Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:17]1([C:23]2[CH:24]=[CH:25][C:26]3[NH:27][C:28]4[C:33]([C:34]=3[CH:35]=2)=[CH:32][C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:29]=4)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1.CCCCCC>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:27]2[C:28]3[CH:29]=[CH:30][C:31]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][C:33]=3[C:34]3[C:26]2=[CH:25][CH:24]=[C:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:35]=3)=[CH:3][CH:4]=1
Reactant: c1ccc(-c2ccc3[nH]c4ccc(-c5ccccc5)cc4c3c2)cc1
Reactant: Brc1ccc(-c2nc3ccccc3o2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3c(c2)c2cc(-c4ccccc4)ccc2n3-c2ccc(-c3nc4ccccc4o3)cc2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
In a 100 mL three-neck flask were put 1.0 g (3.7 mmol) of 2-(4-bromophenyl)benzoxazole, 1.2 g (3.7 mmol) of 3,6-diphenyl-9H-carbazole, and 0.77 g (8.0 mmol) of sodium tert-butoxide. The atmosphere in the flask was replaced with nitrogen. To this mixture were added 15 mL of toluene and 0.10 mL of a 10% hexane solution of tri(tert-butyl)phosphine. This mixture was degassed by reducing the pressure in the flask by using an aspirator. After that, the atmosphere in the flask was replaced with nitrogen. To this mixture was added 0.030 g (0.052 mmol) of bis (dibenzylideneacetone)palladium(0), followed by stirring under a nitrogen stream at 80° C. for 5 hours. After that, toluene was added to this mixture, and this suspension was suction filtered through Celite 545 (produced by Kishida Chemical Co., Ltd., Catalog No. 020-14815), whereby a filtrate was obtained.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[CH:8]=1)(O)=[O:2].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.C[N:26](C=O)C>>[NH2:26][C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[CH:8]=1)=[O:2]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A dry reaction flask equipped with a magnetic stirring bar, nitrogen inlet and rubber septum was charged with 2-carboxy-5-nitrobenzofuran (0.414 g, 2 mmol) and CH2Cl2 (100 mL). To this was added DMF (0.1 mL) followed by a slow addition of oxaloyl chloride (0.519 mL, 6 mmol) over the period of 5 minutes at 0° C. The reaction mixture was further stirred for 30 minutes by the time the formation of a clear solution was observed. The resulting clear solution was concentrated under a reduced pressure and dried under high vacuum for 30 minutes. The resulting residue was suspended in EtOAc (25 mL), cooled to 10° C., to it was added NH4OH (30% solution, 25 mL) and stirred at room temperature for 24 h. The organic phase was separated and dried over anhydrous sodium sulfate and solvent was removed to give 2-aminocarbonyl-5-nitrobenzofuran. 1H NMR (DMSO-d6): δ 8.75 (d, 1H, J=2.7 Hz), 8.28 (m, 2H), 7.86 (d, 1H, J=9.0 Hz), 7.83 (bs, 1H), 7.72 (s, 1H); LCMS: purity: 93%, MS (m/e): 206 (M+).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:10]23[CH2:17][N:14]([CH2:15][CH2:16]2)[CH2:13][CH2:12][CH2:11]3)=[CH:8][N:9]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[OH:2][CH2:3][C:5]1[O:6][C:7]([C:10]23[CH2:17][N:14]([CH2:15][CH2:16]2)[CH2:13][CH2:12][CH2:11]3)=[CH:8][N:9]=1
Reactant: COC(=O)c1ncc(C23CCCN(CC2)C3)o1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1ncc(C23CCCN(CC2)C3)o1
Reaction time: 1 h

Procedure:
A solution of (±)5-(2-methoxycarbonyl-1,3-oxazol-5-yl)-1-azabicyclo[3.2.1]octane (E9) (0.2g, 0.8 mmole) in dry toluene (12 ml), cooled in ice, under nitrogen, was treated with diisobutylaluminium hydride (1.04 ml of a 1.5M solution in toluene, 1.6 mmole) over 15 min. The reaction was allowed to warm up to room temperature over 1h, then more diisobutylaluminium hydride (1.6 mmole) was added and the reaction left for a further 1h. After quenching with methanol (8 ml) and 10% sodium hydroxide solution (10 ml), potassium carbonate was added until the aqueous layer was saturated. The organic layer was separated and the aqueous phase was extracted with chloroform. The combined organic layers were dried over sodium sulphate 9 then concentrated in vacuo. Purification of the residue on neutral alumina in a gradient of 0-5% methanol in chloroform afforded the title compound (E10) as a gum (0.1g, 55%) which was converted into the hydrochloride salt m.p. 152° C. (dec.) (from methanol-ether).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:9][CH2:8]1.[CH3:30][O:31][CH2:32][CH2:33][N:34]1[CH2:43][CH2:42][C:41]2[C:40]([C:44](O)=[O:45])=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]1=[O:47].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][C@H:3]([NH:2][C:44]([C:40]1[C:41]2[CH2:42][CH2:43][N:34]([CH2:33][CH2:32][O:31][CH3:30])[C:35](=[O:47])[C:36]=2[CH:37]=[CH:38][CH:39]=1)=[O:45])[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:9][CH2:8]1
Reactant: COCCN1CCc2c(C(=O)O)cccc2C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cccc2C1=O
Reaction time: 20 h
Yield: 30 %

Procedure:
Poured into a suspension of 242 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 104 mg of 2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 8 mg of hydroxybenzotriazole, 99 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 7 cm3 of dichloromethane is 0.28 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The reaction mixture is kept stirring for 20 h at a temperature close to 20° C. The suspension obtained is filtered and the precipitate is washed 3 times with 5 cm3 of ethyl ether, then dried under vacuum. 79 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:32]([OH:35])([CH3:34])[CH3:33]>>[CH:32]([O:35][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1)([CH3:34])[CH3:33]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OC(C)C)n2)cc1Cl

Procedure:
To a portion of 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-cycloheptyl-[1,3,5]triazine-2,4-diamine (5 g) in isopropanol was added K2CO3 (3.2 g) and refluxed for about 10-12 h. TLC was monitored. After the completion of the reaction, the reaction mass was filtered through vacuum and the filtrate was evaporated to yield the title compound. (Wt. 3.7 g Y: 70%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:4]1)[CH3:2].[Cl:16][S:17](O)(=[O:19])=[O:18].O>ClCCCl>[CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:10]=[C:11]([F:15])[CH:12]=[CH:13][C:14]=2[S:17]([Cl:16])(=[O:19])=[O:18])[CH2:4]1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCN1CC[C@@H](Cc2cccc(F)c2)C1
Solvent: O
Solvent: ClCCCl
Product: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-1-ethyl-3-(3-fluorobenzyl)pyrrolidine (Intermediate 97, 0.24 g) in DCE (1.2 mL) was added carefully to chlorosulfonic acid and the mixture was stirred at room temperature for 2 hours. The mixture was carefully poured into iced water and extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-((R)-1-ethyl-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (0.36 g) as an oil which was used without further charactersiation.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34](O)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:34]([C:29]2[C:30]3[C:25](=[C:24]([F:23])[CH:33]=[CH:32][CH:31]=3)[CH:26]=[CH:27][CH:28]=2)=[O:35])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cccc2c(F)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1ccc(CC(NC(=O)c2cccc3c(F)cccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol (300 mg, 0.94 mmol) in acetonitrile (20 ml) were added 5-fluoronaphthalenecarboxylic acid (180 mg, 0.94 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (217 mg, 1.13 mmol) and 1-hydroxybenzotriazole hydrate (145 mg, 0.94 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the objective substance (0.24 g, 53%).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C>C(OCC)C>[O:12]1[CH2:13][CH2:14][N:9]([C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C(=O)Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
A solution of ethyl 2-chloro-2-oxoacetate (1.25 g, 9.18 mmol) in diethyl ether (5 mL) was added dropwise to a solution of morpholine (1.0 g, 11.48 mmol) in diethyl ether (20 mL) and triethylamine (1.16 g, 11.48 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The yellow-colored oil was transferred into 25 mL iced water and extracted with ethyl acetate (3×20 mL). Combined organic layers were washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give 1 g of the crude product, which was used further without any purification. Crude yield 47%. 1H NMR (400 MHz, CDCl3) δ 4.33-4.38 (q, 2H), 3.72-3.76 (m, 4H), 3.65-3.68 (m, 2H), 3.47-3.50 (m, 2H), 1.37-1.40 (t, 3H). LCMS m/z 187.93 [M+H]+, tR=0.525 min.
Reaction SMILES: [N:1]([CH:4]([C:17]([F:20])([F:19])[F:18])[CH2:5][NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[N+]=[N-].[BH4-].[Na+].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>O1CCCC1.[Co](Cl)Cl>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[NH2:1][CH:4]([C:17]([F:18])([F:19])[F:20])[CH2:5][NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [N-]=[N+]=NC(CNC(=O)OCc1ccccc1)C(F)(F)F
Agent: Cl[Co]Cl
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: NC(CNC(=O)OCc1ccccc1)C(F)(F)F
Reaction time: 16 h

Procedure:
To a solution of benzyl (2-azido-3,3,3-trifluoropropyl)carbamate (107 g, 371 mmol) in tetrahydrofuran (1000 mL) was added cobalt chloride (17.8 g, 137 mmol) followed by sodium borohydride (1.0 M in water, 1.5 L, 1.5 mol) dropwise over a period of 2 hours. After 2 hours post-addition, the reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (3×200 mL). The organics were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. To the residue was added oxalic acid (0.37 M solution in ethyl acetate, 1.5 L, 560 mmol). After 16 hours, the reaction mixture was filtered to afford benzyl (2-amino-3,3,3-trifluoropropyl)carbamate oxalic acid salt. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(C(C)C)C(C)C)C.S(O)(O)(=O)=O.[CH3:41][O:42][C:43]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:44]=1[CH2:51][CH2:52][NH2:53].COC1C=C(OC)C=CC=1CCN.Cl.C(N=C=NCCCN(C)C)C.N1C2C(=NC=CC=2)N(O)N=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:53][CH2:52][CH2:51][C:44]3[CH:45]=[CH:46][C:47]([O:49][CH3:50])=[CH:48][C:43]=3[O:42][CH3:41])=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: COc1ccc(CCN)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(OC)cc4OC)cc3)c(Cl)cc21
Reaction time: 14 h

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1; 9.099 ml, 3.185 mmol) in DMF was treated sequentially with N-ethyl-N-isopropylpropan-2-amine (0.8321 ml, 4.777 mmol), 2-(2,4-dimethoxyphenyl)ethanamine hemisulfate (commercially available from ChemBridge Corporation; 0.95 g; 2.07 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.7326 g, 3.822 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.1300 g, 0.9554 mmol) at ambient temperature. The reaction was stirred for 14 hours. The reaction was partitioned between ethyl acetate and brine, the organic layer dried in vacuo, filtered, concentrated and purified on silica gel. Elution with 20 to 75% ethyl acetate-hexanes provided ethyl 6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate (1.255 g, 2.324 mmol) as an off white solid.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:13]=1[N+:14]([O-])=O)([C:3](OCC)=[O:4])=[O:2].O>C(O)(=O)C.[Zn]>[C:17]1([C:11]2[S:10][C:9]3[NH:8][C:1](=[O:2])[C:3](=[O:4])[NH:14][C:13]=3[CH:12]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(=O)Nc1sc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(-c3ccccc3)sc2[nH]c1=O

Procedure:
2-Ethoxalylamino-5-phenyl-3-nitrothiophene (641 mg, 2 mmol) was suspended in 35 ml of 80% acetic acid, and 1.31 g (20 mmol) of zinc dust was added in one portion with stirring. After 2 hours 70 ml of water was slowly added to the suspension, and the precipitate was isolated by filtration (483 mg). This crude product was purified by suspending in 20 ml of methylene chloride, filtering, and subsequent crystallisation by dissolving in 50 ml of boiling acetic acid and slow addition of 30 ml of water. The yield was 87 mg (17.8%) of the title compound as crystals, melting over 300° C. 1H-NMR (DMSO-D6, δ): 7.05 (s, 1H), 7.3 (t, 1H), 7.4 (t, 2H), 7.6 (d, 2H), 11.9-12.5 (broad, 2H).
Reaction SMILES: NC(N)=O.[N:5]1([S:9]([C:12]2[C:13]([OH:20])=[C:14]([CH:16]=[CH:17][C:18]=2[Cl:19])[NH2:15])(=[O:11])=[O:10])[CH2:8][CH2:7][CH2:6]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[N:5]1([S:9]([C:12]2[C:13]([OH:20])=[C:14]([NH:15][C:29]([NH:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[O:30])[CH:16]=[CH:17][C:18]=2[Cl:19])(=[O:11])=[O:10])[CH2:8][CH2:7][CH2:6]1
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Yield: 53.4 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 3-(azetidin- 1 -yl)sulfonyl-4-chloro-2-hydroxyaniline (235 mg, 0.9 mmol) and 2-chlorophenylisocyanate (1 34 mg, 0.9 mmol) were coupled to form the desired urea (200 mg, 54%). LC-MS 416.0 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[C:25]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([NH:32][NH2:33])=[O:31])=[CH:28][CH:27]=2)=[N:24][N:23]=[N:22]1>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:33][NH:32][C:30](=[O:31])[C:29]3[CH:34]=[CH:35][C:26]([C:25]4[NH:24][N:23]=[N:22][N:21]=4)=[CH:27][CH:28]=3)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Solvent: CN(C)C=O
Product: CC(=NNC(=O)c1ccc(-c2nnn[nH]2)cc1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 100 °C
Reaction time: 26 h
Yield: 13.5 %

Procedure:
1-[5-(4-t-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.404 mmol, 110 mg) and 4-(1-H-tetrazol-5-yl)benzhydrazide (0.404 mmol, 83 mg) synthesized in accordance with WO03/037328 were dissolved in dimethylformamide (5 mL) and stirred at 100° C. for 26 hours. The insolubles were filtered off and washed with methanol, and the filtrate was concentrated and separated by silica gel thin layer chromatography (chloroform/MeOH=4/1) to give the desired product as a yellow solid (25 mg, yield 13%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:13][C:12]=2[C:24]([NH2:26])=[O:25])=[CH:7][CH:6]=1.C([NH:34][CH2:35][CH2:36][OH:37])C1C=CC=CC=1>CO.[Pd]>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:14]1[O:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:34][CH2:35][CH2:36][OH:37])=[CH:6][CH:7]=2)=[C:12]([C:24]([NH2:26])=[O:25])[N:13]=1
Reactant: OCCNCc1ccccc1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCNCCO)cc1

Procedure:
The title compound was prepared by reaction of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide with 2-(benzylamino)ethanol, according to the procedure described in example S-1, step c, followed by deprotection with the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 60° C., 0.05M in MeOH). 1H NMR (DMSO) δ 2.79 (2H, t), 3.17 (2H, t), 3.55 (2H, t), 4.20 (2H, t), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.20-8.30 (2H, m). LCMS (2) 2.17 min; m/z (ES+) 404.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([C:10]#[N:11])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.C1(C2[O:27]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:9])=[O:27])[C:5]([C:10]#[N:11])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: CSc1nc(N)nc(Oc2ccccc2)c1C#N
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CS(=O)c1nc(N)nc(Oc2ccccc2)c1C#N
Reaction time: 24 h
Yield: 26.7 %

Procedure:
To a stirred suspension of 950 mg (3.68 mmol) 2-amino-4-methylsulfanyl-6-phenoxy-pyrimidine-5-carbonitrile in 20 ml dichloromethane was added 3.84 g (14.7 mmol) 3-phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 24 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue resuspended in ether/hexane and filtered to afford 270 mg (27%) 2-amino-4-methanesulfinyl-6-phenoxy-pyrimidine-5-carbonitrile as a light yellow crystalline solid. ES-MS m/e (%): 275 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=2)[C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:31]1C=C(S(Cl)(=O)=O)C=C[CH:36]=1>>[CH2:31]([O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:27]=[CH:28][CH:29]=[C:12]([NH:11][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:9])=[O:10])[CH:13]=2)=[CH:19][CH:20]=1)[CH3:36]
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(Cl)c3)c2)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(Cl)c3)c2)cc1

Procedure:
4-[3-(3-Chloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=429.2 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 3-chloro-benzensulfonyl chloride and yielded 4-[3-(3-chloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)([O-:19])=[O:18].C(N(CC)CC)C.[BH4-].[Na+]>CO>[ClH:1].[ClH:1].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N+:17]([O-:19])=[O:18])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
In this reference example, 5.24 g of 1-benzyl-4-amino-piperidine dihydrochloride, 3.02 g of o-nitrobenzaldehyde, 2.02 g of triethylamine and 30 ml of methanol are mixed and stirred at room temperature for one hour. The resultant solution is cooled with ice and stirred. To the stirred solution, 1 g of sodium borohydride is added little by little over a period of one hour. Then, the mixture is brought back to room temperature and stirred at room temperature for 2 hours. The resultant solution is poured into 200 ml of ice water and extracted with ether. The organic layer is washed with water, dried and concentrated. The oily residue is dissolved in 20 ml of ethanol. The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate. The white crystals deposited are separated by filtration, washed with 20 ml of ethyl acetate and dried to obtain 5.70 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 2.90 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: NCCCN1CCOCC1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCCN2CCOCC2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[3-(4-morpholinyl)propylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-aminopropylmorpholine, and triethylamine essentially as described above in Example 1, Scheme A, step b.