Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=[C:7]2[N:23]([CH3:25])[CH3:24])(=[O:3])[CH3:2].[C:26](OCC)(=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28].CCOCC.[H-].[Na+]>CN(C)C=O.Cl.O>[CH3:25][N:23]([CH3:24])[C:7]1[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]3[O:14][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:2][C:1](=[O:3])[C:4]=3[CH:5]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCc1c(O)c(C(C)=O)cc2c(N(C)C)cc(C(=O)OCC)nc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c2nc(C(=O)OCC)cc(N(C)C)c2cc2c(=O)cc(C(=O)OCC)oc12
Reaction time: 7 h

Procedure:
A mixture of the product of step (b) (1.6 g; 4.8426 mmole) and diethyl oxalate (5.7 g; 39.041 mmole; 5.3 ml) in dry dimethylformamide (60 ml) was added slowly to a stirring suspension of ether washed sodium hydride (0.29 g; 12.0808 mmole) in dry dimethylformamide (10 ml) under nitrogen. After the addition, the mixture was allowed to stir for 7 hours. The reaction mixture was poured onto ice and was then acidified with dilute hydrochloric acid. The pH of the mixture was adjusted to about 6 before being extracted into chloroform. This was washed with water, dried and evaporated to give a yellow solid. The solid was taken up in ethanolic hydrogen chloride (50 ml) and heated to reflux on the steambath for 3 hours. The solution was cooled, treated with water and then concentrated. The pH of the mixture was adjusted to about 7 and then extracted into chloroform. The extract was washed with water, dried and evaporated, to give a brown solid.
Reaction SMILES: C(C1C=C2C(=CC=1)N=C(C(OCC)=O)NC2=O)#N.[CH3:19][C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([O:32]CC)=O)=[N:24][C:23]=2[S:22][CH:21]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:42]2[CH:46]=[N:45][C:44]([S:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]3[CH:54]=[C:55]([CH2:59][NH2:60])[CH:56]=[CH:57][CH:58]=3)=[N:43]2)C=CC=CC=1>>[CH3:19][C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([NH:60][CH2:59][C:55]3[CH:56]=[CH:57][CH:58]=[C:53]([O:52][CH2:51][CH2:50][CH2:49][CH2:48][S:47][C:44]4[N:45]=[CH:46][NH:42][N:43]=4)[CH:54]=3)=[O:32])=[N:24][C:23]=2[S:22][CH:21]=1
Reactant: NCc1cccc(OCCCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(C)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Product: Cc1csc2nc(C(=O)NCc3cccc(OCCCCSc4nc[nH]n4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Example 15, and using, instead of ethyl 6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxylate, ethyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained according to the method described in 034054656 and using, instead of 1-{3-[(3-{(1 (triphenylmethyl)-1H-1,2,4-triazol-3-yl]thiopropyl)oxy}phenyl}methaneamine, 1-{3-[(4-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}butyl)oxy]phenyl}methanamine obtained in Reference Example 11, the title compound was obtained as a pales yellow powder (232 mg, 48%).
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]1([NH:22][S:23](Cl)(=[O:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[C:16]1([NH:22][S:23]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][Br:2])[CH2:11][CH2:12]2)(=[O:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCCCCOC1CCNCC1
Reactant: O=S(=O)(Cl)Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccccc1)N1CCC(OCCCCCCBr)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 135.2 %

Procedure:
A solution of 3 g (10 mmol) 4-(6-Bromo-hexyloxy)-piperidine hydrochloride and 3.44 g (18 mmol) of Phenylsulfamoyl chloride in 100 ml dry CH2Cl2 was treated with 6.95 ml (49.9 mmol) of triethylamine. The reaction was stirred for 4 h at RT, diluted with CH2Cl2 and washed with water. The organic phase was dried (MgSO4) and evaporated to yield 5.67 g (quantitative) of 4-(6-Bromo-hexyloxy)-piperidine-1-sulfonic acid phenylamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([F:16])[CH:4]=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][CH2:2][C:3]2[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([F:16])[CH:4]=2)=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)Nc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 56.6 %

Procedure:
N-(4-Aminomethyl-2-fluoro-6-vinylphenyl)methanesulfonamide (37.8 mg, 0.11 mmol), 1-tert-butyl-4-isocyanatobenzene (1.2 eq, 0.13 mmol, 22.49 μl), and TEA (3 eq, 0.33 mmol, 45.99 μl) were added in methylene chloride. The reaction mixture was stirred for 12 hrs. The reaction mixture was extracted with methylene chloride. A combined organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified with column chromatography (n-Hx:EA=1:1) to yield title compound (26.1 mg, 55%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9](N(OC)C)=[O:10])[N:8]=2)[CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH:1]1([C:4]2[O:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=2)[CH2:3][CH2:2]1
Reactant: CON(C)C(=O)c1coc(C2CC2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1coc(C2CC2)n1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-cyclopropyl-N-methoxy-N-methyloxazole-4-carboxamide (0.102 g, 0.52 mmol) in dry dichloromethane (15 mL) was added diisobutylaluminum hydride (1M in toluene) (1.04 ml, 1.04 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes. The reaction mixture was quenched with aqueous sodium hydroxide (2M) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 2-cyclopropyloxazole-4-carbaldehyde which was used without further purification. (65 mg) MS (API-ES+) (M+H) 138.2.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1.[Cl-].[Cl-].[Ca+2]>C(O)C.O.[Fe]>[F:1][C:2]1[CH:26]=[C:25]([CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)[NH2:27]
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc(N)cc1F
Yield: 83.6 %

Procedure:
5-[4-(2-Fluoro-4-nitrophenoxy)biphenyl-3-yl]-1-methyl-1H-pyrazole (Preparation 29, 870 mg, 2.33 mmol) was dissolved in ethanol (8 mL) and water (2 mL). Iron powder (624 mg, 11.17 mmol) and CaCl2 (248 mg, 2.33 mmol) were then added and the reaction mixture was refluxed for 3 hours. After filtration through Celite™, the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 15% ethyl acetate in hexane) to afford the title compound (700 mg, 84%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C@H:10]([O:35][CH2:36][C@H:37]([OH:41])[CH2:38][O:39][CH3:40])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:43][CH2:44][CH2:45][O:46][CH2:47][C:48]1[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:49]=1[O:55][CH3:56]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:43][CH2:44][CH2:45][O:46][CH2:47][C:48]3[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:49]=3[O:55][CH3:56])=[CH:30][CH:29]=2)[C@H:10]([O:35][CH2:36][C@H:37]([OH:41])[CH2:38][O:39][CH3:40])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(F)cc1COCCCCl
Reactant: COC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(O)cc1
Product: COC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2cc(F)ccc2OC)cc1

Procedure:
In analogy to the procedure described in example 1(e) the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-4-(4-hydroxy-phenyl)-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was treated with the 2-(3-chloro-propoxymethyl)-4-fluoro-1-methoxy-benzene [example 11(α)] to yield the (3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 764 (M+H)+.
Reaction SMILES: [NH:1]([C:9]([CH3:11])=[O:10])[C@@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:34]([O:38][C:39]([C:41]1[C:49]2[CH2:48][CH2:47][O:46][CH:45]([CH2:50][NH2:51])[C:44]=2[S:43][C:42]=1[NH2:52])=[O:40])([CH3:37])([CH3:36])[CH3:35].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[C:34]([O:38][C:39]([C:41]1[C:49]2[CH2:48][CH2:47][O:46][CH:45]([CH2:50][NH:51][C:6](=[O:8])[C@H:2]([NH:1][C:9](=[O:10])[CH3:11])[CH:3]([CH3:4])[CH3:5])[C:44]=2[S:43][C:42]=1[NH2:52])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Reactant: CC(=O)N[C@@H](C(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N[C@@H](C(=O)NCC1OCCc2c1sc(N)c2C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of Ac-D-Val-OH (0.17 g, 1.09 mmol) dissolved in dichloromethane (15 ml) was added N,N-dimethylformamide (1 ml), 1-hydroxybenzotriazole (0.15 g, 1.09 mmol) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (0.21 g, 1.09 mmol). The reaction mixture was stirred for 15 min. at room temperature at which time a solution of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.31 g, 1.09 mmol) in dichloromethane (10 ml) was added followed by N,N-diisopropylethylamine (0.186 ml, 1.09 mmol). The resulting mixture was stirred over night at room temperature diluted with dichloromethane (10 ml) washed with 10% aqueous citric acid (20 ml), sodium hydrogencarbonate, dried (MgSO4), filtered and the solvent was evaporated in vacuo affording 415 mg (90%) of 7-((2-(R)-acetylamino-3-methyl-butyrylamino)methyl)-2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][OH:20]>>[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][O:20][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: Cn1ccnc1CO
Reactant: CCOC(=O)c1ccc(Cl)nc1
Product: Cn1ccnc1COc1ccc(C(=O)O)cn1
Yield: 46 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 46% yield starting from ethyl 6-chloronicotinate and (1-methyl-1h-imidazol-2-yl)methanol; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (d, 1 H), 8.24 (dd, 1 H), 7.58-7.74 (m, 2 H), 7.06 (d, 1 H), 5.69 (s, 2 H), 3.92 (s, 3 H); MS (APPI/APCI) m/z 234[M+H+].
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[CH:2]1.CN(C)C=O.Br[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[C:13]([CH2:12][N:3]1[CH2:4][CH2:5][N:1]=[CH:2]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: C1=NCCN1
Reactant: O=C(CBr)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1C=NCC1)OCc1ccccc1

Procedure:
To a solution of 14.0 g. (0.2 mole) of imidazoline in 150 ml. of dry dimethylformamide is added dropwise with cooling 22.9 g. (0.1 mole) of benzyl bromoacetate. When the addition is complete, the reaction is warmed to 50°-60° C. for several hours, and is then cooled and diluted with water (250 ml.). The product is extracted with diethyl ether, and the extracts are combined and washed several times with a saturated brine solution. The ether phase is dried over sodium sulfate and concentrated to an oil, which is used in the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[CH:6][C:5](Br)=[CH:4][C:3]=1[CH2:10]O.[NH2:12][C:13](N)=[O:14]>O>[OH:14][C:13]1[N:12]=[CH:10][C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:1]=1
Reactant: NC(N)=O
Reactant: Nc1c(Cl)cc(Br)cc1CO
Solvent: O
Product: Oc1ncc2ccccc2n1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
A mixture of (2-amino-5-bromo-3-chlorophenyl)methanol (3.3 g, obtained from step 3) and urea (10.5 g, 15 equiv.) was heated to 180° C. with vigorous stirring for 1 hr. The reaction was cooled to room temperature and water was added. The solid was collected by filtration. Air-dried to give 2-hydroxyquinazoline as a yellow powder (2.18 g, crude). ES/MS m/z 259/261 (MH+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[Cl:22]C1C=C(C=CC=1Cl)C=O>>[Cl:22][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(Cl)c2)s1

Procedure:
The title compound is prepared by an analogous procedure to N-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) by replacing 3,4-difluorobenzaldehyde with 3,4-dichlorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH2:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:14]([NH:22][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCCc1ccccc1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and phenethylamine. The product was purified by mass directed purification to give the title compound as an orange solid. δH (CD3OD): 2.94 (2H, t), 3.63 (2H, t), 7.00 (1H, s), 7.15-7.30 (5H, m), 7.64 (1H, s), 8.57 (1H, s); m/z (ES+)=300 [M+H]+.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[NH:63][N:64]=[C:65]([I:66])[C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:76]>CO.O>[ClH:76].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[NH:63][N:64]=[C:65]([I:66])[C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c(I)n[nH]c54)c3=O)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c(I)n[nH]c54)c3=O)cc2)CCC1
Yield: 56 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(3-iodo-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (2 mL), water (3 mL) and 1 M HCl (0.1 mL) and chromatographed on a 2 g C18 cartridge {gradient 40 to 80% MeOH in water+1 M HCl (60 μL in each 5 mL of eluent)} to give the title compound (2.1 mg, 56%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[NH:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:24]4[NH:23][CH:27]=[CH:26][CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1ccc[nH]1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccc[nH]4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 143 mg (1.5 mmol) of pyrrole-2-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(1H-pyrrol-2-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in DIPE yield 4-(3-chloro-phenylamino)-3-[(1H-pyrrol-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=8.2; FAB-MS: (M+H)+=340.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>O[Li].O>[CH2:1]([S:13][CH2:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CC(=O)OC
Reactant: CCCCCCCCCCCCS
Agent: [Li]O
Solvent: O
Product: CCCCCCCCCCCCSCCC(=O)OC
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
Into the same type of equipment used in Example 1 was charged 405 grams of 98% 1-dodecanethiol with stirring to 1.0 grams of LiOH·H2O and 181 grams of 99% methyl acrylate. The addition was over a period of 20 minutes and the temperature increased to 80°-85° C. The reaction was stirred an extra 2 hours at 85°-95° C. The reaction mixture was then stripped at 122° C. and 10 mm pressure. 582 grams of product was obtained. Product analysis by GC indicated a purity of 92.1%.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:20])[N:8]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:9]3=[N:10]2)=[CH:5][CH:4]=1.[CH3:23]I>>[CH3:23][N:13]1[C:9]2=[N:10][C:11]3[C:6]([C:7](=[O:20])[N:8]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]1=2)=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:12]=3
Reactant: CI
Reactant: O=c1c2ccc(C(F)(F)F)cc2nc2[nH]c3ccccc3n12
Product: Cn1c2ccccc2n2c(=O)c3ccc(C(F)(F)F)cc3nc12

Procedure:
6-Methyl-3-trifluoromethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-trifluoromethylbenzimidazo[2,1-b]-quinazolin-12(6H)one and methyl iodide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[OH:18].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].[H-].[Na+]>CN(C=O)C.CCOCC>[C:19]([O:23][C:24](=[O:27])[CH2:25][O:16][C:13]1[CH:14]=[CH:15][C:10]([S:9][S:8][C:6]2[CH:5]=[CH:4][C:3]([O:18][CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:27])=[C:2]([CH3:1])[CH:7]=2)=[CH:11][C:12]=1[CH3:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(SSc2ccc(O)c(C)c2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(SSc2ccc(OCC(=O)OC(C)(C)C)c(C)c2)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To an ice cooled solution of 4.75 g (17.06 mmol) 4,4′-dithio-bis-(2-methyl-phenol) and 5.55 ml (37.6 mmol) bromo-acetic acid tert-butyl ester in 50 ml DMF was added 204 mg (85.3 mmol) sodium hydride (55% in oil). The reaction mixture was stirred over night at RT and then it was taken up in ether, washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 providing 3.4 g pure [4-(4-tert-butoxycarbonylmethoxy-3-methyl-phenyldisulfanyl)-2-methyl-phenoxy]-acetic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC[O-].[Na+].C([O:18][C:19]([C:21]1[C:25]([NH2:26])=[N:24][N:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:22]=1)=O)C>CCO>[CH2:6]([O:5][C:3]([C:2]1[C:1]([OH:9])=[N:26][C:25]2=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH:22]=[C:21]2[C:19]=1[OH:18])=[O:4])[CH3:7]
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1N
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)nc2nn(Cc3ccc(OC)cc3)cc2c1O

Procedure:
To a solution of diethyl malonate (9.6 g, 60 mmol) in a freshly prepared solution of NaOEt in EtOH (from 2.52 g of 60% oil dispersion NaH and 40 mL of EtOH) was added a solution of 5-amino-2-p-methoxybenzyl4-pyrazolecarboxylic ethyl ester (4.2 g, 15 mmol) in EtOH (60 mL) at rt. The resulting solution was refluxed for 20 h. The mixture was concentrated and the residue was dissolved in H2O (250 mL) and washed with EtOAc (60 mL). The aqueous layer was acidified with AcOH to pH 5. The product (5.1 g) was collected by filtration and dried under high vacuum. LC: 3.47′ (Gradient 1); MH+: 344
Reaction SMILES: [NH2:1][C:2]1[C:17]([CH3:18])=[CH:16][C:15](Br)=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cu](C#N)[C:21]#[N:22]>CN1CCCC1=O>[NH2:1][C:2]1[C:17]([CH3:18])=[CH:16][C:15]([C:21]#[N:22])=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: Cc1cc(Br)cc(C(=O)OCc2ccccc2)c1N
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Product: Cc1cc(C#N)cc(C(=O)OCc2ccccc2)c1N
Yield: 50.9 %

Procedure:
The above-described method (Example 2) was repeated to react benzyl 2-amino-5-bromo-3-methylbenzoate (3.00 g, 7.38 mmol) with copper cyanide (0.772 g, 7.98 mmol) in N-methylpyrrolidone at 170° C. for 6 hours. Following working up similar to Example 2, additional extraction with ethyl acetate, washing with aqueous 5% ethylenediamine solution and column chromatography, benzyl 2-amino-5-cyano-3-methylbenzoate (1.00 g, 47.9% of theory, 97.0 area % LC) was obtained as a pale brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH:18]([F:20])[F:19]>CN(C)C=O.O>[F:19][CH:18]([F:20])[O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(O)c1
Yield: 25 %

Procedure:
To a well stirred suspension of 3,4-dihydroxy benzaldehyde (100 gm) and anhydrous potassium carbonate (120 gm) in dry N,N-dimethylformamide (1.0 lit) was passed chlorodifluoromethane gas for about 30 minutes at about 80-85° C. After an hour another lot of anhydrous potassium carbonate (25.0 gm) was added and stirred for about one and half hours. The third lot of anhydrous potassium carbonate (25.0 gm) was added and stirred for about one and half hours. The reaction mixture was then stirred for about 5-6 hours at an ambient temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified through silica gel column to give 4-difluoromethoxy-3-hydroxy benzaldehyde.