Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:18][C:19]([F:35])([F:34])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]([N:11]1[CH2:16][CH2:15][CH:14]([NH:33][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:34])[F:35])=[CH:21][CH:22]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:12]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)N1CCC(=O)CC1
Reactant: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A mixture of 1,1-dimethylethyl 2-methyl-2-(4-oxo-1-piperidinyl)propanoate (Int. A6) (370 mg, 1.2 equiv), {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amine (Int. A1) (397 mg, 1 equiv), sodium triacetoxyborohydride (400 mg, 1.5 equiv), DCM (10 ml) and acetic acid (0.076 ml, 1 equiv) was combined and stirred at room temperature until LCMS confirmed disappearance of the amine starting material (approx. 18 hours). Aqueous sodium carbonate was added and then extracted with DCM. The organics were dried over sodium sulfate and concentrated to give a solid (420 mg) that was used without further purification.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([F:34])=[C:6]([CH:31]=[CH:32][CH:33]=1)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:29][CH3:30])=[C:15]([O:18][C@H:19]3[CH2:23][N:22]([CH3:24])[CH:21]([C:25]([O:27]C)=[O:26])[CH2:20]3)[CH:16]=2)[N:11]=[CH:10][N:9]=1>CO>[Cl:3][C:4]1[C:5]([F:34])=[C:6]([CH:31]=[CH:32][CH:33]=1)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:29][CH3:30])=[C:15]([O:18][C@H:19]3[CH2:23][N:22]([CH3:24])[CH:21]([C:25]([OH:27])=[O:26])[CH2:20]3)[CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: COC(=O)C1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CC(C(=O)O)N(C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.2 %

Procedure:
2M NaOH (1 ml, 2 mmol) was added to a stirred solution of 4-(3-chloro-2-fluoroanilino)-6-[(2RS,4R)-1-methyl-2-(methoxycarbonyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline (250 mg, 0.54 mmol) in methanol (5 ml) and the mixture stirred at room temperature for 18 hours. The reaction mixture was evaporated and the residues re-dissolved in water (50 ml). This was then washed with ethyl acetate (25 ml) and the aqueous phase evaporated to dryness and azeotroped with toluene. The residues were triturated with methylene chloride/methanol (9/1) (25 ml), filtered and the liquors evaporated to give 4-(3-chloro-2-fluoroanilino)-6-[(2RS,4R)-1-methyl-2-carboxypyrrolidin-4-yloxy]-7-methoxyquinazoline as a white foam (155 mg); Mass Spectrum: (M+H)+ 447,
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]=[CH:18][N:19]([CH2:21][CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[N:38]1[CH:43]=[CH:42][CH:41]=C[CH:39]=1.ClC(OC1C=CC=CC=1)=[O:46].C1(N)CC1>CN(C=O)C.O>[CH:43]1([NH:38][C:39](=[O:46])[NH:1][C:2]2[CH:36]=[CH:35][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[N:17]=[CH:18][N:19]([CH2:21][CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[CH:20]=5)[S:15][C:8]=34)=[C:4]([F:37])[CH:3]=2)[CH2:41][CH2:42]1
Reactant: COCCN(CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1ccncc1
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: COCCN(CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a stirred solution of amine 251 (1.2 g, 2.27 mmol) and pyridine (368 μL, 4.55 mmol) in DMF (11 mL) at 0° C. was added phenyl chloroformate (342 μL, 2.73 mmol) and the reaction mixture was stirred for 30 min. Cyclopropylamine (401 μl, 5.69 mmol) was added at 0° C. and the reaction mixture was heated at 60° C. for 45 min. After cooling to RT, the reaction mixture was diluted with water and a saturated solution of ammonium chloride and extracted with AcOEt. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV), to afford the title compound 252 (1 g, 1.63 mmol, 72% yield) as a beige solid. MS (m/z): 611.70 (M+H).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18](O)[CH:17]=3)[C:12](F)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1N=C(Cl)C([C:32]([F:35])([F:34])[F:33])=CN=1.NC1C=CC([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=CC=1>>[CH2:47]([O:46][C:44]([CH2:43][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:18][CH:17]=3)[C:12]([C:32]([F:33])([F:34])[F:35])=[CH:11][N:10]=2)=[CH:3][CH:2]=1)=[O:45])[CH3:48]
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Product: CCOC(=O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(CC(=O)OCC)cc3)n2)cc1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-trifluoromethylpyrimidine and ethyl 4-aminophenylacetate were reacted to yield N2,N4-bis[4-(ethoxycarbonylmethyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.31 (s, 1H), 7.46 (d, 2H, J=9.0 Hz), 7.45 (d, 2H, J=8.7 Hz), 7.30 (d, 2H, J=9.0 Hz), 7.18 (d, 2H, J=8.7 Hz), 7.16 (bs, 1H), 6.82 (bs, 1H), 4.16 (2q, 4H, J=7.8 Hz), 3.64 (s, 2H), 3.57 (s, 2H), 1.27 (t, 3H, J=7.8 Hz), 1.26 (t, 3H, J=7.8 Hz); 19F NMR (CDCl3): −17223; LCMS: ret. time: 28.07 min.; purity: 99%; MS (m/e): 504 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]2[O:34][N:33]=[C:32]([CH2:35][CH2:36][OH:37])[N:31]=2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]3[O:34][N:33]=[C:32]([CH2:35][CH2:36][OH:37])[N:31]=3)=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cc1nc(Cl)ccc1-c1nc(CCO)no1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1-c1nc(CCO)no1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (51 mg, 0.17 mmol) and 2-[5-(6-chloro-2-methylpyridin-3-yl)-1,2,4-oxadiazol-3-yl]ethanol (40 mg, 0.17 mmol) as starting materials.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([CH:22]=[CH:23][C:24]([OH:26])=O)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(Cl)[Cl:30].C(=O)([O-])[O-].[Na+].[Na+].[C:39](Cl)([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>O>[C:39]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH:23][C:24]([Cl:30])=[O:26])=[CH:27][CH:28]=1)([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: ClC(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1ccc(C=CC(=O)Cl)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 15 g. 4-(hexadecylamino)cinnamic acid in 200 ml. warm chloroform is added 15 g. sodium carbonate in 150 ml. water. To the vigorously stirred solution is added 10 g. carbobenzyloxy chloride. After 2 hours stirring at 40° C., the layers are separated, washed three times with 1 N hydrochloric acid, dried, and evaporated to an oil. The oil is dissolved in 300 ml. toluene, treated with 15 ml. thionyl chloride and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, evaporating each time to yield a viscous, orange oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]4[C:17]=3[CH2:18][CH2:19][CH2:20]4)[CH:12]=[CH:11][C:10]=2[O:29][CH3:30])=[CH:6][CH:7]=1.C([O-])(=[O:33])C.[Na+]>C(O)(=O)C>[CH3:30][O:29][C:10]1[CH:11]=[CH:12][C:13]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[CH:14][C:9]=1[CH2:8][C:5]1[CH:6]=[CH:7][C:2](=[O:33])[NH:3][N:4]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1Cc1ccc(Cl)nn1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1Cc1ccc(=O)[nH]n1
Reaction time: 0.5 h
Yield: 284.7 %

Procedure:
A suspension of 3-chloro-6-[2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)benzyl]pyridazine (760 mg) and sodium acetate (50 mg)in acetic acid (10 mL) was heated at reflux temperature under an argon atmosphere for 2 hours. The reaction mixture was evaporated under reduced pressure to dryness. After adding water (15 mL), the residue was stirred for 30 min. The mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 6-[2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)benzyl]-2H-pyridazine-3-one (707 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](CO)=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: OCc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCc4ccc(Cl)cc4)cc3C)c2cc1OC
Yield: 101.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (4-chlorophenyl)methanol (67 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (154 mg, yield 94%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9]>O>[C:5]1(=[O:10])[O:1][CH2:2][CH2:3][CH2:4]1.[CH2:9]([OH:1])[CH2:8][CH2:7][CH2:6][OH:10]
Reactant: CCCCO
Reactant: C1CCOC1
Solvent: O
Product: O=C1CCCO1
Product: OCCCCO

Procedure:
The resulting product vapors were condensed to give a mixed condensate comprising butyrolactone (GBL), 1,4-butanediol (DIOL), tetrahydrofuran (THF), butanol (BUOH), and water. The condensate obtained was analyzed by gas-liquid chromatography, and it was found that 31.1 parts of butyrolactone and 64.5 parts of butanediol were produced per 100 parts of butyrolactone fed. This corresponds to 68.4% conversion of the butyrolactone and 92.3% selectivity to butanediol.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:7].[CH3:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15](O)[CH:14]=1>>[Cl:7][C:15]1[CH:14]=[C:13]([CH3:12])[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc(O)ncc1[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
Add phosphorus oxychloride (0.6 mmol, 0.05 mL) and phosphorus pentachloride (0.6 mmol, 0.12 g) over 4-methyl-5-nitro-pyridin-2-ol (1.9 mmol, 0.3 g). Stir at 120° C. for 1.5 hours. Cool down, add ice-water and extract in CH2Cl2. Wash combined organic layers with saturated aq. sodium chloride solution. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 2-chloro-4-methyl-5-nitro-pyridine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:20]=[C:21]([C:29]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32][NH:31][CH2:30]2)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:27][C:25]([F:26])([F:28])[C:23]1[CH:22]=[C:21]([C:29]2([C:34]([F:37])([F:35])[F:36])[CH2:33][CH2:32][N:31]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=3)[CH2:30]2)[CH:20]=[C:19]([C:18]([F:17])([F:38])[F:39])[CH:24]=1
Reactant: FC(F)(F)c1cc(C(F)(F)F)cc(C2(C(F)(F)F)CCNC2)c1
Reactant: CCOC(=O)c1ccc(Cl)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 100 °C
Yield: 79.8 %

Procedure:
Ethyl 2-chloro-6-(trifluoromethyl)pyridin-5-carboxylate (0.95 g), 3-[3,5-bis-(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidine (1.4 g) and potassium carbonate (0.7 g) were added to N,N-dimethylformamide (30 ml), and heated for 5 hours at 100° C. After cooling, the reaction mixture was poured in ice water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and purified by silica gel column chromatography to obtain ethyl 6-{3-[3,5-bis-(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-(trifluoromethyl)nicotinate (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[C:14]3[CH:15]=[C:16]([N:19]4[CH2:24][CH2:23][NH:22][C@H:21]([CH3:25])[CH2:20]4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH3:9])=[C:4]([F:26])[CH:3]=1.C(OC([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39](O)=[O:40])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[C:14]3[CH:15]=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([C:39]([C@H:35]5[CH2:36][CH2:37][CH2:38][NH:34]5)=[O:40])[C@H:21]([CH3:25])[CH2:20]4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH3:9])=[C:4]([F:26])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4F)c3c2)CCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4F)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
To a stirred solution of 1-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-6-((R)-3-methylpiperazin-1-yl)-1H-benzo[d]imidazole (0.044 g, 0.11 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.047 g, 0.22 mmol) in dichloromethane (1 mL) was added HATU (0.084 g, 0.22 mmol) and Et3N (0.10 mL, 0.72 mmol). The reaction mixture was stirred at room temperature for 2 h, and diluted with ethyl acetate. The mixture was washed with deionized water, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to afford the desired product (0.018 g, 0.031 mmol, 28%).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])N.[C:6]1([NH2:16])[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1>CN1CCCC1=O.ClC1C=CC=CC=1Cl>[NH2:16][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([S:1]([OH:3])(=[O:5])=[O:4])=[CH:8][CH:7]=1
Reactant: NS(=O)(=O)O
Reactant: Nc1cccc2c1CCCC2
Solvent: Clc1ccccc1Cl
Solvent: CN1CCCC1=O
Product: Nc1ccc(S(=O)(=O)O)c2c1CCCC2
Temperature: 150 °C
Reaction time: 7 h
Yield: 48.6 %

Procedure:
A hot suspension of 20 g of sulphamic acid in 40 ml of N-methylpyrrolidone is added to a solution of 10 g of 5,6,7,8-tetrahydronaphthylamine in 100 ml of 1,2-dichlorobenzene. The mixture is heated with stirring for 7 hours at 150° C. The product is filtered off and washed with dichlorobenzene and then with toluene. The precipitate is resuspended in 70 ml of water and neutralized to pH 7 with 5.5 ml of 30% sodium hydroxide. The insoluble matter is filtered off and the aqueous phase is extracted with ether. The aqueous phase is adjusted to pH 5 by adding HCl, at 5° C.; the mixture is filtered, and the residue is washed with water and dried to obtain 7.5 g of the expected product.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([OH:12])([CH3:11])[CH3:10].[Cl:13][C:14]1[CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[CH:18][C:19]=1F>CC(N(C)C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[CH:18][C:19]=1[O:12][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(O)c1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(Oc1ccc([N+](=O)[O-])cc1Cl)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 220 mg, 5.50 mmol) was suspended in DMA (30 ml) and 2-pyridin-2-ylpropan-2-ol (obtained as described in Organometallics, 1997, 16, 3303, 754 mg, 5.50 mmol) was added under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at ambient temperature, then cooled to 0° C. 3-Chloro-4-fluoronitrobenzene (878 mg, 5.00 mmol) was added as a solution in DMA (15 ml); the mixture was warmed to room temperature, and was stirred for 2 hours. The mixture was concentrated in vacuo, and the residue partitioned between ethyl acetate (75 ml) and water (75 ml). The aqueous layer was extracted with ethyl acetate (75 ml), and the extractions combined with the organic layer. The combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography, eluting with 0 to 20% ethyl acetate in iso-hexane, giving 2-[1-(2-chloro-4-nitrophenoxy)-1-methylethyl]pyridine as a pale yellow solid (810 mg, 55%); NMR Spectrum (DMSO-d6, 400 MHz, CDCl3) 1.91 (s, 6H), 6.40 (d, 1H), 7.25 (ddd, 1H), 7.50 (d, 1H), 7.70 (ddd, 1H), 7.82 (dd, 1H), 8.30 (d, 1H), 8.65 (d, 1H); Mass spectrum MH+ 293.0, 295.0.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[CH:15]=[C:14]([CH2:16]O)[NH:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C)C=O.ClCCl>[Cl:3][CH2:16][C:14]1[NH:13][N:12]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(-c2ccccc2)n[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cc(-c2ccccc2)n[nH]1

Procedure:
At 20° C., 6.1 ml of thionyl chloride and 10 drops of dimethylformamide are added to a solution of 7.3 g (42.0 mmol) of (3-phenyl-1H-pyrazol-5-yl)methanol in 220 ml of dichloromethane. The mixture is then boiled under reflux for 12 h. The solvent is then removed from the reaction mixture. The residue is taken up in 100 ml of dichloromethane, and a saturated sodium bicarbonate solution is added to the mixture until a pH of from 6 to 7 is established. The mixture is then freed from the solvent under reduced pressure and dried. This gives 5.65 g of the desired product which is reacted further without further purification; log P(HCOOH): 2.05 with MS (ESI): 193.1/195.1 ([M+H]+).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[C:8]([C:15]([F:18])([F:17])[F:16])[C:7]=1[NH2:19]>O1CCCC1.[Zn]>[Cl:5][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[C:8]([C:15]([F:18])([F:17])[F:16])[C:7]=1[NH2:19]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(N)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
Acetic acid (13 mL) was added slowly to a mixture of zinc dust (12.4 g) and 2-chloro-4-nitro-6-trifluoromethyl-phenylamine (4 g) in tetrahydrofuran (40 mL). The reaction mixture was stirred for 1 hour, filtered through silica and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 2.9 g (83%) of the title compound as a black solid. 1H NMR (500 MHz, CDCl3): 3.44 (b, 2H), 4.16 (b, 2H), 6.77 (d, 1H), 6.86 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]3[CH2:14][CH2:13][C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:8]3=[N:9][C:10]=2[CH:11]=1.[C:23]([CH2:27][CH2:28][C:29](Cl)=[O:30])([O:25][CH3:26])=[O:24].N1C=CC=CC=1>CC(N(C)C)=O>[CH3:26][O:25][C:23](=[O:24])[CH2:27][CH2:28][C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]3[CH2:14][CH2:13][C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:8]3=[N:9][C:10]=2[CH:11]=1)=[O:30]
Reactant: Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Reactant: COC(=O)CCC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Temperature: 0 °C

Procedure:
6-amino-3-benzylidene-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one (2.5 g) was reacted with 3-carbometoxy propionyl chloride (1.95 g) in dimethylacetamide (110 ml) in the presence of pyridine (2 ml) at room temperature for 18 hours. The reaction mixture was then diluted with ice water and the precipitate was filtered and washed with water to give 3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-propanoic acid methyl ester, m.p. 288°-291° C. (3.3 g) which was dissolved in dimethylformamide (120 ml) and treated with 5% aqueous NaOH (32.5 ml) at room temperature for 3 hours. The precipitate, 3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-propanoic acid, sodium salt, m.p. >300° C., was filtered and washed with water, then it was dissolved in formic acid and the solution was diluted with water to give a precipitate which was filtered and washed with water until neutral to give 2.07 g of 3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-propanoic acid, m.p. 250°-255° C. dec., NMR (DMSO d6) δ ppm., 2.62 (bs) (4H, --COCH2CH2 --COOH), 3.18 (m) (2H, C-2 protons), 4.08 (t) (2H, C-1 protons), 7.30-7.70 (m) (7H, C-5 and C-7 protons and phenyl protons), 7.98 (d) (1H, C-8 proton), 8.07 (t) (1H, --CH=), 10.31 (ds) (1H, --NHCO--).