous sodium hydroxide solution. The saponification is complete after 48 hours. 500 ml of water are added thereto and the methanol is removed under reduced pressure. The aqueous solution is washed with ethyl acetate, treated with 250 ml of 1N aqueous hydrochloric acid and concentrated to half of the volume. The acid which crystallizes out is filtered off and dried. There are obtained 55.3 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-[(1-piperidinecarbonyl)methoxy]imino]-acetic acid of melting point 177° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:27])[CH:17]=3)[CH2:13][CH:12]([C:28]([OH:30])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:32]=[C:33]([NH2:38])[CH2:34][CH2:35][O:36][CH3:37]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[C:18]([CH3:27])[CH:17]=3)[CH2:13][CH:12]([C:28]3[O:30][N:38]=[C:33]([CH2:34][CH2:35][O:36][CH3:37])[N:32]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: COCCC(N)=NO
Reactant: Cc1cc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)ccc1OC(F)(F)F
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)c(C)c3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
100 mg (0.221 mmol) of the compound from Example 170A and 52 mg (0.331 mmol) of the compound from Example 64A were reacted according to the General Method 2. Yield: 39 mg (35% of theory)
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CC1N([C:26]([CH2:28][C:29]#[N:30])=[O:27])N=C(C)C=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:27]=[C:26]([N:1]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1)[CH2:28][C:29]#[N:30]
Reactant: c1nc(N2CCCC3(CCCN3)C2)c2cc[nH]c2n1
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CCCC12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 110 °C
Reaction time: 1.25 h
Yield: 84.6 %

Procedure:
4-(1,7-Diazaspiro[4.5]dec-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (30 mg) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (38 mg), N,N-diisopropylethylamine (42 μl) and 1,4-dioxane (1 ml), and the mixture was stirred at 110° C. for 75 minutes. The mixture was cooled to room temperature, and then thereto was added saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=1/2, followed by chloroform/methanol=25/1 to 20/1) to give the titled compound (32 mg).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N:10]1([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl.C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH2:20][CH:15]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: BrCc1ccc(I)cc1
Solvent: CCO
Solvent: ClCCl
Product: Ic1ccc(CN2CCC(N3CCCC3)CC2)cc1

Procedure:
Prepared analogously to Example 1.1.c. from 4-iodobenzyl bromide and 4-pyrrolidin-1-ylpiperidine. Yield: 0.57 g (51% of theory); C16H23IN2 (M=370.28); calc.: molecular ion peak (M+H)+: 371; found: molecular ion peak (M+H)+: 371; Rf value: 0.3 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[N:9][CH:10]=1>O1CCCC1.C(O)C>[CH3:1][N:2]([CH3:3])[C:5]1[CH:10]=[N:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)c1ccc([N+](=O)[O-])nc1
Temperature: 140 °C

Procedure:
6 ml of a 2M solution of dimethylamine in tetrahydrofuran are added to a solution of 1 g of 5-bromo-2-nitropyridine in 5 ml of ethanol. The reaction mixture is heated at 140° C. for 2 hours in a microwave device. After cooling, the solid formed is separated off and washed with ethyl ether to give 850 mg of N,N-dimethyl-6-nitropyridine-3-amine in the form of a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH2:15][CH3:16])([F:14])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>Cl.C(O)(C)C>[CH:17]1([N:7]2[CH2:8][C:9]([CH2:15][CH3:16])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCC1(F)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CC(C)O
Product: CCC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Temperature: 100 °C
Reaction time: 20 h
Yield: 82.7 %

Procedure:
A mixture of 2-chloro-9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (630 mg, 1.93 mmol), 4-amino-3-methoxybenzoic acid (484 mg, 2.9 mmol), isopropanol (20 ml), and concentrated hydrochloric acid (10 drops) was stirred at 100° C. for 20 h. Solid was filtered to give 730 mg product as white solid (83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.3 Hz, 3 H) 1.56 (br. s., 3 H) 1.67-1.96 (m, 6 H) 3.28 (s, 3 H) 3.74-3.92 (m, 3 H) 3.94 (s, 3 H) 4.91 (t, J=7.8 Hz, 1 H) 7.21-7.43 (m, 1 H) 7.47-7.69 (m, 2 H) 8.13 (d, J=8.1 Hz, 1 H) 8.24 (s, 1 H) 9.32 (br. s., 1 H). [M+H] calc'd for C23H28FN5O4, 458; found 458.
Reaction SMILES: [OH-].[Na+].O.[C:4]1([CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[OH:5].[Cl:12][C:13]1[CH:14]=[C:15]([F:20])[C:16](F)=[N:17][CH:18]=1>CS(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]([F:20])[C:16]([O:5][C:4]2[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=2)=[N:17][CH:18]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Reaction time: 0.33 h
Yield: 26.1 %

Procedure:
A solution of NaOH (1.76 g, 0.044 mol) in a few ml of water was added to hydroquinone (4.86 g, 0.040 mol) in 250 ml DMSO. The mixture was stirred under nitrogen for 20 minutes. 5-Chloro-2,3-difluoropyridine (6.0 g, 0.040 mol) was added. The reaction mixture was heated at 60°-70° C. for 3 hours, then poured over ice. Aqueous NaOH was added to pH 12 and the solid diether side-product was filtered off. The filtrate was acidified, extracted with ether, treated with Norite adsorbent, and the solvent was removed by rotary evaporation to give a yellow oil which solidified on standing and was purified by high pressure liquid chromatography (HPLC) (80% hexane/20% ethyl acetate) to give a white solid (2.5 g, 26% yield, m.p. 90°-92° C.).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:21][S:29]([CH3:28])(=[O:31])=[O:30])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)c1cn2c3c(c(O)c(F)cc3c1=O)CCN2C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cn2c3c(c(OS(C)(=O)=O)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
304 mg of the compound (167) obtained in Example 44 was added to 2 ml of pyridine, and 120 mg of methane-sulfonyl chloride was added to the solution. The solution was stirred for 3 hours at room temperature. 50 ml of chloroform was added to the solution, and the solution was washed with aqueous 5% citric acid solution. The organic layer was separated, and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and washed with isopropyl ether to obtain 260 mg of the subject compound (168).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>CO>[CH:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15](=[O:16])[N:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]2
Reactant: CCOC(=O)c1ccc2ccccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2ccccn2c1=O
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
To a solution of 3-ethoxycarbonyl-4H-quinolizin-4-one (2.17 g) in methanol (65.2 ml) was added dropwise 6 N aqueous sodium hydroxide (6.5 ml) at room temperature. After stirring for 20 minutes, water (10 ml) was added. After stirring for 20 minutes, water (30 ml) was also added. After stirring for an hour, the reaction mixture was acidified to pH 3 with 4N aqueous hydrochloric acid. The precipitate was filtered and washed with water to give 4H-quinolizin-4-one-3-carboxylic acid (1.75 g) as pale yellow crystal. mp 233° C.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(N(CC)CC)C>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(Cc1ccc(OCCCO)cc1)C(=O)OCC
Solvent: CCN(CC)CC
Product: CCCCC(Cc1ccc(OCCCOS(C)(=O)=O)cc1)C(=O)OCC

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 2-butyl-3-[4-(3-hydroxypropoxy)phenyl]propionate (3.02 g), triethylamine (2.05 ml) and methanesulfonyl chloride (0.83 ml) and the reaction mixture was treated to afford the desired compound (3.49 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]([CH:14]1[O:19][CH2:18][CH2:17][NH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH2:24](N(CC)CC)C.CI>C1C=CC=CC=1>[CH3:24][N:16]1[CH2:17][CH2:18][O:19][CH:14]([CH:6]([O:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=2[O:2][CH3:1])[C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[CH2:15]1
Reactant: CCN(CC)CC
Reactant: COc1ccccc1OC(c1ccc(Cl)cc1)C1CNCCO1
Solvent: CI
Solvent: c1ccccc1
Product: COc1ccccc1OC(c1ccc(Cl)cc1)C1CN(C)CCO1
Reaction time: 20 h
Yield: 58.2 %

Procedure:
To a solution of 2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine (11.6 g) and triethylamine (3.5 g) in benzene (100 ml) a solution of CH3I (5.5 g) in benzene (20 ml) was added dropwise at room temperature over 1 hour. Stirring was continued at room temperature for 20 hours, the mixture was filtered and the solvent was evaporated to dryness so obtaining an oil which was separated on silica gel column to give 4-methyl-2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine (7 g; yield 57%).
Reaction SMILES: Br[Mg][C:3]#[CH:4].[O:5]=[C:6]1[CH2:9][CH:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7]1>O1CCCC1>[C:3]([C:6]1([OH:5])[CH2:9][CH:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7]1)#[CH:4]
Reactant: C#C[Mg]Br
Reactant: CCOC(=O)C1CC(=O)C1
Solvent: C1CCOC1
Product: C#CC1(O)CC(C(=O)OCC)C1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed bromo(ethynyl)magnesium (0.5M in THF, 50 mL, 1.20 equiv). This was followed by the addition of a solution of ethyl 3-oxocyclobutane-1-carboxylate (3.0 g, 21.10 mmol, 1.00 equiv) in tetrahydrofuran (3 mL) dropwise with stirring at −70° C. in 15 min. The resulting solution was stirred for 30 min at −70° C. The reaction was then quenched by the addition of 10 mL of sat. aq. ammonium chloride. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 2.6 g (66%) of ethyl 3-ethynyl-3-hydroxycyclobutane-1-carboxylate as light yellow oil (single undetermined diastereomer).
Reaction SMILES: O=[C:2]1[C:15]2[C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2.O.[NH2:21][NH2:22]>CC(N(C)C)=O>[N:21]1[NH:22][C:16](=[O:18])[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=1[NH:9]3
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCCC3
Reactant: NN
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC1=C2CCCC1
Temperature: 130 °C
Reaction time: 12 h

Procedure:
To the solution of the crude methyl 9-oxo-5,6,7,8,9,10-hexahydroacridine-1-carboxylate in DMA (4 mL) was added hydrazine hydrate (4 mL) at room temperature, and the mixture was heated at 130° C. for 4.0 h. The reaction mixture was cooled to room temperature and stirred for another 12 hours. Then the mixture was filtered and recrystallized from MeOH (twice) to give the product (20 m g, 15%) as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:29][C@@:30]2([CH3:33])[CH2:32][O:31]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:29][C@:30]1([CH2:33][O:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[CH2:32][O:31]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@]2(C)CO2)cc1
Reactant: CC(=O)Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1OC[C@@]1(C)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.6 %

Procedure:
To 2-acetamidophenol (90.5 mg, 0.598 mmol) and cesium carbonate(234 mg, 0.718 mmol) was added [(2R)-2-methyloxiranyl]methyl 4-methylbenzene-sulfonate (145 mg, 0.598 mmol) dissolved in DMF (1 ml). The mixture was stirred at room temperature for four hours and then partitioned between ethyl-acetate and water. After extraction the combined organic phases were dried and concentrated in vacuo. The residue was purified on silica (Heptane/EtOAc 3:1-2:1) to give 63 mg (48%) of the title compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[F:10][C:11]([F:25])([F:24])[C:12]([NH:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)=[O:13]>ClCCCl>[Cl:5][CH2:6][C:7]([C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH2:16][C@H:15]2[NH:14][C:12](=[O:13])[C:11]([F:24])([F:10])[F:25])=[CH:19][CH:20]=1)=[O:8]
Reactant: O=C(Cl)CCl
Reactant: O=C(N[C@@H]1CCc2ccccc21)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCl)c1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)CC2
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
To a suspension of AlCl3 (89.2 g, 0.67 mol) in 1,2-dichloroethane (600 ml) was added chloroacetyl chloride (55.7 ml, 78.9 g, 0.7 mol) dropwise at 0-5° C. under nitrogen for 20 minutes and it was then left to warm up to 20-25° C. To this mixture was added N-trifluoroacetyl-(R)-1-aminoindan (34.4 g, 0.15 mol) for 3 hours at 20-25° C. The resulting mixture was then stirred for an additional 30 minutes and poured into a mixture of ice-cold water (1.5 l) and 1,2-dichloroethane (1l). The mixture was stirred for 5 minutes and the layers were separated. The aqueous layer was extracted with 1,2-dichloroethane (2×750 ml). The combined organic layers were washed with water (2×900 ml) and 5% aqueous NaHCO3 solution (3×900 ml). The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure to give a solid, which was recrystallized from ethanol to give 15 g (48%) of a white solid mp: 166-167° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]1[O:32][N:31]=[C:30]([CH:33]=O)[CH:29]=1.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>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:30]3[CH:29]=[C:28]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)[O:32][N:31]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1cc(-c2cccs2)on1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
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: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc(-c5cccs5)on4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 267 mg of 5-(2-thienyl)-3-isoxazolecarbaldehyde, 100 mg of acetic acid was added, and stirred at room temperature for 2 hours. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 18 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was 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 60N, eluent; chloroform:methanol=10:1], to give 0.63 g of 7-methoxy-1-(2-(4-((5-(thiophen-2-yl)isoxazol-3-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Reactant: COc1ccc(OC)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(Nc2cc(C(F)(F)F)nc(-c3ccccc3)n2)c1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 2,5-dimethoxyaniline (44 mg, 0.290 mmol) and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 48 h. The mixture was cooled to room temperature and then basified with aqueous 2N NaOH to pH 10-12. The resulting precipitate was filtered, washed with water, water:ethanol (2:1) and dried under vacuo to give a gray solid (36 mg, 50%). 1H NMR (CDCl3): 8.51-8.48 (m, 2H), 8.14 (s, 1H), 7.51-7.48 (m, 4H), 6.89 (s, 1H), 6.88 (d, J=9.3 Hz, 1H), 6.66 (dd, J=3.0, 8.7 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=O)=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][N:39]([C:25]([C:22]2[N:23]=[CH:24][C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)=[CH:20][CH:21]=2)=[O:27])[CH2:38]1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CN(C)C1CCNC1
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CCC(N(C)C)C4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50A, Step 1) and 3-(dimethylamino)pyrrolidine (TCI, Cat. No. D1859). LCMS (M+H)+: m/z=556.3.