Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21].[NH2:26][C:27]1[N:28]=[CH:29][NH:30][C:31]=1[C:32]#[N:33]>>[F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[N:28]3[CH:29]=[N:30][C:31]([C:32]#[N:33])=[C:27]3[N:26]=2)=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21]
Reactant: N#Cc1[nH]cnc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(OCC(F)(F)F)c(C(F)(F)F)c1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(OCC(F)(F)F)c(C(F)(F)F)c3)nc12
Yield: 40.1 %

Procedure:
Reaction of 1-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (382 mg, 1.0 mmol), prepared from 4-trifluoroethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (182 mg, 40%). MS (ISP) 453.0 [M+]; mp 189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[C:9]([CH3:18])=[N:8]2)=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][CH2:40][C:41](=[O:43])[N:42]=2)[CH2:34][C@@H:33]1[CH2:44][OH:45])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][C:40](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]=3[C:21]([F:24])([F:22])[F:23])[N:8]=[C:9]4[CH3:18])[C:41](=[O:43])[N:42]=2)[CH2:34][C@@H:33]1[CH2:44][OH:45])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=O)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)C[C@@H]1CO
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=C3SC(N4CCN(C(=O)OC(C)(C)C)[C@@H](CO)C4)=NC3=O)cc12

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazole-5-carbaldehyde and 2-(R)—Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester following general procedure D.
Reaction SMILES: [CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH3:21])([CH3:3])[CH3:2].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH3:21])([CH3:3])[CH3:2]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1NC(C)C
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCc1nc2c(N)nc3c(c2n1NC(C)C)CCCC3
Reaction time: 144 h
Yield: 38.1 %

Procedure:
A solution of N1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.59 g, 2.1 mmol) in 15 mL of trifluoroacetic acid was treated with platinum(IV) oxide (0.55 g, 2.4 mmol) and shaken under an atmosphere of hydrogen (3.8×105 Pa). After 6 days, the reaction mixture was filtered through a pad of CELITE filter agent and rinsed with a mixture of 85:15:0.1 CHCl3:MeOH:TFA until the filtrate ran clear. The filtrate was concentrated under reduced pressure to yield a white foam. The material was suspended in water and treated with 50% NaOH solution until the pH reached 13. A white solid precipitated and was triturated in the basic mixture for 1 h. The white solid was collected by vacuum filtration. The solid was purified by chromatography (SiO2, 95:5:0.1 CHCl3:MeOH:NH4OH) to yield 0.23 g of N1-isopropyl-2-propyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1,4-diamine as a white solid.
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.[BH4-].[Na+]>>[OH:15][CH:14]1[C:2]2[N:1]=[CH:6][C:5](=[O:7])[NH:4][C:3]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Agent: [BH4-]
Agent: [Na+]
Product: O=c1cnc2c([nH]1)-c1ccccc1C2O
Yield: 104.7 %

Procedure:
9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione (5.0 g, 25.23 mmol) was reduced with sodium borohydride (1.72 g, 45.5 mmol) as described in example 11. Yield 5.29 g (96%) of the title compound. M.p. 251°-253° C. 1H-NMR (DMSO-d6, δ): 5.32 (d, 1H), 5.92 (d, 1H), 7.47 (m, 2H), 7.64 (m, 1H), 7.8 (m, 1H), 7.9 (s, 1H), 12.5 (s, 1H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:27][C@@H:28]2[C:34](=[O:35])[N:33]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[C:32]3[CH:44]=[CH:45][CH:46]=[CH:47][C:31]=3[S:30][CH2:29]2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[BrH:48].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:48].[BrH:48].[CH2:25]([O:24][C:22]([C@@H:21]([NH:27][C@@H:28]1[C:34](=[O:35])[N:33]([CH2:36][C:37]([OH:39])=[O:38])[C:32]2[CH:44]=[CH:45][CH:46]=[CH:47][C:31]=2[S:30][CH2:29]1)[CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 1.5 h

Procedure:
In 1 ml of acetic acid is dissolved 0.75 g of tertbutyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether (200 ml) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is washed with ethyl ether and dried to give 0.6 g of 3(R)-[1(S)-ethoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid.dihydrobromide as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]3[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:26][CH:25]=1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2cccc(Cl)c21
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(-c3ccc(OC)cc3)c21
Temperature: 80 °C

Procedure:
To a stirred solution of 7-chloro-3-(4-methoxyphenyl)-1-propyl-1H-indazole (0.10 g, 0.33 mmol) in anhydrous dioxane (3 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.004 g, 0.0043 mmol) and 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene HCl (0.0035 g, 0.0099 mmol). 4-Methoxyphenylmagnesium bromide (1.2 mL, 0.5M in diethyl ether) was added and the reaction mixture degassed. The reaction was heated to 80° C. for 18 hours. The reaction mixture was partitoned with 1N HCl and ethyl acetate. The organic layer was washed with water and brine. After drying (Na2SO4), the organic phase was concentrated in vacuo to yield crude title compound. The oil was purified by flash chromatography (silica gel, hexane/ethyl acetate, 5:1) to provide the title compound as a white solid (0.028 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH:13]([CH3:17])[C:14]([OH:16])=[O:15])([O-:3])=[O:2].CO.[CH3:20][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1>[CH3:20][O:15][C:14](=[O:16])[CH:13]([C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:17]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 90 %

Procedure:
A 250 ml three-necked conical flask equipped with a nitrogen inlet and a stirrer was purged with nitrogen, and was added with 2,4-dinitrophenylpropanoic acid (2.40 g, 0.01 mole), methanol (20 ml) and toluene (83 ml). Stirring was conducted at room temperature until 2,4-dinitrophenylpropanoic acid was dissolved. Trimethylsilyldiazomethane (8.3 ml) was then added, and reaction was conducted for 3 hours at room temperature. Solvent was removed by distilling under a reduced pressure and by drying at 70° C. to obtain 2,4-dinitrophenylpropanoic acid methyl ester (2.29 g, yield: 90%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]CC2C=CC=CC=2)=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[F:23])(=[O:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[F:23])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)c(C(C)(C)C)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(O)c(C(C)(C)C)c1F

Procedure:
Following General Procedure G and using tert-butyl-4-benzyloxy-2-fluoro-phenyl acetate (Compound 13, 2.2 g, 6.96 mmol), ethyl acetate (15 mL) and 5% palladium on carbon (0.436 g) the title compound was obtained as a white solid (1.5 g, 95%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[CH:29]=[CH:30][C:16]1=2)[CH3:14].[C:44](O)(=[O:51])[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1.ON1C2C=CC=CC=2N=N1>C(#N)C>[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[C:44](=[O:51])[C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)[CH:29]=[CH:30][C:16]1=2)[CH3:14]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNCCc3cccnc3)ccc21
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCc3cccnc3)C(=O)c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.8 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (WSC) (0.16 g, 0.85 mmol) was added to an acetonitrile solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.3 g, 0.71 mmol), isonicotinic acid (96 mg, 0.78 mmol), and 1-hydroxybenzotriazole (HOBT) (0.138 g, 0.85 mmol), and then stirred at room temperature for 2 days. The solvent was concentrated under reduced pressure. Ethyl acetate and a sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and stirred for 1 hour. Water was added to the reaction mixture, and extraction with ethyl acetate was conducted. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by medium pressure liquid chromatography (silica gel, dichloromethane:methanol=92:8). The purified product was concentrated under reduced pressure and crystallized from ethyl acetate, diethylether and n-hexane. The precipitated crystals were collected by filtration and dried to thereby obtain 0.21 g (yield:56%) of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-ylethyl)isonicotinamide as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31](Cl)=[N:30][CH:29]=1>>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][C:3]([CH:10]([CH3:24])[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)([OH:16])[C:12]([F:15])([F:14])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[N:30][CH:29]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(c1ccc(CO)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1ccc(OCc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-(2-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (obtained in Example 120, step 1) by alkylation with methyl-6-chloronicotinate [CAS Reg. No. 73781-91-6]. MS (m/e)=515.1 [MH+].
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[H-].[Na+].C([Li])CCC.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:17]1([C:16]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:23][C:1](=[O:6])[CH:2]=[CH:3][CH2:5]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=CCC(c2ccccc2)(c2ccccc2)O1

Procedure:
The title compound was prepared as described in General Method 1 using 20 mmol of methyl acetoacetate, 22 mmol of NaH 60% dispersion in oil, 21 mmol of 1.6 M n-butyl lithium in hexane, 20 mmol of benzophenone and 70 mL of tetrahydrofuran. Upon concentrating the reaction a solid precipitated out which was triturated with ether and filtered (m.p. 170.5-173° C.). 1H NMR (CDCl3) δ 3.18 (s, 2 H), 3.4 (s, 2 H), 7.3-7.5 (m, 10 H).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]2[CH2:10][N:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:20][Li].O.Cl.[OH-].[Na+]>C1COCC1.O>[CH:1]1([CH2:6][C@H:7]([CH2:10][NH:9][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([OH:19])=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1[C@H](CC2CCCC2)CN1OCc1ccccc1
Reactant: [Li]O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H](CNOCc1ccccc1)CC1CCCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 106.9 %

Procedure:
A mixture of (3R)-3-(cyclopentylmethyl)-1-[(phenylmethyl)oxy]-2-azetidinone (20 g, 77.1 mmol) and LiOH.H2O (32.4 g, 0.77 mol) in THF/water (500 mL/170 mL) was stirred at room temperature for 36 h. To the reaction mixture was added 6M HCl (130 mL), and then 1 N NaOH was added until a neutral pH was obtained. The layers were separated, and the aqueous layer was extracted once with EtOAc. The combined organics were dried (MgSO4) and concentrated to provide (2R)-3-cyclopentyl-2-({[(phenylmethyl)oxy]amino}methyl)propanoic acid (22.85 g, >100%) as a clear, colorless oil. LCMS: (M+H)+: 277.9.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:24](I)([CH3:26])[CH3:25]>C(#N)C.O>[CH:24]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH2:5][CH2:6]1)([CH3:26])[CH3:25]
Reactant: O=c1[nH]cc(C2=CCNCC2)c2ccccc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)N1CC=C(c2c[nH]c(=O)c3ccccc23)CC1
Temperature: 40 °C

Procedure:
4-(1,2,3,6-Tetrahydropyridin-4-yl)-2H-isoquinolin-1-one (0.4 g) obtained in Example 205 and potassium carbonate (1 g) were suspended in acetonitrile (10 mL) and water (1 mL), and isopropyl iodide (0.35 mL) was added at room temperature. The mixture was stirred under heating overnight at 40° C. After the completion of the reaction, the solvent was evaporated. Aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography (NH silica gel, Fuji Silysia Chemical Ltd.). The fraction eluted with chloroform:methanol=25:1 was concentrated, and the precipitated crystals were collected by filtration to give 4-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-isoquinolin-1-one.
Reaction SMILES: [C:1]([N:8]1[CH:12]=CN=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].CNC>C1COCC1>[CH3:9][N:8]([CH3:12])[C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=S)n1ccnc1
Temperature: 55 °C

Procedure:
To a stirred mixture of thiocarbonyldiimidazole (44.9 mmol) in THF (40 mL) at room temperature was added portionwise 2 M Dimethylamine in THF (44 mmol) and a temperature increase was observed. 40 min after final addition the reaction mixture was heated to 55° C. for 1 h, then allowed to reach room temperature again. The reaction was then concentrated in vacuo and the residue purified by flash chromatography (silica gel, Petroleum ether-EtOAc) to give the intermediate imidazole-1-carbothioic acid dimethylamide. This material was treated with freshly prepared sat. ammonia in methanol (40 ml) for 60 h, then concentrated in vacuo and the precipitated residue was suspended in diethyl ether and collected by filtration. The precipitate was washed with diethyl ether and air-dried to give a slight yellow solid (1.71 g, 16.4 mmol) which was used in the subsequent step. 4-(2-bromoacetyl)benzoic acid (1.23 mmol) and 1-piperidinethiocarboxamide (1.23 mmol) were mixed in THF (10 mL), then refluxed for 3 h. The reaction mixture was then allowed to reach room temperature and the obtained precipitate was collected by filtration and washed with 3 portions of diethyl ether. The crude product was crystallized from hot 1:1 EtOH-EtOAc to give a first harvest of colorless needles (0.1 g, 0.40 mmol). 1H NMR (DMSO-d6, 400 MHz) δ 7.94 (4H, m), 7.37 (1H, s), 3.11 (6H, m).
Reaction SMILES: [CH:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)([CH3:3])[CH3:2].[Br:14]Br.S([O-])([O-])=O.[Na+].[Na+]>>[Br:14][C:6]12[CH2:12][CH:10]3[CH2:9][CH:8]([CH2:13][C:4]([CH:1]([CH3:3])[CH3:2])([CH2:11]3)[CH2:5]1)[CH2:7]2
Reactant: CC(C)C12CC3CC(CC(C3)C1)C2
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CC(C)C12CC3CC(CC(Br)(C3)C1)C2
Yield: 83 %

Procedure:
Mix 0.034 mol of isopropyl adamantane (IV) with a ten times excess of bromine (0.33 mol). Heat slowly and stir under reflux for 4 h. Subsequently, allow to cool and pour onto ice water. Decompose the excess bromine with sodium sulfite until the aqueous solution has discolored. Then extract with ether, wash the combined organic phases with sodium bicarbonate solution, dry with magnesium sulfate, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 83%).
Reaction SMILES: [N:1]1([C:7]2[C:8]([C:13]#[N:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N>CO.[Ni]>[N:1]1([C:7]2[C:8]([CH2:13][NH2:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#Cc1ncccc1N1CCOCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ncccc1N1CCOCC1
Yield: 94.1 %

Procedure:
A solution of 3-morpholin-4-yl-pyridine-2-carbonitrile (0.500 g, 2.64 mmol) in MeOH (10 mL) was added to a flask charged with Raney Ni (pre-washed with methanol) (˜0.5 g) in MeOH (10 mL). After saturated with NH3 gas the mixture was shaken under H2 (40 psi) for 3 h. The reaction mixture was then filtered through a celite cake, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (500:25:6 CH2Cl2/MeOH/NH4OH), affording C-(3-morpholin-4-yl-pyridin-2-yl)-methylamine as a pale yellow oil (0.480 g, 94%). 1H NMR (CDCl3) 2.90-2.93 (m, 4H), 3.85-3.90 (m, 4H), 4.02 (s, 2H), 7.16 (dd, 1H, J=4.5, 8.1 Hz), 7.35 (dd, 1H, J=1.2, 8.1 Hz), 8.33 (dd, 1H, J=1.2, 4.5 Hz).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[C:4]([CH3:24])[C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cc3C)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2cc(C)c(C(=O)N3CCN(c4ncc(C)cc4C)CC3)cn2)C1=O
Yield: 53.4 %

Procedure:
Using (6-bromo-4-methylpyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (389 mg) described in Preparation Example 228 and 1-acetylimidazolidin-2-one (128 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (233 mg) was obtained.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][NH:17][C:12]3=[N:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][N:28]=[C:27]([CH2:30]Cl)[N:26]=2)[CH:22]=[CH:23][CH:24]=1>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][N:28]=[C:27]([CH2:30][N:17]3[CH2:16][CH2:15][CH2:14][N:13]4[C:9]([C:6]5[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=5)=[N:10][N:11]=[C:12]34)[N:26]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Reactant: c1cc(-c2nnc3n2CCCN3)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(-c2nc(CN3CCCn4c(-c5ccncc5)nnc43)no2)c1
Temperature: 25 °C
Yield: 32.4 %

Procedure:
32 mg (1.31 mmol) NaH was added to a solution of 193 mg (0.96 mmol) 3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine in 10 ml DMF at room temperature. After 10 min 200 mg (0.87mmol) 5-(3-chloro-phenyl)-3-chloromethyl-[1,2,4]oxadiazole was added to the reaction mixture. The reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with NH4Cl(sat) and extracted twice with EtOAc. The combined organic phases were washed with water, dried and concentrated. Flashchromatography (CH2Cl2/MeOH 20:1) afforded 111 mg (32%) of a white solid. 1H NMR (CDCl3), d (ppm): 2.24 (m, 2 H), 3.57 (m, 2 H) 4.15 (m, 2 H) 5.01 (s, 2 H) 7.46 (t, 1 H) 7.56 (d, 1 H) 7.62 (d, 2 H) 7.99 (d, 1 H) 8.10 (s, 1 H) 8.70 (d, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]#[C:10][C:11]([O:13]C)=[O:12])=[O:8])=[CH:5][CH:4]=1.[OH-].[K+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]#[C:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:15][CH:16]=1
Reactant: COC(=O)C#CC(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)C#CC(=O)O)cc1
Reaction time: 1 h

Procedure:
A solution of 6.2 g (28 mmol) of methyl 3-(4-methoxybenzoyl)propiolate in 60 ml of tetrahydrofuran was treated slowly at 0° with 80 ml of 3% potassium hydroxide solution and stirred at 0° for a further 1 hour. The reaction mixture was treated with water and extracted once with ether. The ether phase was discarded. The aqueous phase was adjusted to pH 1 with 1N hydrochloric acid and extracted twice with ether. The combined organic phases were dried over sodium sulphate and concentrated. Precipitation of the residue from methylene chloride/ether/hexane yielded 3-(4-methoxybenzoyl)propiolic acid as an amorphous powder.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]2[O:9][CH:8]([CH3:10])[S:7][C:6]=2[C:11]=1[CH3:12].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:15]([O:1][C:2]1[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]2[O:9][CH:8]([CH3:10])[S:7][C:6]=2[C:11]=1[CH3:12])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)SC(C)O2
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1OC(=O)c1ccccc1)SC(C)O2
Yield: 67.1 %

Procedure:
A mixture of 2.0 g of 5-hydroxy-2,4,6,7-tetramethyl-1,3-benzoxathiole (prepared as described in Example 40), 1.2 g of benzoyl chloride and 5 ml of pyridine was reacted for 24 hours at room temperature, and was then subjected to the same subsequent treatment and purification as described in Example 4, to give 1.8 g of the title compound, melting at 100°-102° C.