Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[S:29])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[S:29][CH:38]=[C:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[N:30]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4nc(-c5ccccc5)cs4)CC3)nc3ccccc32)cc1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4.3 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea, 2.1 parts of potassium carbonate and 40 parts of methanol was added dropwise a solution of 2 parts of 2-bromo-1-phenylethanone in methanol. Upon completion, stirring was continued for overnight at room temperature. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.5 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(4-phenyl-2-thiazolyl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 176.2° C. (compound 89).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=[C:16]3[C:12]=2[CH2:13][CH:14]([CH3:24])[C:15]3=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>CCOCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=[C:16]3[C:12]=2[CH2:13][C:14]([CH3:24])=[CH:15]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1Cc2c(cc3c(c2-c2ccc(C(C)(C)C)cc2)OCO3)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC1=Cc2cc3c(c(-c4ccc(C(C)(C)C)cc4)c2C1)OCO3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.7 %

Procedure:
8-(4-tert-Butylphenyl)-6-methyl-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-5-one (30.63 g, 95 mmol) in Et2O (200 ml) was added to a cooled (−40° C.) suspension of LiAlH4 (1.08 g, 28.5 mmol) in Et2O (60 ml). The resulting mixture was allowed to warm to room temperature and stirred for additional 1.5 h. Then 2% HCl (100 ml) was added, the resulting mixture was extracted with CH2Cl2 (4×100 ml). The organic phase was washed with water, dried over MgSO4 and evaporated. The flask was sparged with argon; benzene (300 ml) and p-TSA (0.2 g) were added, and the resulting solution was refluxed with Dean-Stark head (control by TLC, benzene) for 2 h. Then the resulting yellow solution was washed with water, aq. KHCO3, water, dried over MgSO4, passed through silica gel and evaporated. The residue was recrystallized from hexane —Et2O (ca. 10:1) yielding 19.7 g (67.7%) of white crystalline product.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][CH3:30])=[CH:24][CH:23]=1>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:31])[C:22]2[CH:23]=[CH:24][C:25]([CH2:28][O:29][CH3:30])=[CH:26][CH:27]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COCc1ccc(C(=O)N(C)OC)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COCc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)cc1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-4-methoxymethyl-N-methylbenzamide. The product is crystallized from diisopropyl ether.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>CN(C)C=O>[CH3:3][C:1]([C:5]1[CH:11]=[C:10]([O:12][CH2:16][CH2:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])[CH:9]=[CH:8][C:6]=1[O:7][CH2:16][CH2:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: COC(=O)C(C)(C)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCOc1ccc(OCCCC(C)(C)C(=O)OC)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 3.32 g of t-butylhydroquinone in 15 ml of dimethylformamide is added dropwise to a suspension of 2.4 g of 50% sodium hydride in 25 ml of dimethylformamide, and allowed to stir for 1/2 an hour at room temperature. 11.2 g of methyl 5-bromo-2,2-dimethylpentanoate is added followed by heating the mixture at 60°-70° C. for 6 hrs. Dimethylformamide is distilled off, the residue is poured into water and the organic material is extracted with ether. The ether extract is washed with water until neutral, dried over anhydrous magnesium sulfate and the ether is evaporated. The residue is purified by distillation yielding the product, dimethyl 5,5'-[[2-(1,1-dimethylethyl)1,4-phenylene]bis(oxy)]bis[2,2-dimethylpentanoate] b.p. 200° C. at 0.5 mm of Hg; yield 4 g.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:45].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:70]([NH:72][C:73]4[CH:78]=[CH:77][N:76]=[CH:75][CH:74]=4)=[O:71])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1>>[ClH:45].[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:70]([NH:72][C:73]4[CH:78]=[CH:77][N:76]=[CH:75][CH:74]=4)=[O:71])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)Nc6ccncc6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)Nc6ccncc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-2-yl)-cyclopentane-1,2-diol (Intermediate FC) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-4-yl-urea hydrochloride (Example 108). MS (ES+) m/e 715.54 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7](Cl)(=[O:9])=[O:8])[N:4]=[CH:3]1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[C:21]([O:27][CH2:28][CH2:29][O:30][C:31]4[N:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=4)=[N:22][N:23]([CH3:26])[C:24]=3[NH2:25])=[CH:19][C:14]=2[O:13][CH2:12]1.CN(C1C=CC=CN=1)C.N1C=C(S(N)(=O)=O)N=C1>N1C=CC=CC=1>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[C:21]([O:27][CH2:28][CH2:29][O:30][C:31]4[N:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=4)=[N:22][N:23]([CH3:26])[C:24]=3[NH:25][S:7]([C:5]3[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=3)(=[O:9])=[O:8])=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1N
Agent: CN(C)c1ccccn1
Agent: NS(=O)(=O)c1c[nH]cn1
Solvent: c1ccncc1
Product: Cn1cnc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)c1
Reaction time: 48 h

Procedure:
1-Methyl-1H-imidazole-4-sulfonyl chloride (45 mg) was carefully added at room temperature under an atmosphere of nitrogen to a solution of 4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-ylamine (Preparation 48) (50 mg) and dimethylaminopyridine (16 mg) in anhydrous pyridine (2.4 ml). The reaction was stirred for two days, then the mixture was concentrated under reduced pressure and a saturated solution of ammonium chloride (6 ml), ethyl acetate (6 ml) and brine (6 ml) were sequentially added. The aqueous phase was extracted with ethyl acetate (2×8 ml) and the combined organic phases were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The black residue was purified by preparative TLC (silica) eluted with dichloromethane:methanol (95:5) yielding a mixture of title compound and N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-1-methyl-N-[(1-methyl-1H-imidazol-4-yl)sulfonyl)]-1H-imidazole-4-sulfonamide. The title compound was purified by HPLC (5.4 mg).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:5]([O:19][CH3:20])=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])([CH3:13])[CH3:11])[CH:7]=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:5]=1[O:19][CH3:20]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
NaOH (199 mg, 4.97 mmol) was added to an ice-bath cooled solution of N-[3-amino-5-(1,1-dimethylethyl)-2-methoxyphenyl]-methanesulfonamide (for reference procedure see for example WO2010026096, which is incorporated herein by reference in its entirety; 500 mg, 1.84 mmol). The ice bath was removed and complete dissolution of reagents occurred. 2,2,2-trichloroethyl chloroformate (380 μL, 2.76 mmol) was added and the reaction mixture was warmed to RT and stirred for 90 min. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-60% EtOAc in cyclohexane, to afford the title compound (620 mg, 75%) as a white solid. LCMS (Method 1): Rt 3.98 min, m/z 445, 447, 449 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[O:11])(=[O:10])[NH2:9].Br[CH2:13][C:14]([NH:16][CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:13][C:14]([NH:16][CH3:17])=[O:15])(=[O:11])(=[O:10])[NH2:9]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: CNC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)COc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.4 %

Procedure:
To a solution of crude 1-(hydroxy)-2-sulfamoylbenzene (400 mg, 2.4 mmol.) in 60 mL of acetonitrile was added 2-bromo-N-methylacetamide (332 mg, 2.4 mmol.), K2CO3 (662 mg, 4.8 mmol.) and KI (400 mg, 2.4 mmol.). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was filtered, concentrated and purified by prep-TLC to afford 2-(2-sulfamoylphenoxy)-N-methylacetamide (260 mg, 47%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:15].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:14]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:15]
Reactant: CCCCCCCNCC
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A mixture of p-nitrophenylacetic acid (7.14 g, 0.0394 mol), ethylheptylamine (5.64 g, 0.0394 mol) and 1-hydroxybenzotriazole (6.0 g, 0.044 mol) in 35 ml of dimethylformamide (DMF), under nitrogen, is cooled in an ice bath. The mixture is then treated with the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (7.68 g, 0.04 mol) in portions over 15 min. The mixture is stirred in the cold for 1 hr and at room temperature overnight. The mixture is diluted with 400 ml of ethyl acetate and washed twice with saturated NaHCO3. (Each wash is back extracted with ethyl acetate.) The pooled organic extract is washed sequentially with water (50 ml), 1N KHSO4 solution (3×50 ml), water (50 ml) and finally brine (50 ml). It is dried (Na2SO4) and concentrated in vacuo to yield the title compound. This residue is treated with Et2O-pentane, a solid filtered off and the filtrate concentrated in vacuo. The residue is chromatographed over 1400 ml of silica gel with 25% EtOAc-SSB with 42 ml fractions being collected. Fractions at approximately 70-104 yield the title compound as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[CH2:20][CH2:21]Br>>[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[CH2:20][CH2:21][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: Brc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: Fc1ccc(CCBr)c(F)c1
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)c(F)c1
Yield: 60.1 %

Procedure:
1-(Piperidin-4-yl)-6-bromoindoline (3.0 g) and 2,4-difluorophenethyl bromide (3.1 g) were treated as in Example 2 to give the title compound (2.7 g) as a white powder (yield: 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N+:14]2=[N:17]O[C:19]([O-])=[C:13]2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N1CCNC(C(O)=O)C1)=O)C1C=CC=CC=1.[F:40][C:41]([F:45])([F:44])[C:42]#C>CC1C=CC=CC=1C>[F:40][C:41]([F:45])([F:44])[C:42]1[CH:19]=[C:13]2[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:16][CH2:15][N:14]2[N:17]=1
Reactant: C#CC(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CC[n+]2noc([O-])c2C1
Agent: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Solvent: Cc1ccccc1C
Product: O=C(OCc1ccccc1)N1CCn2nc(C(F)(F)F)cc2C1
Temperature: -78 °C
Yield: 61 %

Procedure:
5-[(Benzyloxy)carbonyl]-4,5,6,7-tetrahydro[1,2,3]oxadiazolo[3,4-a]pyrazin-8-ium-3-olate (C58, prepared from 4-[(benzyloxy)carbonyl]piperazine-2-carboxylic acid using the general procedure described by T. S. Mansour et al., 2006, PCT Intl. Appl. WO 2006/130588) (65 g, 0.24 mol) was dissolved in o-xylene (250 mL) and cooled to −78° C. in a bomb reactor. 3,3,3-Trifluoroprop-1-yne (25 g, 0.27 mol) was injected into the reaction mixture, and the bomb was heated to 270° C. for 24 hours. After cooling to room temperature, the reaction was concentrated in vacuo, and the residue was purified by silica gel chromatography to provide C60 as white crystals. Yield: 7.5 g, 23 mmol, 10%. [The major regioisomer, benzyl 2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (C59), was also isolated, in 61% yield.]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:29])[CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:28])=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=2)[CH:18]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:36][CH2:35]1)(=[O:33])=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][C:10](=[O:11])[NH:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:26])[NH:47][C:44]3[CH:45]=[CH:46][C:41]([CH2:40][N:37]4[CH2:36][CH2:35][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:39][CH2:38]4)=[CH:42][CH:43]=3)=[CH:21][CH:20]=2)[C:16]([Cl:28])=[CH:15][CH:14]=1)[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: CN(CC(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(CC(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cc3)cc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5′-[2-(tert-Butoxycarbonyl-methyl-amino)-acetylamino]-2′-chloro-biphenyl-4-carboxylic acid (85 mg), 4-(4-methanesulfonyl-piperazin-1-ylmethyl)-phenylamine (81 mg) and HBTU (120 mg) in dry DMF (4 ml) containing N-methylmorpholine (65 μl) was stirred at room temp for 18 h.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1)([CH3:6])[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH3:6][C:2]([C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1)([CH3:1])[CH2:3][OH:4]
Reactant: CC1(C)CCC(C)(C)c2cc(C(C)(C)C(=O)O)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.66 g of 2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propanoic acid dissolved in 14 ml THF were treated with 24 ml of 1M lithium aluminium hydride solution in ether. The mixture was stirred at room temperature for 18 hours. The mixture was quenched by slowly adding Na2SO4.H2O until no more H2 evolved. The solid was filtered off and the solvent was evaporated, giving a pale yellow oil which was purified by flask chromatography (SiO2, 10% ethyl acetate/hexanes). 1H NMR (CDCl3): 7.29 (d, J=2.2 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.12 (dd, J=8.3, 2.2 Hz, 1H), 3.55 (br. d, J=5.4 Hz, 2H), 1.67 (s, 4H), 1.31 (s, 6H), 1.28 (s, 6H), 1.27 (s, 6H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([O:24][CH3:25])=[O:23])[CH2:3]1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O.Cl>N1C=CC=CC=1>[CH3:25][O:24][C:22]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([C:15](=[O:21])[CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C@H:4]([CH2:3][C@@H:2]([O:1][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)=[O:23]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 96 h

Procedure:
3β-Hydroxy-17β-methoxycarbonyl-5α-androstan-11-one (4.75 g.) and toluene-p-sulphonyl chloride (5 g.) in pyridine (50 ml.) were allowed to stand at room temperature for four days. Water (10 ml.) was added, the resulting solution was stirred for an hour and was then poured into stirred water (1.1). The mixture was acidified with hydrochloric acid and the product collected, washed well with water and dried over sodium hydroxide in vacuo. Recrystallisation from chloroform/hexane containing a trace of ether afforded pure title compound (3.4 g.) as needles; m.p. 158°-160°; [α]D + 42.5°, (c 1.09).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:23]1[N:24]=[C:25]([NH2:41])[C:26]2[N:27]=[CH:28][N:29]([C:39]=2[N:40]=1)[C@@H:30]1[O:38][C@H:35]([CH2:36][OH:37])[C@@H:33]([OH:34])[C@H:31]1[OH:32]>>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:23]3[N:24]=[C:25]([NH2:41])[C:26]4[N:27]=[CH:28][N:29]([C:39]=4[N:40]=3)[C@@H:30]3[O:38][C@H:35]([CH2:36][OH:37])[C@@H:33]([OH:34])[C@H:31]3[OH:32])[CH2:5][CH2:6]2)=[O:11])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Product: Nc1nc(C#CCC2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Batch: AB-9-149. 4-nitrophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-97 (0.630 g, 2.185 mmol) was added to a solution of 2-iodoadenosine (0.727 g, 1.849 mmol) according to general procedure 2. Yield: 1.192 g, 65%. %. 1H NMR (CD3OD) δ 8.26 (m, 1H), 8.25-7.34 (2×m, 4H), 5.94 (d, 1H), 4.72 (m, 2H), 4.32-4.14 (2×m, 3H), 3.91-3.71 (2×d, 2H), 3.17-2.90 (2×bt, 4H), 2.48 (d, 5H), 1.45 (m, 5H). m/z MH+=554.15. HPLC rt=7.3 min.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[S:9](N)(N)(=[O:11])=[O:10].O.Cl>COCCOCCOC>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][S:9]1(=[O:11])=[O:10]
Reactant: NS(N)(=O)=O
Reactant: Nc1ccccc1N
Agent: Cl
Solvent: O
Solvent: COCCOCCOC
Product: O=S1(=O)Nc2ccccc2N1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
A solution of orthophenylenediamine (20 g) and sulfamide (20.4 g) in diglyme (200 ml) was stirred at 160° C. for 2 hours, the reaction mixture was cooled to room temperature, water (200 g) was poured thereto, hydrochloric acid was added until pH 1, extracted with ethyl acetate, and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a reddish brown solid (14.2 g). Further recrystallization from ethanol-diethyl ether afforded the title compound as colorless crystals (13.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16])[C:10]([N:27]1[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)[C@H](CNC(=O)c2ccc(Cl)s2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Intermediate 88 (13.4 g, 38.42 mmol) was dissolved in 200 ml DCM and N-methyl piperazine (8.52 ml, 76.83 mmol) was added followed by DIPEA (26.77 ml, 153.67 mmol) and TBTU (18.5 g, 57.63 mmol). After 16 h stirring at RT, the solution was evaporated to dryness and purified by silica gel chromatography. Yield: 13.05 g, 79%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][CH:12]=[C:13]3C#CC2C=CC=CC=2)[CH2:4][CH2:3]1>CO.O=[Pt]=O>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13]3)[CH2:6][CH2:7]1
Reactant: CN1CCC(OC2c3ccccc3CCn3c(C#Cc4ccccc4)cnc32)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: CN1CCC(OC2c3ccccc3CCn3cc(CCc4ccccc4)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-methylpiperidin-4-yloxy)-2-phenylethynyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 34) (50 mg, 0.126 mmole) in MeOH (1.3 mL) is added PtO2 (1.4 mg). The flask is evacuated and filled with hydrogen (balloon). The reaction mixture is stirred at room temperature overnight, then filtered on celite and cake washed with MeOH. Solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.2) to (95:5:0.5) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford 4-(1-methylpiperidin-4-yloxy)-2-phenethyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.