Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](Cl)[N:11]=[C:10]([N:15]3[CH2:20][C@@H:19]4[CH2:21][C@H:16]3[CH2:17][N:18]4[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:9]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].Cl.[CH:34]12[CH2:39][CH:37]([CH2:38]1)[CH2:36][NH:35]2.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:35]3[CH2:36][CH:37]4[CH2:39][CH:34]3[CH2:38]4)[N:11]=[C:10]([N:15]3[CH2:20][C@@H:19]4[CH2:21][C@H:16]3[CH2:17][N:18]4[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:9]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(-c2cnc(N)c(C(F)(F)F)c2)nc(Cl)n1
Reactant: C1NC2CC1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(-c2cnc(N)c(C(F)(F)F)c2)nc(N2CC3CC2C3)n1
Temperature: 90 °C
Yield: 53.4 %

Procedure:
To a solution of (1S,4S)-tert-butyl 5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-chloropyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (220 mg, 0.47 mmol) in DMSO (2 mL) was added 2-azabicyclo[2.1.1]hexane hydrochloride (68 mg, 0.56 mmol) and potassium carbonate (130 mg, 0.93 mmol). The mixture was heated at 90° C. for 16 h. After cooling to room temperature, water (50 mL) was added to. The mixture was extracted with ethyl acetate (30 mL (3 times)). The organic layer was dried over sodium sulfate, concentrated and purified by flash column chromatography (50% ethyl acetate in petroleum ether to 100% ethyl acetate) to provide (1S,4S)-tert-butyl 5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (130 mg, 53.7% yield). LCMS (ESI): [MH]+=518.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([NH2:22])=[CH:20][C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31]>CCOC(C)=O.C1CCCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:21]([NH:22][C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31])=[CH:20][C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:18]2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(C2CCN(C(=O)OCc3ccccc3)CC2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(C2CCN(C(=O)OCc3ccccc3)CC2)n1
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
To a solution of Intermediate 16b (550 mg, 1.54 mmol) in aqueous NaOH solution (1M, 3.85 mL, 3.85 mmol) and EtOAc (5 mL) at RT, was added 2,2,2-trichloroethyl chloroformate (0.32 mL, 2.31 mmol) over 2 min, then the mixture stirred vigorously for 30 min. The aqueous layer was extracted with EtOAc (10 mL), then the combined organics washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to leave a yellow-brown oil. FCC, using 0-30% EtOAc in cyclohexane, gave the title compound as a white foam (337 mg, 41%). LCMS (Method 3): Rt 4.81 min, m/z 531, 533 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23][CH2:22][C:21]=4[CH:34]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl.O1CCOCC1>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[CH2:26][NH:25][CH2:24][CH2:23][CH2:22][C:21]=4[CH:34]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCNC4)no2)cc1Cl
Reaction time: 1.5 h

Procedure:
1,1-Dimethylethyl 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (Preparation 7) (75 mg, 0.155 mmol) was treated with 4N HCl in dioxan (1162 μl, 4.65 mmol) and the clear solution left standing for 1.5 hours. A white precipitate formed. Ether (1 ml) was added and the white solid was filtered off, washing with ether. The title compound was obtained on drying of the solid (45 mg). δH (400 MHz, d6DMSO) 1.36 (6H, d), 1.91-1.98 (2H, m), 3.11-3.14 (2H, m), 3.36-3.39 (2H, m), 4.41 (2H, s), 4.85-4.94 (1H, m), 7.46 (1H, d), 7.64 (1H, d), 7.95-7.80 (2H, m), 8.11 (1H, dd), 8.19 (1H, d), 9.04 (2H, broad s); MS (ES) C21H2235ClN3O2 requires 383; found 384.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13].Cl>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.8 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(3-pyridylmethyloxy)benzoate (0.165 g, 0.353 mmol) was dissolved in a mixed solution of an aqueous 1N NaOH solution (3 ml) and 1,4-dioxane (3 ml) and the resulting solution was stirred at room temperature for 6 hours. The reaction solution was diluted with water, rendered acidic with concentrated hydrochloric acid and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:3) to obtain the titled compound (0.150 g, 0.331 mmol, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N+:18]([O-:29])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1cccc(Nc2nccc(-c3ccncc3)n2)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(-c2ccnc(Nc3cccc(Cl)c3)n2)cc1

Procedure:
10 g (35.4 mmol) of N-(3-chloro-phenyl)-4-(4-pyridyl)-2-pyrimidineamine and 11.1 g (35.4 mmol) of m-chloroperbenzoic acid are stirred for 5 h at RT in 500 ml of methylene chloride. Concentration and crystallisation (acetic acid) of the residue give N-(3-chloro-phenyl)-4-(N-oxido4-pyridyl)-2-pyrimidineamine; m.p. 274°-275°, Rf =0.6 (methylene chloride:methanol=9:1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(COc2cccnc2N)cc1
Reactant: S=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(COc2cccnc2NC(=S)Nc2ccccc2)cc1

Procedure:
A mixture of 2-amino-3-(4-methoxybenzyloxy)pyridine (1.91 g, 0.0083 mol), phenyl isothiocyanate (1.4 g, 0.01 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.18 g (72%), m.p. 123°-125 ° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:17][NH2:18])=[CH:11][C:10]=1[C:30]([CH3:33])([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:17][NH:18][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:11][C:10]=1[C:30]([CH3:33])([CH3:32])[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(CC(CN)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(CC(CNS(C)(=O)=O)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 3-(4-benzyloxy-3-tert-butylphenyl)-2-benzyloxycarbonylaminopropylamine (1.27 g, 2.84 mmol) in methylene chloride (29 ml), TEA (0.6 ml, 4.26 mmol) and then methanesulfonyl chloride.(0.3 ml, 3.69 mmol) were added slowly under cooling with ice. After stirring for 30 min., the mixture was mixed with water and extracted with chloroform. The organic layer was dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:ethyl acetate:n-hexane=1:1:2), giving the titled compound (1.23 g, 83%).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[N:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[N:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=23)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:21]([O:25][C:26](=[O:27])[NH:28][C@H:29]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:30][C:31]([N:14]1[CH2:15][CH2:16][N:11]2[C:10]([C:17]([F:18])([F:20])[F:19])=[N:9][C:8]([C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])=[C:12]2[CH2:13]1)=[O:32])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: O=C(c1nc(C(F)(F)F)n2c1CNCC2)C1CCCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)C3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 70.8 %

Procedure:
Cyclopentyl-(3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl)-methanone 28b (83 mg, 0.258 mmol) and (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (0.129 g, 0.388 mmol) were dissolved in 10 mL of dichloromethane under stirring, and triethylamine (0.143 mL, 1.03 mmol) was then added to the solution. After stirring to mix well, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.099 g, 0.388 mmol) was added. The reaction mixture was reacted overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-cyclopentanecarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 28c (0.11 g, yield 72%) as an orange oil.
Reaction SMILES: [OH:1][C:2]1([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl.[NH4+].[Cl-]>ClCCl>[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25][O:1][C:2]1([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: OC1(c2nccs2)CCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCOC1(c2nccs2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
To a solution of the alcohol 2-[(1-Hydroxy)cyclobutyl]thiazole from Step 1 (5 g, 32 mmol) and Hunig's base (10.4 mL, 60 mmol) in dichloromethane (100 mL) at 0° C. was added 2-(trimethylsilyl)ethoxymethyl chloride (6.5 mL, 36.7 mmol). The resulting solution was stirred at 0° C. for 1 h, was heated at reflux temperature for 3.5 h and finally was stirred at room temperature for 15 h. Sat. aq. NH4Cl was added and the resulting mixture was extracted with dichloromethane (3×). The combined organics were washed with water, brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; dichloromethane to dichloromethane/ethyl acetate 95:5) provided 2-{1-[(2-Trimethylsilylethoxy)methoxy]cyclobutyl}thiazole (2 g).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[C:12]([O:16][C:17]([N:19]1[CH:24]2[CH2:25][CH2:26][CH:20]1[CH2:21][C:22](=[O:27])[CH2:23]2)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH:24]2[CH2:25][CH2:26][CH:20]1[CH2:21][C:22]([OH:27])([C:8]1[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=1)[CH2:23]2)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: Cn1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1ccnc1C1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
n-Butyl lithium (2.5 M, 1 mL, 2.5 mmol) was added dropwise to a solution of 1-methyl imidazole (0.193 g, 2.35 mmol) in THF (10 mL), under nitrogen at −78° C. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.55 g, 2.45 mmol) in THF (2.5 mL) was added and the mixture stirred at −78° C. for 1 hour before warming to room temperature. A solution of saturated aqueous ammonium chloride was added and the mixture extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 1:1 ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.12 g). LCMS m/z 308.2 [M+H]+. R.T.=2.14 min (Analytical Method 3).
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].S(Cl)([Cl:25])=O>N1C=CC=CC=1.C(Cl)Cl>[C:1]([Cl:25])(=[O:22])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)Cl
Yield: 94.4 %

Procedure:
Under a nitrogen atmosphere, one drop of pyridine was added to 2.0 g of phytanic acid and 10 ml of methylene chloride, and 1.14 g of thionyl chloride was added dropwise at room temperature. After the completion of dropwise addition, the mixture was refluxed for 1 hour, and then concentrated under reduced pressure to obtain about 2 g of phytanic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1

Procedure:
To a suspension of 6-chloronicotinoyl chloride (10.5 g, 59.7 mmole) in dry dichloromethane (100 mL) was added 4-fluoroaniline (5.6 mL, 59.7 mmole), followed by the dropwise addition of N,N-diisopropylethylamine (21 mL, 19 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[CH:34]=[CH:33][C:16]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]3[CH:30]=[CH:31][CH:32]=[C:21]3[CH2:20]2)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[CH:34]=[CH:33][C:16]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]3[CH:30]=[CH:31][CH:32]=[C:21]3[CH2:20]2)=[O:18])=[CH:15][CH:14]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NS(=O)(=O)c2ccccc2Cl)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
To a solution of 0.418 g of 2-chlorobenzenesulfonyl chloride in 5 ml of dichloromethane, cooled to 0° C. is added 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.346 μl of triethylamine. The mixture is stirred at room temperature overnight and diluted with 50 ml of dichloromethane. The mixture is washed with 20 ml each of H2O, 2N citric acid, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer silica gel plates (4) with the solvent ethyl acetate-hexane (1:1) to give a solid. Crystallization from ethyl acetate gives 0.165 g of white crystals, m.p. 206°-210° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[C:9](=[O:15])[NH:10][CH:11]=[CH:12][C:13]=1[I:14].Br[CH2:17][CH2:18][C:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1>[F:7][C:8]1[C:9](=[O:15])[N:10]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=[CH:12][C:13]=1[I:14]
Reactant: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Reactant: O=c1[nH]ccc(I)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCn1ccc(I)c(F)c1=O)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Cesium carbonate (1.50 g, 4.60 mmol) was added to a solution of 3-fluoro-4-iodopyridin-2(1H)-one (354 mg, 1.48 mmol) and ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (595 mg, 2.07 mmol in THF (25 mL). The resulting suspension was heated to 50° C. and stirred overnight. The reaction was heated to 70° C. and stirred at this temperature overnight. The reaction was filtered through celite (−1 inch), and the filter pad was washed with ethyl acetate (2×30 ml). The combined filtrates were concentrated and the crude was purified via flash chromatography on an Analogix SF15-24 g column and an eluant of ethyl acetate in heptane (50-100%) to afford the title compounds as a clear gum (366 mg, 55.5%). LC-MS m/z 445.9 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.12 Hz, 3H) 1.76 (s, 3H) 2.43-2.56 (m, 2H) 3.11 (s, 3H) 3.97-4.10 (m, 1H) 4.20-4.38 (m, 3H) 6.50 (dd, 1H) 6.75-6.98 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][CH2:15][Cl:16]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][Cl:16])[CH:6]=1
Reactant: ClCCBr
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: ClCCn1cc(Br)cn1
Temperature: 60 °C
Yield: 87.1 %

Procedure:
4-bromopyrazole (700 mg, 4.76 mmol, available from Aldrich), cesium carbonate (2328 mg, 7.14 mmol) and 1-bromo-2-chloroethane (0.592 ml, 7.14 mmol, available from Acros) were suspended in N,N-Dimethylformamide (DMF) (14 ml) and heated to 60° C. under microwave conditions in an Emrys Optimiser for 1 hour. The mixture was partitioned between water (20 ml) and ethyl acetate (60 ml). The aqueous layer was run off and the organic washed (water 3×10 ml), brine (10 ml)), dried (magnesium sulfate) and evaporated to dryness to give the desired product (868 mg).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[C:18]1([CH3:33])[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:26]2[CH:25]=[C:24]([C:21]3[CH:20]=[CH:19][C:18]([CH3:33])=[CH:23][CH:22]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: Cc1ccc(-c2cccc(B(O)O)c2)cc1
Product: Cc1ccc(-c2cccc(-c3cnc(N)c(C(=O)Nc4ccncc4)c3)c2)cc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with [3-(p-tolyl)phenyl]-boronic acid gives the compound “A23”;
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[NH:5][C:4]=2[CH:3]=1.Cl[CH2:27][C:28]1[N:29]=[N:30][N:31]([CH2:33][CH3:34])[N:32]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[I-].[Na+]>C1COCC1>[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:27][C:28]3[N:29]=[N:30][N:31]([CH2:33][CH3:34])[N:32]=3)[C:4]=2[CH:3]=1
Reactant: CCn1nnc(CCl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(Br)sc3c2=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Temperature: 45 °C
Reaction time: 48 h

Procedure:
To a solution of tert-butyl 4-(6-bromo-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (5.00 g, compound B53) in anhydrous THF (100 ml) is slowly added 5-(chloromethyl)-2-ethyl-2H-tetrazole (5.62 g, compound D32), sodium bis(trimethylsilyl)amide (11.6 ml, 1.0 M solution in THF) and sodium iodide (348 mg). The reaction mixture is stirred for 48 h at 45° C. Afterwards all volatiles are removed under reduced pressure and the residue is treated with DCM (100 ml) and water (50 ml). The organic layer is separated and dried over sodium sulfate. After purification by flash column chromatography [silica gel, eluation gradient: EtOAc/cyclohexane, 1/1 (v/v)] the title compound is obtained as a solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][N:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][OH:30])[N:21]=2)=[CH:4][CH:3]=1.C(Cl)Cl.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][N:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][O:30][C:34](=[O:36])[CH3:35])[N:21]=2)=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([C:12]#[N:13])[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Cc3nn(CO)c4nnccc34)c2F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCn1nc(Cc2ccc(Br)c(Oc3cc(Cl)cc(C#N)c3)c2F)c2ccnnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 12 (0.1 g, 0.2 mmol) and DCM (3 mL) was added pyridine (0.08 mL, 1.0 mmol) and acetic anhydride (612 mg, 6 mmol). The resulting solution was stirred overnight at RT under an inert atmosphere. Starting material was still evident and additional aliquots of pyridine (0.08 mL) and Ac2O (0.612 g) were added and the resulting mixture stirred at 55° C. for ca. 5 h. The volatile contents were evaporated and the residue purified in two batches on a preparative SiO2 TLC plate developed with 60% EtOAc/hexane containing 1% TEA. The product was eluted from the plate and crystallized from DCM/hexane to afford 0.076 g of I-8: Anal. Calcd. for C22H14BrClFN5O3: C, 49.79; H, 2.66; N, 13.20. Found: C, 49.87; H, 2.63; N, 12.92.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:26]3[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)N1CCNCC1
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (INTERMEDIATE 18) and 1-(methylsulfonyl)piperazine.