Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OC(=O)[CH2:7][CH2:8][N:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:10][CH:11]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[C:12](OCC)=[O:13])C.O>C1(C)C=CC=CC=1.C(O)C>[CH2:25]([N:9]1[CH2:8][CH2:7][C:12](=[O:13])[CH:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:10]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)CC(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of sodium hydride (60% in oil, 4.85 g) in toluene (109 mL) was added a solution of the compound (34.6 g) obtained in step 3 in ethanol (25.1 mL), and the mixture was stirred at 75° C. for 2 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. A solution of the obtained residue (30.3 g) in concentrated hydrochloric acid (100 mL) and acetic acid (34 mL) was stirred at 140° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was made basic with aqueous sodium hydroxide solution. The resultant product was extracted with ethyl acetate, and the organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→50% ethyl acetate/hexane) to give 1-benzyl-3-(3,4-dichlorophenyl)-4-piperidinone (18.2 g, 73%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH3:21][O:22][CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[CH3:21][O:22][CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]3[O:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: COCc1cccc(CN)c1
Reactant: Cc1ccc(CN)o1
Product: COCc1cccc(CNc2cccc3nc(NCc4ccc(C)o4)ccc23)c1

Procedure:
The title compound, MS: m/e=388.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 3-methoxymethyl-benzylamine (CAS 148278-90-4).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:7])[CH:2]([CH3:4])[CH3:3].[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:7])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)COC(=O)Nc1cccc(Cn2ccc3cc(C(=O)O)ccc32)c1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)Nc1cccc(Cn2ccc3cc(C(=O)NS(=O)(=O)c4ccccc4)ccc32)c1

Procedure:
The carboxylic acid (Example 28 ) (0.25 g) was stirred at room temperature in dichloromethane (3 ml) with benzene sulphonamide (0.10 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.15 g) and 4-dimethylaminopyridine (0.02 g) for 144 hours. The reaction mixture was diluted with chloroform and washed with 0.5N hydrochloric acid, then water. The organic extract was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Purification by preparative reverse-phase HPLC (1 inch LP1-ODS column), eluting with 75:25:0.1 methanol:water:acetic acid, gave N-{1-[3-(isobutoxycarbonylamino)benzyl]indol-5-ylcarbonyl}benzene sulphonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1[CH:21]=O>C(O)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=3[OH:18])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CC(C)(N)CNc1ccnc2cc(Cl)ccc12
Solvent: CCO
Product: COc1ccc(CNC(C)(C)CNc2ccnc3cc(Cl)ccc23)c(O)c1
Product: Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.25 g of N1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine and 0.76 g of 2-hydroxy-4-methoxy-benzaldehyde were stirred under reflux overnight in 20 ml of ethanol in the presence of 1.25 g of molecular sieve (E. Merck, 3 Å). The mixture was filtered, the solvent was evaporated and the residue was again taken up in 20 ml of ethanol. After the addition of 0.19 g of sodium borohydride the mixture was stirred at room temperature for 6 hours, thereafter 5 ml of glacial acetic acid were added thereto and the mixture was evaporated to dryness. 10 ml of methanol were added to the residue and the mixture was again evaporated. Addition of methanol and evaporation were repeated twice. Finally, the residue was taken up in 10 ml of hot ethanol, 10 ml of 3N isopropanolic hydrochloric acid were added thereto and the product was left to crystallize out as the dihydrochloride. Yield 1.8 g (78%) of colourless crystalline powder, m.p. 220° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:31])[CH2:10][O:11]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:31])[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1ccc(I)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(CO)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
To a solution of 1-iodo-4-{[1-(trityloxy)propan-2-yl]oxy}benzene (350 mg, 0.67 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and purified by combiflash (petroleum ether:ethyl acetate=10:1 to 4:1) to give the title compound (100 mg, 55%) as a white solid, which was used into next step directly.
Reaction SMILES: [Cl-].[F:2][C:3]([F:18])([F:17])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][NH2+:13]3)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS([C:29]1[N:34]=[CH:33][C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][N:30]=1)(=O)=O>CN(C=O)C.O.C(OCC)(=O)C>[F:18][C:3]([F:2])([F:17])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][N:13]3[C:29]2[N:30]=[CH:31][C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][N:34]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: FC(F)(F)c1cccc(N2C[C@@H]3C[C@H]2C[NH2+]3)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.5 %

Procedure:
Compound 558 (500 mg, 1.794 mmol) and cesium carbonate (1461 mg, 4.49 mmol) were suspended in DMF (5 mL) to give a yellow suspension. Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (496 mg, 2.153 mmol) was then added and the reaction was stirred at room temperature for 3 days. The mixture was diluted with water and ethyl acetate. The organic layer was washed twice with water then brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography (25-50% EtOAc in Hexanes) to obtain compound 559 as a white solid (313 mg, 45%). LRMS: 392.1 (found) 393.2 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14]CC)=[O:13])=[C:7]2[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.O[Li].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[C:7]2[NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cnc2c(Br)cccc2c1NCc1ccc(OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(CNc2c(C(=O)O)cnc3c(Br)cccc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.4 %

Procedure:
To a solution of ethyl 8-bromo-4-((4-methoxybenzyl)amino)quinoline-3-carboxylate (1.2 g, 2.89 mmol) in THF-MeOH—H2O (10:7:3, 20 mL) was added LiOH—H2O (452 mg, 10.77 mmol) and the reaction mixture was stirred at rt for 12 h. Then the reaction mixture was acidified with citric acid and the organic volatiles were removed. The residue was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated to afford 1.0 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.96 (s, 1H), 8.42-8.39 (d, J=8.7 Hz, 1H), 8.11-8.09 (d, J=7.2 Hz, 1H), 7.35-7.30 (m, 3H), 6.95-6.92 (d, J=8.7 Hz, 2H), 4.91 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17]>CN(C)C=O>[Br:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[C:16]([F:18])([F:17])[F:15])=[CH:5][N:6]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1cnc(Br)s1)C(F)(F)F
Yield: 38.9 %

Procedure:
According to Reference Example 8-2, by use of 2-bromothiazole-5-carbaldehyde (500 mg, 2.60 mmol) dissolved in N,N-dimethylformamide (7.5 mL), potassium carbonate (72 mg, 0.52 mmol) and (trifluoromethyl)trimethylsilane (0.461 mL, 3.12 mmol), the mixture was stirred and reacted at room temperature for 1.7 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=40/1) was performed to give 1-(2-bromothiazol-5-yl)-2,2,2-trifluoroethanol (Compound EG) (265 mg, yield: 39%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)=[O:16])[CH:11]=2)[CH:6]=1)=[O:4].[CH:41]1([Mg]Br)[CH2:43][CH2:42]1>C1COCC1>[CH:41]1([C:15]([OH:16])([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:14]=[CH:13]3)[CH2:43][CH2:42]1
Reactant: Br[Mg]C1CC1
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C3CC3)ccc2c1

Procedure:
The similar reaction as described in Example 50-(i) was carried out by using N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (500 mg) and cyclopropyl-magnesium bromide in THF (1M; 4 mL) to give the titled compound (332 mg) as colorless powder.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Si:14]([O:31][C@H:32]([CH3:44])[C@H:33]([NH2:43])[C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[C:36]([F:42])[CH:35]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C=O)C>[Si:14]([O:31][C@H:32]([CH3:44])[C@H:33]([NH:43][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[C:36]([F:42])[CH:35]=1)([C:27]([CH3:28])([CH3:29])[CH3:30])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CBr
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](N)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 11 h

Procedure:
Cesium carbonate (242 mg) and ethyl bromoacetate (103 μl) are added to a solution of (1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamine obtained in Example 26 (274 mg) in DMF (5 ml), and the reaction solution was stirred at room temperature for 11 hours. Ice water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with half-saturated brine and brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:diethyl ether=19:1) to obtain 190 mg of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[C:17]([CH3:22])[C:18]([C:19](=[S:21])[NH2:20])=[C:12]2[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH:24]([C:29](OC)=[O:30])[C:25]([O:27][CH3:28])=[O:26].O>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[C:17]([CH3:22])[C:18]([C:19]3[S:21][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:29]([OH:30])[N:20]=3)=[C:12]2[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(Cl)C(=O)OC
Reactant: Cc1nn2ccc(OCc3ccccc3)cc2c1C(N)=S
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc(-c2c(C)nn3ccc(OCc4ccccc4)cc23)nc1O
Temperature: 100 °C
Reaction time: 7.5 h

Procedure:
To a suspension of 5-(benzyloxy)-2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (3.45 g, 10.3 mmol) in DMF (100 mL), was added 94% dimethyl chloromalonate (2.79 mL, 20.6 mmol) and the mixture was stirred for 7.5 h at 100° C. The reaction mixture was allowed to cool to 50° C. and then was dropwise added water (100 mL). The resulting precipitate was collected by filtration and then washed with EtOH (20 mL) and diethyl ether (20 mL) to obtain methyl 2-[5-(benzyloxy)-2-methylpyrazolo[1,5-a]pyridin-3-yl]-4-hydroxy-1,3-thiazole-5-carboxylate as a orange solid, which was used in the next step without further purification. 1H-NMR (DMSO-d6, 300 MHz) 2.59 (3H, s), 3.75 (3H, s), 5.27 (2H, s), 6.87 (1H, dd, J=2.6, 7.6 Hz), 7.32-7.51 (3H, m), 7.52-7.64 (2H, m), 7.88 (1H, d, J=2.6 Hz), 8.67 (1H, d, J=7.6 Hz), 11.79 (1H, br s).
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[CH:3][S:4](Cl)(=[O:6])=[O:5].[C:9]([O:13][C:14]([NH:16][CH2:17][C@H:18]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.O>ClCCl>[C:9]([O:13][C:14]([NH:16][CH2:17][C@H:18]([N:23]1[CH2:24][CH2:25][N:26]([S:4]([CH2:3][CH:2]([CH3:8])[CH3:1])(=[O:6])=[O:5])[CH2:27][CH2:28]1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCNCC1
Reactant: CC(C)=CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(=O)(=O)CC(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
479 mg (3.0 mmol) of 2-methylpropene-1-sulfonyl chloride are added to a solution of 800 mg (2.8 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate (prepared as described in example 23.1) and 775 μl (5.5 mmol) of triethylamine in 8 ml of dichloromethane, cooled beforehand to 0° C. The reaction medium is stirred at ambient temperature for 18 h and then water is added and the medium is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The residue obtained Is purified by chromatography on silica gel, elution being carried out with a 5/5 heptane/ethyl acetate mixture. 785 mg (71%) of methyl (S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoate are obtained in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH3:16][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:13]=[C:6]([C:7](=[O:8])[CH3:16])[C:5]([O:14][CH3:15])=[N:4][CH:3]=1
Reactant: COc1ncc(Br)cc1C(=O)N(C)OC
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ncc(Br)cc1C(C)=O
Temperature: 20 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of 5-bromo-N,2-dimethoxy-N-methylnicotinamide (5.0 g, 18.18 mmol) in THF (50 mL), MeMgBr (10 mL, 30.0 mmol) was added dropwise at −78° C. The reaction mixture was stirred at 20° C. overnight. Then the reaction mixture was added to NH4Cl solution. The mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using column chromatography (eluted with petroleum ether:EtOAc=10:1) to provide 1-(5-bromo-2-methoxypyridin-3-yl)ethanone (3.0 g, yield: 71%). 1H-NMR (CDCl3, 400 MHz) δ 8.33 (d, J=2.4 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 4.03 (s, 3H), 2.63 (s, 3H). MS (M+H)+: 230/232
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][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]>CN(C=O)C>[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:33])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1ccc(N=C=O)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: CN(C)C=O
Product: CCCCc1ccc(NC(=O)N2CCC(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Yield: 41.1 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (30 mg, 0.110 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-butyl-4-isocyanato-benzene (28.8 mg, 0.165 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a light yellow solid (20.3 mg, 41%). 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.40 (s, 1H), 7.28 (m, 3H), 7.13-7.10 (m, 2H), 6.36 (br s, NH), 4.30-4.26 (m, 2H), 4.08 (s, 6H), 3.61 (m, 1H), 3.17 (m, 2H), 2.57 (m, 2H), 2.17 (m, 2H), 2.02-1.98 (m, 2H), 1.34 (m, 4H), 0.94-0.80 (m, 3H); LC/MS (ESI): calcd mass 448.3, found 449.3 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:11]=[C:12]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=4)[CH:13]=[CH:14][C:15]=3[O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([S:24]([NH:27][C:28]4[S:29][CH:30]=[N:31][N:32]=4)(=[O:26])=[O:25])=[C:19]([F:33])[CH:18]=3)=[CH:8][CH:7]=[N:6]2)[CH2:2]1.C=O.[C:46](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl.C(O)(=O)C>[Cl:23][C:22]1[C:17]([O:16][C:15]2[CH:14]=[CH:13][C:12]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:38][CH:39]=3)=[CH:11][C:10]=2[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH3:46])[CH2:4]3)[N:6]=[CH:7][CH:8]=2)=[CH:18][C:19]([F:33])=[C:20]([S:24]([NH:27][C:28]2[S:29][CH:30]=[N:31][N:32]=2)(=[O:26])=[O:25])[CH:21]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnn2C2CNC2)cc1F
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CN1CC(n2nccc2-c2cc(-c3ccc(C(F)(F)F)cc3)ccc2Oc2cc(F)c(S(=O)(=O)Nc3nncs3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 122.7 %

Procedure:
To a suspension of 4-{[3-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4′-(trifluoromethyl)biphenyl-4-yl]oxy}-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 41, 46.3 mg, 0.0711 mmol) in methanol (0.11 mL), dichloromethane (1.86 mL) and acetic acid (0.11 mL) was added formaldehyde (37% w/w, 19.6 μL, 0.263 mmol). The reaction was then stirred under nitrogen at room temperature for 45 minutes. Sodium triacetoxyborohydride (45.9 mg, 0.217 mmol) was added to the reaction which was stirred for 18 hours at room temperature. The reaction was diluted with dichloromethane (20 mL) and washed with water (3×2 mL). The combined aqueous phases were extracted with dichloromethane (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a clear gum (58.0 mg). The clear gum was purified by B-HPLC to afford the title compound.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11]([NH2:15])[CH:12]([CH3:14])[CH3:13].[Cl:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21]>>[Cl:16][CH2:17][CH2:18][NH:19][C:20]([N:15]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:9]1[O:10][CH2:2][C@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:21]
Reactant: CC(C)CN
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Product: CC(C)CN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 69.2 %

Procedure:
3.0 g of L-arabinose, 1.8 g of isobutylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 4.3 g of 1-(2-chloroethyl)-3-isobutyl-3-L-arabinopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.S(=O)(=O)(O)O>ClCCl>[O:14]=[C:3]1[C:2]2[N:1]=[C:21]([C:20]3[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[O:22][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(o2)C(=O)c2ccccc2C3=O)cc1
Yield: 56 %

Procedure:
To a solution of 5.0 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 80 mL of dichloromethane, one adds, with protection from light and at ambient temperature, 16 mL (120 mmol) of 4-methoxybenzoic acid chloride, then 0.003 mL of concentrated sulfuric acid. After 3 h of reflux, the reaction mixture is evaporated to dryness; the black oily residue obtained is redissolved in 300 mL of dichloromethane, washed with a solution of 10N sodium hydroxide, then with water, and finally dried over calcium chloride. The product is then purified on a flash column (support: silica 6-35 mm; conditioning: heptane; eluant: dichloromethane/heptane, 60/40), to produce 4.1 g of 4,9-dihydro-4,9-dioxo-2-(4-methoxyphenyl)-naphtho[2,3-d]oxazole in the form of yellow-orangish crystals after recrystallization and color removal with animal charcoal.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([Br:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: COc1cccc(C(=O)O)c1N
Solvent: ClC(Cl)Cl
Product: COc1cc(Br)cc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a 0.24 M chloroform solution of 2-amino-3-methoxybenzoic acid (4, 11.87 g, 71.7 mmol) at 0° C. was added bromine (1.08 eq. 0.31 M) in chloroform dropwise. The mixture was warmed to room temperature and stirred under argon for 16 hours. The resulting precipitate was collected by filtration and washed thoroughly with chloroform. The crude material was dried in vacuo to give the title as an HBr salt in 99% yield. ES/MS m/z 248/250 (MH+).