Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.CS(OS(C)(=O)=O)(=O)=O.[CH3:19][C:20]1[N:24]2[C:25]3[CH:31]=[C:30]([CH3:32])[N:29]([CH2:33][C:34]4[CH:35]=[C:36]([CH2:40]O)[CH:37]=[CH:38][CH:39]=4)[C:26]=3[CH:27]=[CH:28][C:23]2=[N:22][N:21]=1.S([O-])(=O)(=O)C.[CH2:47]([CH2:49][NH2:50])[OH:48]>C(Cl)Cl.C1COCC1.CO>[CH3:19][C:20]1[N:24]2[C:25]3[CH:31]=[C:30]([CH3:32])[N:29]([CH2:33][C:34]4[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=4)[CH2:40][NH:50][CH2:49][CH2:47][OH:48])[C:26]=3[CH:27]=[CH:28][C:23]2=[N:22][N:21]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(CO)c1
Reactant: NCCO
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: CS(=O)(=O)[O-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(CNCCO)c1
Reaction time: 1.5 h

Procedure:
Diisopropylethylamine (26 μL, 0.15 mmol) and methanesulphonic anhydride (13 mg, 0.073 mmol, Aldrich) were added to a solution of {3-[(1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]phenyl}methanol (15 mg, 0.049 mmol, from Step 1) in DCM (1.0 mL). The mixture was stirred until mesylate formation was determined complete as judged by LCMS, and the mixture was then concentrated. The residue was re-dissolved in a mixture of THF (0.50 mL) and MeOH (0.50 mL) and ethanolamine (12 μL, 0.20 mmol, Aldrich) was added and the reaction was stirred for 1.5 hours. The crude reaction mixture was purified using preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (8.5 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](OC(C)(C)C)=[O:9])=[C:6]([C:15]2[CH2:16][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH2:19][CH:20]=2)[CH:5]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[N:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1COCC1>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:15]2[CH2:16][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH2:19][CH:20]=2)[CH:5]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[N:3]=1
Reactant: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c(CO)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a cooled (0° C.) solution of di(tert-butyl) 2′-amino-6′-{2-[(4-methoxy-benzyl)oxy]phenyl}-5,6-dihydro-3,4′-bipyridine-1,3′(2H)-dicarboxylate (50.0 mg, 0.09 mmol) in THF (4.5 mL) was added sodium bis(2-methoxyethoxy)aluminum hydride (0.10 mL) dropwise, then stirred for 1 hr at 0° C. The reaction was quenched by an addition of saturated NH4Cl solution, filtered, and washed with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by preparative silica gel TLC (15% acetone in chloroform) to give tert-butyl 2′-amino-3′-(hydroxymethyl)-6′-{2-[(4-methoxybenzyl)oxy]phenyl}-5,6-dihydro-3,4′-bipyridine-1(2H)-carboxylate as a white foam (25 mg, yield 57%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:12])[CH:10]=[CH2:11])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:12])[CH:10]=[CH2:11])=[CH:7][CH:8]=1
Reactant: C=CC(O)c1ccc(C(F)(F)F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: C=CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 18.0 g (89.0 mmol) of the compound from Example 184A in 360 ml of dichloromethane was added dropwise to a solution of 45.3 g (107 mmol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one in 360 ml of dichloromethane at RT. After stirring at RT for 1 h, the reaction mixture was added to a mixture of saturated aqueous sodium bicarbonate solution and sodium thiosulfate and extracted three times with dichloromethane. The organic phase was dried, filtered and concentrated. 17.5 g (98% of theory) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[N:17]=2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([O:32][CH3:33])[CH:3]=1.O.[OH-].[K+]>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([O:32][CH3:33])=[CH:3][C:2]([Cl:1])=[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=3)[N:17]=2)[CH:14]=1
Reactant: COc1cc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)cc1CNC(=O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)cc1CN
Yield: 93.1 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-methoxybenzyl)-2,2,2-trifluoroacetamide (0.200 g), water (5 mL), KOH (0.200 g) and THF (10.0 mL) to afford 0.150 g of the desired product.
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][O:10][C:11]([C:13]1[C:21]2[S:20][C:19](N)=[N:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:12]>C1COCC1>[CH3:9][O:10][C:11]([C:13]1[C:21]2[S:20][CH:19]=[N:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: COC(=O)c1cccc2nc(N)sc12
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2ncsc12

Procedure:
Isoamyl nitrite (22.0 mmol) is added to a solution of 2-amino-benzothiazole-7-carboxylic acid methyl ester (10.1 mmol) in THF (29 mL). The mixture is heated to reflux for 4 h, the solvents are removed in vacuo and the residue is purified by flash chromatography (gradient: heptane to EtOAc/heptane 4/6) to give the desired product. LC-MS: tR=0.85 min; [M+H]+=194.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([CH:10]2[CH2:15][CH2:14][CH:13](C)[CH2:12][CH2:11]2)=[CH:7][C:8]=1[CH3:9].C1(C2N=NC(OC)=C(C)C=2C)CCCCC1.C1(C2N=NC=CC=2)C=CC=CC=1>>[CH:10]1([C:6]2[N:5]=[N:4][C:3]([O:2][CH3:1])=[C:8]([CH3:9])[CH:7]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1nnc(C2CCC(C)CC2)cc1C
Agent: COc1nnc(C2CCCCC2)c(C)c1C
Agent: c1ccc(-c2cccnn2)cc1
Product: COc1nnc(C2CCCCC2)cc1C

Procedure:
A mixture of 4-methyl-3-methoxy-6-phenylpyridazine (5.0 g), platinum dioxide (400 mg) and trifluoroacetic acid (20 mL) is shaken in a Parr apparatus until hydrogen uptake ceases. The catalyst is removed by filtration, and the cake is washed with additional acid. The filtrate is poured into water and adjusted to basic ph with sodium hydroxide. The solids which precipitate are collected, washed with water, and dried to give 4.6 g (90%) of product which, on crystallization from pentane, gives an analytically pure product having a melting point of 72°-74° C. 3-Methoxy-4-methyl-6-(4-methylcyclohexyl)pyridazine, melting point 84°-98° C. (Example 29a), and 3-cyclohexyl-6-methoxy-4,5-dimethylpyridazine, melting point 99°-101° C. (Example 29b) are also made by the above procedure using the corresponding 6-phenylpyridazine.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:4][N:3]1[S:5]([C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[N:23]([CH3:24])[C:22]([CH3:25])=[N:21][CH:20]=3)[CH:16]=[CH:15][N:14]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[O:32]1[CH2:33][CH2:34][N:29]([CH2:4][C:2]([NH:3][S:5]([C:8]2[CH:27]=[CH:26][C:11]([NH:12][C:13]3[N:18]=[C:17]([C:19]4[N:23]([CH3:24])[C:22]([CH3:25])=[N:21][CH:20]=4)[CH:16]=[CH:15][N:14]=3)=[CH:10][CH:9]=2)(=[O:7])=[O:6])([CH3:1])[CH3:28])[CH2:30][CH2:31]1
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)N4CC4(C)C)cc3)n2)n1C
Reactant: C1COCCN1
Product: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NC(C)(C)CN4CCOCC4)cc3)n2)n1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
2-[4-(2,2-Dimethylaziridin-1-ylsulphonyl)anilino]-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Example 47; 200 mg, 0.502 mmol) was dissolved on warming in morpholine (4.7 ml, excess) and stirred at room temperature for 3 days. The excess morpholine was removed in vacuo and the residue dissolved in EtOAc (40 ml) and washed with water (3×40 ml), dried the solvent evaporated in vacuo. The crude product was triturated with ether filtered washed with ether and air-dried to give the title compound (200 mg, 82%) as a white solid. NMR 1.03 (s, 6H), 2.27 (s, 2H), 2.38 (s, 3H), 2.47 (m, 4H), 3.52 (m, 4H), 3.95 (s, 3H), 7.05 (s, 1H), 7.2 (d, 1H), 7.63 (s, 1H), 7.72 (d, 2H), 7.88 (d, 2H), 8.43 (d, 1H), 9.86 (s, 1H); m/z 486.
Reaction SMILES: [N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[Cl:12]N1C(=O)CCC1=O>CN(C=O)C>[Cl:12][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[CH2:10][OH:11]
Reactant: OCc1cn2ccccc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: OCc1nc2ccccn2c1Cl
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a solution of imidazo[1,2-a]pyridin-2-ylmethanol (1.0 g, 6.75 mmol) in anhydrous DMF was added 1-chloropyrrolidine-2,5-dione (0.898 g, 6.75 mmol) at room temperature. The reaction mixture was allowed to stir for 2 hours. The solvent was evaporated, and the residue was purified by CombiFlash using dichloromethane and methanol (0-10%) to provide {3-chloroimidazo[1,2-a]pyridin-2-yl}methanol as a grey solid (0.799 g, 65% yield); M+1 183.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23]O)=[CH:21][C:20]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[N:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:25]4[CH:26]=[CH:27][C:28]([O:31][C:32]([F:34])([F:33])[F:35])=[CH:29][CH:30]=4)[CH:21]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2cc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)ccc21

Procedure:
In analogy to the procedure described for example 3 c], (5-hydroxy-indol-1-yl)-acetic acid ethyl ester was reacted with [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {5-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as colorless oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Mg].C1(CCO[C:20](=[O:32])[C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:22])C=CC=CC=1.[NH4+].[Cl-]>C1COCC1.C(C1C=C(O)C=CC=1O)(C)(C)C.CCCCCCC.C(OCC)(=O)C>[O:32]=[C:20]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)[C:21]([O:23][CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:22]
Reactant: O=C(OCCc1ccccc1)C(=O)OCCc1ccccc1
Reactant: C=Cc1ccc(Br)cc1
Agent: CC(C)(C)c1cc(O)ccc1O
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)C(=O)OCCc2ccccc2)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A Grignard reagent prepared from freshly distilled 4-bromostyrene (9.45 g, 51.6 mmol) and magnesium (1.31 g, 54.0 mmol) in THF (70 mL) was added dropwise to a stirred solution of bis(2-phenylethyl)oxalate (14.0 g, 46.9 mmol) in THF (120 mL) at −60° C. The mixture was left warming to room temperature, and then poured onto a mixture of ice (200 g) and a saturated solution of NH4Cl (200 mL). Extraction with diethyl ether (500 mL), washing with a saturated solution of NaCl (300 mL, 3×), re-extraction of the aqueous phase with ether, drying of the combined organic phases (Na2SO4), adding of tert-butyl hydroquinone (TBHQ, ca. 0.3 mg), concentrating and drying under vacuum (0.5 mbar, 0.5 h) afforded 19.40 g of the crude compound. Column chromatography (SiO2, heptane/ethyl acetate 98:2), adding of TBHQ (0.2 mg) to the product fractions, concentrating and drying under vacuum gave 8.95 g (68%) of the desired compound.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[O:21][C:20]=2[CH3:30])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[O:21][C:20]=2[CH3:30])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2cc(-c3ccncc3)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccncc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of cyclohexyl[2-methyl-5-(pyridin-4-yl)furan-3-yl]methanol (407 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (274 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (757 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (5% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give methyl 4-{cyclohexyl[2-methyl-5-(pyridin-4-yl)furan-3-yl]methoxy}benzoate as an amorphous compound. The obtained methyl 4-{cyclohexyl[2-methyl-5-(pyridin-4-yl)furan-3-yl]methoxy}benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N sodium hydroxide (2.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (261 mg, 45%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[N:16][CH:17]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:28][C:29]1[CH:33]=[C:32]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[O:31][N:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:14]([CH2:28][C:29]3[CH:33]=[C:32]([C:34]4[S:35][C:36]([Cl:39])=[CH:37][CH:38]=4)[O:31][N:30]=3)[C:15]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[N:16][CH:17]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COCCOCCOCc1ncc(C(=O)NC2CCN(C(C)C)CC2)[nH]1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOCCOCc1ncc(C(=O)NC2CCN(C(C)C)CC2)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 80 °C
Reaction time: 3 h
Yield: 7.1 %

Procedure:
A mixture of 2-[2-(2-Methoxy-ethoxy)-ethoxymethyl]-3H-imidazole-4-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide (55 mg), 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (46 mg), Cs2CO3 (98 mg), tetrabutylammonium iodide (8 mg) and DMF (3 mL) was stirred at 80° C. for 3 h. The solvent was removed in vacuo and the residue was taken up in DCM, washed with water, and the organic layer was dried over anhydrous MgSO4 and concentrated. The title compound (6 mg) was isolated after HPLC purification of the residue as its trifluoroacetate salt. MS (ESI+): m/e=566 [M+H]+, chloro pattern.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1.Cl[C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1>CN(C=O)C>[N:12]1[CH:13]=[CH:14][N:15]=[CH:16][C:11]=1[N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1
Reactant: Clc1cnccn1
Reactant: O=Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(-c2cnccn2)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.4 %

Procedure:
Sodium hydride (60% in oil, 720 mg, 18.0 mmol) was added to a 0° C. solution of 1H-imidazole-4-carboxaldehyde (2.20 g, 18.0 mmol) in DMF (8 mL). After stirring for 20 min at 0° C., the mixture was allowed to warm to RT and a solution of 2-chloropyrazine (2.06 g, 17.9 mmol) in DMF (4 mL) was added. The resulting mixture was heated to 100° C. for 18 h. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4), and concentrated to provide 3.10 g (86%) of the title compound. MS 175 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:24]C)[C:10](=[O:23])[N:11]3[CH2:19][CH:18]([CH2:20][OH:21])[O:17][C:16](=[O:22])[C:12]3=2)[C:7]1=[O:26].Br.[C:32](O)(=[O:34])[CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:24])[C:10](=[O:23])[N:11]3[CH2:19][CH:18]([CH2:20][O:21][C:32](=[O:34])[CH3:33])[O:17][C:16](=[O:22])[C:12]3=2)[C:7]1=[O:26]
Reactant: CC(=O)O
Reactant: COc1c2c(c3n(c1=O)CC(CO)OC3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Product: CC(=O)OCC1Cn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9-(3-chloro-4-fluorobenzyl)-3-(hydroxymethyl)-7-methoxy-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione (50 mg, 0.11 mmol) and 33% hydrogen bromide in acetic acid (0.1 g) in acetic acid (1 μL) was stirred at room temperature for 30 minutes. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2.[OH-].[Na+].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21]>>[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][N:14]([CH2:21][CH2:20][C:19]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2
Reactant: C=CC(=O)OCC
Reactant: c1cc(N2CCNCC2)c2ccsc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)CCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
5.05 g (19.8 mmol) of 1-Benzo[b]thiophen-4-yl-piperazine hydrochloride was added to an aqueous solution of sodium hydroxide, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 50 ml of ethanol and ethyl acrylate (2.44 ml, 21.8 mmol) was added thereto, then the reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Isopropyl ether was added to the residue to filter out insoluble matters. The insoluble matters were washed with isopropyl ether and dried to obtain ethyl 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propionate (5.26 g) as white powder.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C=C[S:42]C=3CCC2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[CH:14]=[CH:13][S:42][C:18]=3[CH2:17][CH2:16][CH2:15]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCCc3sccc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCCc3sccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ 7.10, 6.91, 5.32, 4.47, 2.83, 2.53, 2.10, 1.93, 1.27; (MS/CI) calcd for C16H20BrN3S+H 369.9, found 369.9.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[CH:10]=1)[CH3:2]>C(O)(=O)C>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[CH:10]=1)[CH3:2]
Reactant: CCn1cccc1Cc1cccc(NC(N)=O)c1
Solvent: CC(=O)O
Product: CCN1CCCC1Cc1cccc(NC(N)=O)c1
Reaction time: 1.25 h
Yield: 45.7 %

Procedure:
A solution of 4 g (20 mmol) of 1-ethyl-2-(3'-ureidobenzyl)pyrrole, prepared, for example, as described in Preparation 4D, in 100 ml of glacial acetic acid was hydrogenated at 45 p.s.i. in the presence of 3 g of 5% rodium on activated alumina as catalyst, for 75 minutes. The catalyst was then separated by filtration and the filtrate evaporated in vacuo. The residue was suspended in 100 ml of methylene chloride and 20 ml of concentrated ammonium hydroxide was added. The mixture was dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from ethyl acetate-hexane, to yield 2.26 g (46%) of the title compound, 1-ethyl-2-(3'-ureidobenzyl)pyrrolidine. M.P. 114°-116°
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:9]([O:11]C)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1)[C:9]([OH:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 0 °C

Procedure:
(S)-Methyl 2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propanoate (6.20 g, 17.9 mmol) was dissolved in THF (180 mL) and cooled to 0° C. A 0.2 M of aq. LiOH (89.3 ml, 17.9 mmol) was added dropwise and stirred 20 minutes before TLC analysis (2:1 Hexanes/EtOAc) showed no starting material. The PH of the reaction was carefully adjusted to PH=8 with 1 N HCl. The aqueous layer was washed with diethyl ether and the organics were back extracted with 1% aqueous sodium bicarbonate and the combined aqueous layers were carefully brought to a PH =4 and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to afford (S)-2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propanoic acid, which was used without further purification.
Reaction SMILES: [N:1]1(CCOC2C=CC(NC(N)=O)=CC=2)CCCC1.[N:19]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH2:25][N:26]([CH3:28])[CH3:27])=[C:20]=[S:21].N(C1C=CC(OCCN2CCCC2)=CC=1)=C=S.CN(CC1C=C(N)C=CC=1)C>C(Cl)Cl.CO>[CH3:27][N:26]([CH2:25][C:24]1[CH:23]=[C:22]([NH:19][C:20]([NH2:1])=[S:21])[CH:31]=[CH:30][CH:29]=1)[CH3:28].[N:19]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH2:25][N:26]([CH3:28])[CH3:27])=[C:20]=[S:21]
Reactant: NC(=O)Nc1ccc(OCCN2CCCC2)cc1
Agent: CN(C)Cc1cccc(N)c1
Agent: CN(C)Cc1cccc(N=C=S)c1
Agent: S=C=Nc1ccc(OCCN2CCCC2)cc1
Solvent: CO
Solvent: ClCCl
Product: CN(C)Cc1cccc(NC(N)=S)c1

Procedure:
The title compound is prepared as described in Example 1 for [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea but using (3-isothiocyanato-benzyl)-dimethyl-amine. Title compound: ES-MS: 210.0 [M+H]+; single peak at tR=3.38 min (System 1); Rf=0.63 (CH2Cl2/MeOH, 80/20). (3-Isothiocyanato-benzyl)-dimethyl-amine is prepared as described in Example 1 for 1-[2-(4-isothiocyanato-phenoxy)ethyl]-pyrrolidine but using 3-dimethylaminomethyl-phenylamine. (3-Isothiocyanato-benzyl)dimethyl-amine is obtained and used as an impure crude material.