Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].Cl.[F:20][C:21]([F:34])([F:33])[C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][CH:23]=1>>[CH2:1]([S:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:30]1[CH2:31][CH2:32][N:27]([C:25]2[S:26][C:22]([C:21]([F:34])([F:20])[F:33])=[CH:23][N:24]=2)[CH2:28][CH2:29]1)=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CC(C)CSc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)CSc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 88 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isobutylsulfanyl-5-methanesulfonyl-benzoic acid (Example A25) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a light yellow solid (yield 88%). MS (m/e): 508.3 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3([OH:18])[C:15](=[O:16])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:7]3([OH:17])[O:8][C:4]=2[CH:3]=1.[C:21]([OH:24])(=O)[CH3:22].N1C=CC=CC=1.C1C[O:34][CH2:33][CH2:32]1>>[C:33]([O:8][C:4]1[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=1[C:6]1([O:18][C:21](=[O:24])[CH3:22])[C:7](=[O:17])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]1=[O:16])(=[O:34])[CH3:32]
Reactant: O=C1c2ccccc2C2(O)Oc3cc(Cl)ccc3C12O
Reactant: C1CCOC1
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(Cl)ccc1C1(OC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 19 %

Procedure:
7-Chloro-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (2.00 g, 6.9 mmol) was completely dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (1.41 ml, 13.8 mmol), pyridine (0.55 ml, 6.9 mmol), and 4-dimethyl aminopyridine (0.2 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:3) to afford the title compound (0.51 g, 19%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:24]1[CH:29]=[CH:28][C:27]2=[N:30][N:31]=[C:32]([C:33]([F:36])([F:35])[F:34])[N:26]2[N:25]=1>C(O)C>[F:35][C:33]([F:34])([F:36])[C:32]1[N:26]2[N:25]=[C:24]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[CH:29]=[CH:28][C:27]2=[N:30][N:31]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 70 °C
Yield: 90.7 %

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (8.29 g, 44.5 mmol) and ethanol (90 mL) was added to a mixture of diisopropylethylamine (9.16 mL, 52.6 mmol) and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (9.0 g, 40.4 mmol) in ethanol (90 mL) The mixture was heated at 70° C. for 11 hours and then allowed to cool to ambient temperature to give a precipitate. The precipitate was collected by filtration, washed with chilled ethanol and then with water, and dried under vacuum to afford tert-butyl 4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carboxylate (13.64 g, 90.6%) as a white solid that was used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[OH:8].[C:9]([O:13][C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:9]([O:13][C:14]([NH:16][C:17]1([C:20]([O:8][CH:3]2[CH:4]([CH3:7])[CH2:5][CH2:6][CH:2]2[CH3:1])=[O:21])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC1CCC(C)C1O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1CCC(C)C1OC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of 2,5-dimethylcyclopentanol (0.55 g.), compound 1 (0.97 g), and 4-(dimethylamino)pyridine (0.06 g.) in methylene chloride (100 ml) was added dicyclohexylcarbodiimide (1.09 g.), and the resulting mixture was stirred overnight. The precipitated dicyclohexylurea was removed by filtration, and the filtrate was evaporated. Ethyl acetate was then added to the residue, and the mixture was filtered again. The filtrate was washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate, and water, dried over magnesium sulfate, and the solvent was evaporated to a colorless oil (1.18 g. 83%). The product was purified by column chromotography on silica gel, 4:1 hexane:ethyl acetate, eluent.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]3[N:17]=[CH:18][CH:19]=[CH:20][C:8]=3[N:7]=2)=[CH:2]1.[H-].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][C:8]2[CH:20]=[CH:19][CH:18]=[N:17][C:9]1=2
Reactant: c1cnc2c(c1)N=C(c1ccsc1)c1ccccc1N2
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2ccsc2)=Nc2cccnc21

Procedure:
Following the procedure of Example 23, 6-(3-thienyl)11H-pyrido[2,3-b][1,4]benzodiazepine is reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to give the title compound.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[NH2:31])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].C(=O)([O-])[O-].[K+].[K+].[C:38](ON1C(=O)CC(S(O)(=O)=O)C1=O)(=[O:40])[CH3:39].[Na]>O.CS(C)=O>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[NH:31][C:38](=[O:40])[CH3:39])([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](N)[C@H]1O
Reactant: CC(=O)ON1C(=O)CC(S(=O)(=O)O)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)OP(=O)(O)OP(=O)(O)O
Yield: 11.9 %

Procedure:
3'-Amino-3'-deoxyadenosine 5'-triphosphate (15 mg, 26 mmol) and potassium carbonate (21 mg, 0.13 mmol) were dissolved in 2 ml of water. Sodium sulfosuccinimidyl acetate (36 mg, 0.13 mmol; Pierce Chemical, Rockford, Ill.) in 0.2 ml of dimethylsulfoxide (DMSO) was added at 0° C., and the reaction was allowed to proceed at room temperature for twenty-four hours. The product was purified by repeated injections on HPLC using a Synchropak RP-100 column (1×25 cm) applying a linear gradient of acetonitrile 5-22% TEAA (0.85 %/min, flow rate 3 ml/min, t=8.5 min). The appropriate fractions were collected and lyophilized to dryness. The product was obtained as a triethylammonium salt (8.5 mg, 39 %). UV: lmax =259 nm. High resolution MS for C12H18N6O13P3 : calcd. 547. 0145, found 547.0170 (MH3-).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][C:12]([C@@H:15]([NH2:17])[CH3:16])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.[F:20][C@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[CH:34]=[CH:33][N:32]=[C:31](F)[N:30]=1)[CH3:22].CCN(C(C)C)C(C)C>CS(C)=O>[F:20][C@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:17][C@H:15]([C:12]2[N:11]=[CH:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:8]=3)=[CH:14][CH:13]=2)[CH3:16])[N:30]=1)[CH3:22]
Reactant: C[C@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Reactant: C[C@H](N)c1ccc(-c2ccnc(C(F)(F)F)c2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)F)n1)c1ccc(-c2ccnc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of (S)-1-(2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine (27 mg, 0.10 mmol), (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (23 mg, 0.10 mmol) and DIPEA (52.4 μl, 0.30 mmol) in DMSO (500 μl) was heated at 110° C. for 1 hr. The solution was then cooled to rt and RP-HPLC purification (acetonitrile:water) provided the 32 mg of the major product as a white solid. 1H NMR (400 MHz, MeOD) δ 8.98 (s, 1H), 8.79 (d, J=5.1 Hz, 1H), 8.23 (dd, J=8.2, 2.4 Hz, 1H), 8.17 (br s, 1H), 8.17-8.12 (m, 1H), 7.98 (dd, J=5.1, 1.7 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.40 (d, J=5.8 Hz, 1H), 5.11 (br s, 1H), 4.69 (br d, J=27.2 Hz, 1H), 4.55-4.12 (m, 3H), 1.60 (d, J=7.1 Hz, 3H), 1.03 (br s, 3H); HRMS (B) m/z 477.1699 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][CH2:27][C@@H:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH2:29])([CH3:25])([CH3:24])[CH3:23].N1C(C)=CC=CC=1C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([NH:29][C@H:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC[C@H](NC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
(2R)-{[(Benzyloxy)carbonyl]amino}(phenyl)acetic acid (Z-(R)-Phg-OH) (2.0 g, 7.0 mmol) and tert-butyl O-(tert-butyl)-L-serinate (2.0 g, 7.9 mmol) and 2.6-lutidine were dissolved in DCM (30 ml). After stirring 5 minutes at 0° C. TBTU (2.5 g, 7.8 mmol) was added and stirring was continued 30 minutes at 0° C. and 4 hours at room temperature. The reaction mixture was washed with water (2×100 ml), dried and purified with flash chromatography (DCM) to give the title compound (3.3 g, 97%). NMR (300 MHz, CD3OD): 1.05 (s, 9H), 1.45 (s, 9H), 3.4-3.8 (m, 2H), 4.5 (bs, 1H), 4.85 (s, 2H), 5.1 (s, 2H), 5.4 (s, 1H), 7.25-7.5 (m, 10 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Br)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round-bottom flask were charged with dimethyl 5-bromoisophthalate (0.50 g, 1.8 mmol), barium hydroxide octahydrate (0.43 g, 1.4 mmol) and methanol (10 mL). The mixture was stirred at room temperature overnight. HCl (2 N ethyl ether solution, 10 mL) was added and the volatiles were removed under reduced pressure. The residue was purified via flash chromatography to afford the desired product as a white solid. 1H NMR (400 MHz, DMSO-d6): 13.70 (br, 1H), 8.42 (t, J=1.5 Hz, 1H), 8.31-8.24 (m, 2H), 3.90 (s, 3H).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[CH:8]=[C:9]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22](Cl)[N:23]=3)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]2)[C:10]([F:14])=[CH:11][C:12]=1[F:13].[NH2:31][C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.C(N(CC)CC)C>C(O)C>[CH:32]([O:27][CH:18]([CH3:17])[CH3:19])([CH3:36])[CH3:33].[NH2:6][C:7]1[CH:8]=[C:9]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22]([N:34]4[CH2:35][CH2:36][C@H:32]([NH2:31])[CH2:33]4)[N:23]=3)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]2)[C:10]([F:14])=[CH:11][C:12]=1[F:13]
Reactant: N[C@H]1CCNC1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC(C)C
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](N)C4)nc32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 191.2 %

Procedure:
To 6,500 mg of N,N-dimethylformamide were added 1,300 mg of 1-(3-amino-4,6-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 600 mg of (3S)-3-aminopyrrolidine, and 1,000 mg of triethylamine. The solution was stirred at 90° C. for 1 hour. The reaction solution was allowed to cool down, combined with 25 ml of ethanol, heated at reflux for 5 minutes, and allowed to cool down. The precipitate was collected by filtration and washed with ethanol and then with diisopropyl ether to give 1,410 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN1C(=O)N(C)CCC1.Cl[C:20]1[N:25]=[CH:24][C:23]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[CH:39]=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[CH:22][CH:21]=1>O1CCCC1>[CH:3]1([S:9][C:20]2[N:25]=[CH:24][C:23]([C:26]([N:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH2:32][N:31]4[CH:39]=[CH:40][CH:41]=[C:30]4[CH2:29]3)=[O:27])=[CH:22][CH:21]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: SC1CCCCC1
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(c1ccc(SC2CCCCC2)nc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 35 mg of sodium hydride (60% in oil) in 3 ml of tetrahydrofuran is added under argon 0.10 g of cyclohexylmercaptan. A white precipitate forms and after 0.5 hour at room temperature, 1 ml of N,N'-dimethylpropyleneurea is added. To the mixture is added 0.13 g of 10-[(6-chloro-3-pyridinyl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 2 ml of tetrahydrofuran. The mixture is stirred at room temperature for 18 hours, quenched with water and ammonium chloride and concentrated under vacuum. The aqueous suspension is filtered and the solid washed with water and hexane. The solid is purified by chromatography on silica gel prep-plates with ethyl acetate-hexane (1:4) as eluent to give 0.13 g of white solid; mass spectrum (CI): 404 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]1[CH2:37][C@@:35]2([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]2[OH:38])[C@@:30]2([CH:39]=[CH2:40])[C@H:21]1[C:22]1[CH:23]=[CH:24][C:25]([OH:41])=[CH:26][C:27]=1[CH2:28][CH2:29]2>>[N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]2[CH2:37][C@@:35]3([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[OH:38])[C@@:30]3([CH:39]=[CH2:40])[C@H:21]2[C:22]2[CH:23]=[CH:24][C:25]([OH:41])=[CH:26][C:27]=2[CH2:28][CH2:29]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCCl)C[C@@]1(C)[C@H]2CC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCN1CCCCC1)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with piperidine (10 equivalents) with the addition of sodium carbonate analogously to instructions 17.2, 34 mg of mixture 30b yields 40 mg of amine 34b as a colorless foam (GC-MS: m/z theor.: 465, pract.: 465).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]=1.[CH2:20]([Br:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[Br-:27].[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N+:5]=1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)=NCC2
Solvent: CCO
Product: COc1cc2c(cc1OC)C(C(CO)CO)=[N+](Cc1ccccc1)CC2
Product: [Br-]
Yield: 59 %

Procedure:
0.015 mole (4 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-3,4-dihydroisoquinoline is dissolved in 40 ml of absolute ethanol. 0.02 mole (3.4 g) of benzyl bromide is added to the solution and the reaction mixture is refluxed for 4 hours, under stirring. After cooling the crystals separated out are filtered off and recrystallized from ethanol. The aimed compound is obtained with a melting point of 178° to 179° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[C:5]#[N:6].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[CH:21]([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[CH3:23][N:22]1[C:15]2[N:16]([C:17](=[O:19])[N:18]=[C:13]([O:11][CH2:10][C:8]3[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[CH:9]=3)[C:5]#[N:6])[CH:14]=2)[CH2:20][CH:21]1[CH3:24]
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1cc(F)cc(CO)c1
Product: CC1Cn2c(cc(OCc3cc(F)cc(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 3-fluoro-5-(hydroxymethyl)benzonitrile and 7-chloro-1,2-dimethyl-2,3-dihydroi-midazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.Br[C:7]1[CH:20]=[CH:19][C:10]2[C:11]3[CH2:12][CH2:13][CH2:14][O:15][C:16]=3[CH:17]=[CH:18][C:9]=2[CH:8]=1.[CH:21]([C:23]1[N:24]=[CH:25][N:26](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:27]=1)=[O:22].[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:12]1[C:11]2[C:10]3[CH:19]=[CH:20][C:7]([C:21]([C:23]4[N:24]=[CH:25][NH:26][CH:27]=4)([OH:22])[CH:2]([CH3:3])[CH3:1])=[CH:8][C:9]=3[CH:18]=[CH:17][C:16]=2[O:15][CH2:14][CH2:13]1
Reactant: [Li]CCCC
Reactant: Brc1ccc2c3c(ccc2c1)OCCC3
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)OCCC3)c1c[nH]cn1
Reaction time: 0.5 h

Procedure:
n-Butyl-lithium in hexane (1.6M; 41 mL) was added to a solution of 8-bromo-2,3-dihydro-1H-benzo[f]chromene (13.35 g) in THF (250 ml) at −78° C. and stirred at the same temperature for 30 min. A solution of 4-formyl-1-trityl-1H-imidazole (16.83 g) in THF (150 ml) was added to the mixture and the whole was allowed to room temperature. Aqueous ammonium chloride solution was added to the mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was washed with ethyl acetate to give the titled compound (11.80 g) as a colorless solid.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:5][C:4]=2[CH:3]=1.[F:25][C:26]([F:55])([F:54])[C:27]1[C:31](B(O)O)=[CH:30][N:29]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[O:11]=[C:8]1[NH:7][C:6]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:5][C:4]2[CH:3]=[C:2]([C:31]3[C:27]([C:26]([F:54])([F:55])[F:25])=[N:28][N:29]([C:35]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:30]=3)[S:10][C:9]1=2
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1c1nc2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3C(F)(F)F)sc2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
tert-butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (1.41 g) produced in Example 83, step B, [3-(trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]boronic acid (1.72 g), sodium carbonate (902 mg), ethanol (15 mL) and water (3 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. Tetrakis(triphenylphosphine)palladium(0) (197 mg) was added, the atmosphere in the flask was purged again with argon, and the mixture was stirred at 80° C. for 15 hr. Ethyl acetate (20 mL) and water (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give tert-butyl (2S)-2-{4-oxo-6-[3-(trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1-carboxylate as a colorless oil. To a solution of tert-butyl (2S)-2-{4-oxo-6-[3-(trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1-carboxylate produced above in methanol (4 ml) was added 4M hydrochloric acid/ethyl acetate solution (1 mL), and the mixture was stirred at 60° C. for 15 hr. The precipitated solid was collected by filtration to give the title compound (530 mg) as a colorless solid.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.C(O[O:14][C:15]([CH3:18])(C)C)(C)(C)C.[C]=O.[CH2:21]([OH:23])C>>[CH3:8][C:1]1[CH:2]=[C:3]([CH2:7][C:21]([O:14][CH2:15][CH3:18])=[O:23])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(C)c1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCO
Agent: [C]=O
Product: CCOC(=O)Cc1cccc(C)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
m-Xylene (1.59 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 80 mg ethyl m-methylphenylacetate was obtained by column chromatography, in a yield of 90%. 1HNMR (400 MHz, CDCl3) δ 1.23 (t, J=7.2 Hz, 3H), 2.33 (s, 3H), 3.57 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 7.06-7.09 (m, 3H), 7.19-7.24 (m, 3H); 13CNMR (100 MHz, CDCl3) δ14.2, 21.4, 41.4, 60.8, 126.3, 127.8, 128.5, 130.0, 134.1, 138.2, 171.8; HRMS (ESI) calcd. for C11H14NaO2 [M+Na]: 201.0886. found: 201.0887. The ethyl m-methylphenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 63 mg product m-methylphenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 93%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([CH3:17])[CH2:15][NH:14][C:13](=[O:18])[C@@H:12]1[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([Cl:34])=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.C(OCC)(=O)C>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH:16]([CH3:17])[CH2:15][N:14]([CH2:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28]([Cl:34])=[CH:29][CH:30]=[N:31]3)=[CH:26][CH:25]=2)[C:13](=[O:18])[C@@H:12]1[CH3:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CNC(=O)[C@H](C)N1C(=O)OCc1ccccc1
Reactant: Clc1ccnc2cc(CBr)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccc3c(Cl)ccnc3c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 95.2 %

Procedure:
(2S,6RS)-2,6-Dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (380 mg, 1.45 mmol) is dissolved in 10 mL of THF and 1 mL of DMF. Sodium hydride (60%, 72 mg, 3.14 mmol) is added at 0° C. and left to stir at room temperature for thirty minutes before 7-bromomethyl-4-chloro-quinoline (257 mg, 1.0 mmol) is added. The reaction is stirred for four hours. Ethyl acetate is added to the mixture, and the reaction is quenched with 3 mL of H2O. The two layers are separated and ethyl acetate (2×30 ml) is used to extract before dried over magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel (60% EtOAc/Hexane) to give (2S, 6RS)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (417 mg, 95% yield). C22H20ClN3O3 MS m/z: 438, 440.