Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[Si]([N:36]=[C:37]=[O:38])(C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH:23]4[CH2:24][CH2:25][N:26]([C:37]([NH2:36])=[O:38])[CH2:27][CH2:28]4)[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: NC(=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4SCc4cccnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
4-(8-Chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-1-(4-piperidine-acetyl)piperazine (270 mg, 0.591 mmol) was added to anhydrous CH2Cl2 (2.7 ml). TMSNCO (320 mg, 0.37 ml, 2.36 mmol) was added by syringe. The mixture was stirred at room temperature for 90 hours and then quenched with saturated NaHCO3. More water and CH2Cl2 were added, and the mixture was shaken and separated. The aqueous phase was extracted with CH2Cl2 (4×20 ml), and the combined organic phases were washed with brine, dried (Na2SO4), decanted and concentrated. The crude residue was purified by flash chromatography (5%MeOH/CH2Cl2 to 10%MeOH/CH2Cl2 /NH4OH) and the pure product was obtained (295 mg, 66%) MS (FAB, M+H)=529.
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][N:12]([CH3:16])[C:13]([NH2:15])=[O:14]>C1(C)C=CC=CC=1>[Cl-:10].[CH3:11][N:12]([CH3:16])[C:13](=[O:14])[NH:15][CH2:8][P+:3]([CH2:1][NH:15][C:13]([N:12]([CH3:16])[CH3:11])=[O:14])([CH2:4][NH:15][C:13]([N:12]([CH3:16])[CH3:11])=[O:14])[CH2:6][NH:15][C:13]([N:12]([CH3:16])[CH3:11])=[O:14]
Reactant: CN(C)C(N)=O
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)NC[P+](CNC(=O)N(C)C)(CNC(=O)N(C)C)CNC(=O)N(C)C
Yield: 99.7 %

Procedure:
Reaction of THPC (9.53 g, 0.05 mol) with 1,1-dimethylurea (17.62 g, 0.2 mol) in toluene (75 ml), following Example 1, gave 23.47 g (99.7%) of tetrakis(3,3-dimethylureidomethyl)phosphonium chloride (I, R=H, R'=R"=CH3, X=Cl) as a colorless, hygroscopic resin.
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:7])[CH2:5][CH3:6])[NH2:3].O=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:4](=[O:7])[CH2:5][CH3:6])[N:3]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CCC(=O)N(C)N
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=NN(C)C(=O)CC)C(=O)OCC
Yield: 48.4 %

Procedure:
A solution of N-methylpropionohydrazide (18.78 g, 183.9 mmol) and diethyl ketomalonate (56.1 mL, 368 mmol) in toluene (136 mL) was refluxed with a Dean-Stark trap for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 5 to 10% EtOAc in hexanes) to afford 23 g (49%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[N:12]1[CH:21]=[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:20])[C:14]2=[N:13]1.ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[N:12]1[CH:21]=[C:15]2[CH:16]=[N+:17]([O-:30])[CH:18]=[C:19]([F:20])[C:14]2=[N:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cc(Cl)c(-n2cc3cncc(F)c3n2)c(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)c(-n2cc3c[n+]([O-])cc(F)c3n2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
2-(2,6-Dichloro-4-nitrophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (4.78 g, 14.62 mmol) was dissolved in DCM (90 mL) and a solution of meta-chloroperbenzoic acid (3.78 g, 21.93 mmol) in DCM (60 mL, which had been pre-dried over anhydrous sodium sulfate and passed through a phase separator), was added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 4 hours. Another portion of meta-chloroperbenzoic acid (1.26 g, 7.30 mmol) in DCM (20 mL, dried as above) was added and the reaction mixture was stirred for a further 1.25 hour at room temperature. The resultant mixture was sequentially washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and brine. The combined aqueous extracts were further extracted with DCM and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether (×3) and the solid was collected by filtration and dried under reduced pressure to afford the title compound as a pale yellow solid (4.20 g, 84% yield). 1H NMR (300 MHz, CDCl3): δ 8.64 (d, J=1.4 Hz, 1H), 8.42 (s, 2H), 8.20 (d, J=2.3 Hz, 1H), 8.02 (dd, J=5.4, 1.4 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:22])=[CH:7][CH:8]=2)[N:3]=1.[CH3:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CC#N>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.O>[F:22][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[C:2]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][CH3:23])=[N:3]2)=[CH:8][CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cc2ccc(F)cc2nc1Cl
Reactant: CSc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CSc1ccccc1-c1nc2cc(F)ccc2cc1[C@H](C)NC(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 92.9 %

Procedure:
A mixture of (S)-tert-butyl (1-(2-chloro-7-fluoroquinolin-3-yl)ethyl)carbamate (382 mg, 1.2 mmol), 2-(methylthio)phenylboronic acid (257 mg, 1.3 eq), Na2CO3 (623 mg, 5.0 eq), Pd(PPh3)4 (93 mg, 5%), MeCN (9 mL) and water (3 mL) was heated to 85° C. under N2 overnight. After cooling to rt, the reaction was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was separated, washed, dried and concentrated. The residue was purified by column chromatography on silica gel to give a white solid (S)-tert-butyl (1-(7-fluoro-2-(2-(methylthio)phenyl)quinolin-3-yl)ethyl)carbamate (460 mg, 94.8%). Mass Spectrum (ESI) m/e=413 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.[Cl:16][C:17]1[CH:30]=[CH:29][C:20]2[S:21][C:22]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([CH3:24])[C:19]=2[CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:25]([C:22]2[S:21][C:20]3[CH:29]=[CH:30][C:17]([Cl:16])=[CH:18][C:19]=3[C:23]=2[CH3:24])(=[O:27])=[O:26])=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: CN1CCN(c2cc(N)ccc2Cl)CC1
Product: Cc1c(S(=O)(=O)Nc2ccc(Cl)c(N3CCN(C)CC3)c2)sc2ccc(Cl)cc12

Procedure:
The title compound (E119) was prepared from 4-chloro-3-(4-methylpiperazin-1-yl)benzenamine (EP 0533267A, intermediate 42) (50 mg, 0.22 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (62 mg, 0.22 mmol) using the method of Example 1 (49 mg, 44%) MH+=470/472.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([C:16]3[S:17][C:18]([C:22]([O-:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)[C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: Cc1nc(-n2c(=O)n(Cc3ccc(F)cc3)c3ccccc32)sc1C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-n2c(=O)n(Cc3ccc(F)cc3)c3ccccc32)sc1C(=O)O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of 2-(3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-4-methylthiazole-5-carboxylate in a mixture of tetrahydrofuran and water (2/1) is added lithium hydroxide monohydrate (6.9 equivalents) at ambient temperature. The reaction mixture is stirred at ambient temperature for 17 h and concentrated in vacuo. The residue is acidified by the addition of 4 M hydrochloric acid solution to pH˜3. The solid is collected by filtration, washed with water and hexane, and dried in vacuo to afford the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14]/[C:13](=[CH:16]\[CH:17]=[CH:18]\[C:19]([O:21]CC)=[O:20])/[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1COCC1.CO.[OH-].[Li+]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14]/[C:13](=[CH:16]\[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20])/[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)/C=C/C=C1\CCN(Cc2ccc3c(c2)OCO3)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/C=C1\CCN(Cc2ccc3c(c2)OCO3)C1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A solution of ester 275 (0.15 g, 0.485 mmol) in 2:1 THF:MeOH (6 mL) was treated with a solution of lithium hydroxide (59 mg, 1.41 mmol) in H2O (3 mL) and stirred for 18 h. The reaction mixture was quenched with 1N HCl (2.0 mL), concentrated, diluted with H2O, cooled to −78° C. and lyophilized to provide title compound 276 (quantitative, in a mixture with LiCl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:23][CH2:22][C@@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:24][C@@H:21]1[CH2:22][CH2:23][N:19]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:6]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1

Procedure:
To a solution of tert-butyl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate (480 mg, 1.11 mmol) in CH2Cl2 (10 mL) was added TFA (4 mL). The reaction was stirred for an hour, diluted with 10 mL CH2Cl2, and neutralized with a saturated aqueous NaHCO3 solution. The aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 3-20% EtOAc/CH2Cl2 gave 2-(4-((R)-3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol. LC/MS: m/z 325.5 (M+H)+ at 1.26 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>CO>[C:1]([C:5]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC(=O)N1CC(Oc2ccc(F)cc2C(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(F)ccc1OC1CN(C(=O)CCC(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a stirred solution of methyl 4-[3-(2-tert-butyl-4-fluorophenoxy)azetidin-1-yl]-4-oxobutanoate (214 mg, 0.63 mmol) obtained in Example 79 in methanol (6.0 mL) was added lithium hydroxide (1.0M aqueous solution, 1.9 mL, 1.9 mmol) at 0° C. The reaction mixture was warmed to room temperature, and stirred for 1 h. After cooling to 0° C., the mixture was adjusted to about pH 1 with 1.0N hydrochloric acid. The obtained solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give 4-[3-(2-tert-butyl-4-fluorophenoxy)azetidin-1-yl]-4-oxobutanoic acid (0.19 g, 92%) as a white powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[CH3:39][C:40]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH2:43][CH2:42][C:41]=1[C:55]([O:57][CH2:58][CH3:59])=[O:56]>>[NH2:32][C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:44]2[CH2:43][CH2:42][C:41]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[C:40]([CH3:39])[CH:45]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCOC(=O)C1=C(C)C=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC(C)=C(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method for the preparation of Example 1, Step 1 described above, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and ethyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-1,3-dienecarboxylate as reactants. MS: m/e 557.4 (M−16)+, 2.47 min (method 2). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.65 (s, 1H), 5.28 (d, J=5.8 Hz, 1H), 4.72 (s, 1H), 4.59 (s, 1H), 4.25-4.16 (m, 2H), 2.62-2.48 (m, 1H), 2.48-2.34 (m, 2H), 2.31-2.17 (m, 2H), 2.15 (s, 3H), 2.09-1.97 (m, 2H), 1.80-1.35 (m, 17H), 1.35-1.18 (m, 9H), 1.18-1.04 (m, 6H), 1.02-1.00 (s, 3H), 0.96 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[C:20]5[CH2:21][CH2:22][CH:23]([C:25]([OH:27])=O)[CH2:24][C:19]=5[S:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:25]([CH:23]2[CH2:22][CH2:21][C:20]3[C:13]4[C:12]([NH:11][C:9]5[CH:8]=[CH:7][C:5]6[NH:6][C:2](=[O:1])[S:3][C:4]=6[CH:10]=5)=[N:17][CH:16]=[N:15][C:14]=4[S:18][C:19]=3[CH2:24]2)=[O:27])[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Product: CN1CCN(C(=O)C2CCc3c(sc4ncnc(Nc5ccc6[nH]c(=O)sc6c5)c34)C2)CC1

Procedure:
76.4 mg (192 μmol) (RS)-4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to example 2) were transformed in analogy to example 3 using 1-methylpiperazine to give after working up and purification 66.5 mg (69%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.NC1C=[C:25]2[C:21]([C:22]([CH3:30])(C)[C:23](=[O:28])[N:24]2[CH3:27])=CC=1.[N+](C1C=C2C(C3(CCCC3)C(=O)N2)=CC=1)([O-])=O>>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:23](=[O:28])[C:22]3[CH:21]=[CH:25][N:24]=[CH:27][CH:30]=3)[CH:10]=2)[C:6]2([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:7]1=[O:12]
Reactant: CN1C(=O)C2(CCCC2)c2ccc(N)cc21
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Agent: O=C1Nc2cc([N+](=O)[O-])ccc2C12CCCC2
Product: CN1C(=O)C2(CCCC2)c2ccc(NC(=O)c3ccncc3)cc21

Procedure:
Prepared in analogy to example 2 using 6′-amino-1′-methyl-spiro[cyclopentane-1,3′-indoline]-2′-one (prepared in analogy to procedures described in W. von der Saal et al., J. Med. Chem. 1989, 32(7), 1481-1491 for the preparation of 6-amino-1,3,3-trimethylindolin-2-one by methylation and nitro reduction of 6′-nitro-spiro[cyclopentane-1,3′-indolin]-2′-one (A. Mertens et al. J. Med. Chem. 1987, 30 (8), 1279-1287)). The title compound was obtained as light yellow solid.
Reaction SMILES: O=O.C(NC(C)C)(C)C.C([Li])CCC.[C:15]([O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)([CH3:18])([CH3:17])[CH3:16].Br[CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34].[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C.C1CCCCC1.C(OCC)(=O)C>[F:34][C:33]([F:36])([F:35])[CH2:32][CH2:31][CH:21]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:29]
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Reactant: FC(F)(F)CCBr
Agent: O=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C(CCC(F)(F)F)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under exclusion of oxygen, 0.88 ml (6.3 mmol) of diisopropylamine was initially charged in 20 ml of THF, the mixture was cooled to −78° C. and 2.52 ml (6.3 mmol) of a 2.5 M solution of n-butyllithium in hexane were added slowly. The reaction solution was then warmed to −10° C. and stirred at this temperature for 10 min. The reaction solution was then once more cooled to −78° C., and 1 g (4.85 mmol) of tert-butyl(4-methylphenyl)acetate, dissolved in 10 ml of THF, was added slowly. The reaction solution was then slowly warmed to −30° C. and subsequently once more cooled to −78° C. After this temperature had been reached, 0.62 ml (5.82 mmol) of 3-bromo-1,1,1-trifluoropropane was slowly added dropwise. After the addition had ended, the solution was slowly warmed to room temperature and stirred overnight. After TLC check (mobile phase cyclohexane/ethyl acetate 10:1), saturated ammonium chloride solution was added and the mixture was taken up in ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 542 mg (1.79 mmol, 37% of theory) of a yellowish oil.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[C:14]([O:24][CH3:25])(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[K+]>>[C:17]1([C:16]2[C:15]([C:14]([O:24][CH3:25])=[O:23])=[CH:10][NH:11][CH:12]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C=Cc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)c1c[nH]cc1-c1ccccc1
Yield: 52.2 %

Procedure:
Using p-toluenesulfonylmethyl isocyanide (10.1 g), methyl cinnamate (8.33 g) and potassium tert-butoxide (6.97 g), a procedure as in Reference Example 39 was performed to give the title compound as pale-yellow crystals (yield 5.40 g, 52%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]([NH:17][C:18](=[O:20])[CH3:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].Cl>CO>[C:18]([NH:17][C:14]1[C:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:12][C:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)=[CH:16][N:15]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1ncc(-c2ccc(OC(C)=O)cc2)nc1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
5-(4-Acetoxyphenyl)-2-acetylamino-3-benzylpyrazine (c-33) (355 mg, 982 μmol) was dissolved in methanol (8 mL), to which was added 10% (w/v) aqueous solution of sodium hydroxide (1.8 mL) while stirring at room temperature and then stirred for an hour. To this was added 2 M hydrochloric acid to stop the reaction and extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure. After purifying the residue by column chromatography (37 g, n-hexane/ethyl acetate=1/2), the obtained solid was recrystallized from methanol to give 2-acetylamino-3-benzyl-5-(4-hydroxyphenyl)pyrazine (coelenteracetamide) (c-25) as a colorless solid (109 mg, 34.8%). Rf=0.23 (n-hexane/ethyl acetate=1/2). UV (MeOH) λmax (log ε) 332 (4.14), 294 (4.15), 275.5 (4.12). UV (pH 7.4 PB) λmax (log ε) 328 (4.14), 289.5 (4.03), 270 (4.08). 1H NMR (400 MHz, DMSO-d6) δ 2.03 (s, 3H), 4.13 (s, 2H), 6.84-6.89 (AA′BB′, 2H), 7.14-7.21 (m, 3H), 7.23-7.29 (m, 2H), 7.89-7.94 (AA′BB′, 2H), 8.80 (s, 1H), 9.91 (s, 1H), 10.21 (s, 1H). IR (KBr, cm−1) 592, 631, 702, 746, 837, 1128, 1157, 1173, 1211, 1231, 1279, 1314, 1368, 1435, 1497, 1518, 1543, 1582, 1591, 1611, 1672, 3026, 3073, 3254. HRMS (FAB+) m/z 320.1399 (M+H, C19H18N3O2 requires 320.1399).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[N+:12]([O-])=O>CO.[Pd]>[CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[NH2:12]
Reactant: COC(Cc1cccc(C)c1[N+](=O)[O-])OC
Agent: [Pd]
Solvent: CO
Product: COC(Cc1cccc(C)c1N)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
Add to a round bottomed flask containing 1-(2,2-dimethoxyethyl)-3-methyl-2-nitrobenzene (1.1 g) in methanol (50 mL), 10% palladium on carbon (0.13 g). Purge with nitrogen then place under a hydrogen atmosphere using a balloon of hydrogen. Stir overnight at room temperature. Filter through Celite, wash with methanol. Concentrate to give product (0.98 g, 103%) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 2.05 (s, 3H), 2.71 (d, J=5.36 Hz, 211), 3.23 (s, 6H), 4.52 (m, 3H), 6.42 (m, 1H), 6.80 (d, J=7.31 Hz, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]3[CH2:22][NH:21][C:20]([CH3:24])([CH3:23])[C:12]=3[N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].CCOC(C)=O.CCCCCC>ClCCl>[CH3:38][C:37]([CH3:40])([CH3:39])[C:36]([N:21]1[CH2:22][C:11]2[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:26][CH:25]=3)=[N:14][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12]=2[C:20]1([CH3:23])[CH3:24])=[O:41]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(F)cc2)c2c1C(C)(C)NC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)n1nc(NC(=O)c2ccc(F)cc2)c2c1C(C)(C)N(C(=O)C(C)(C)C)C2
Yield: 81.7 %

Procedure:
Ethyl 3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate hydrochloride (2.0 g, 5.77 mmol) in dichloromethane (70 ml) was treated, at 0° C., with N,N-diisopropylethylamine (1.6 ml, 9.2 mmol, 1.6 eq) and with pivaloyl chloride (780 μL, 6.3 mmol, 1.1 eq). Gradually, the reaction was brought to room temperature and stirred overnight (TLC: CH2Cl2/EtOAc 90/10). The solution was washed with saturated sodium hydrogencarbonate aqueous solution and brine. The organic phase was dried over sodium sulfate, evaporated and purified by flash chromatography (eluent: CH2Cl2/EtOAc 90/10) to afford 2.03 g of the title compound in 82% yield.