Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2([CH2:16][CH2:15][NH:14][C:13]2=[O:17])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[C:12]2([CH2:16][CH2:15][N:14]([C:19]3[CH:24]=[N:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[C:13]2=[O:17])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC12CCNC2=O
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CC(C)(C)OC(=O)N1CCCC12CCN(c1ccc([N+](=O)[O-])nc1)C2=O
Yield: 79.1 %

Procedure:
Following general N—C coupling procedure 1, 6-oxo-1,7-diaza-spiro[4,4]nonan-1-carboxylic acid tert-butyl ester (1.3 g, 5.41 mmol) was combined with 5-bromo-2-nitropyridine (1.10 g, 5.41 mmol) which gave 7-(6-nitro-pyridin-3-yl)-6-oxo-1,7-diaza-spiro[4,4]nonane-1-carboxylic acid tert-butyl ester (1.55 g) in 79% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][NH:10][C:9](=O)[C:8]=2[CH:13]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:16])=O.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:16][C:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[S:11][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]sc2ccc([N+](=O)[O-])cc12
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Temperature: 109 °C
Reaction time: 8 h

Procedure:
A mixture of 5-nitro-1,2-benzisothiazol-3(2H)-one (10.0 g, 0.0510 mol), phosphorus oxychloride (40.0 mL, 0.429 mol) and tributylamine (12.0 mL, 0.050 mol) is heated at 103-115° C. for six hours, stirred at room temperature overnight, and poured into an ice-water mixture. The resultant aqueous mixture is extracted with methylene chloride. The combined organic extracts are washed sequentially with water and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a gum. Column chromatography of the gum using silica gel and methylene chloride gives the title product as an orange-yellow solid which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([CH:16]([F:18])[F:17])=[CH:14][N:13]=[C:12]([O:19]C)[CH:11]=2)[CH:3]=1.Br.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([CH:16]([F:17])[F:18])=[CH:14][NH:13][C:12](=[O:19])[CH:11]=2)[CH:3]=1
Reactant: COc1cc(-c2cc(Cl)ccc2C#N)c(C(F)F)cn1
Agent: Br
Agent: c1cc[nH+]cc1
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1C(F)F

Procedure:
216 mg (0.73 mmol) of 4-chloro-2-[5-(difluoromethyl)-2-methoxypyridin-4-yl]benzonitrile and pyridinium hydrobromide were reacted according to General Method 3A. Yield: 215 mg (purity 64%, 67% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]1=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]1=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCC(NC(=O)OC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
(3RS)-3-tert-butoxycarbonylaminopiperidin-2-one (16.07 g) was dissolved in N,N-dimethylformamide (DMF, 350 ml) and the mixture was cooled to 0° C. Sodium hydride (3.6 g of a 50% dispersion in mineral oil) was added and then the mixture was stirred at 0° C. for one hour. A solution of ethyl bromoacetate (13.78 g) in DMF (20 ml) was then added. The mixture was stirred for 16 hours at ambient temperature, then cooled to 0° C. and ice added. Volatile material was removed by evaporation and the residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over Na2SO4 and concentrated by evaporation. The resulting oil was purified on silica eluting with 40% ethyl acetate/petroleum ether (60-80° C.) to give ethyl 2-[(3RS)-3-tert-butoxycarbonylamino-2-oxopiperidin-1-yl]acetate as a colourless oil (18.15 g).
Reaction SMILES: C1C2C(=CC=CC=2)CN1.[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]C[N:11]1[C:20]([Cl:22])=[O:21]>>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][N:11]1[C:20]([Cl:22])=[O:21]
Reactant: O=C(Cl)N1CCc2ccccc2C1
Agent: c1ccc2c(c1)CNC2
Product: O=C(Cl)N1Cc2ccccc2C1
Yield: 77 %

Procedure:
1,3-Dihydro-isoindole-2-carbonyl chloride (27A) is prepared from 2,3-dihydro-1H-isoindole as described for 24A.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][OH:14].Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:16]1[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=1
Reactant: Cc1sc(-c2ccccc2)nc1CO
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a mixture of (5-methyl-2-phenyl-4-thiazolyl)methanol (5.0 g), 6-chloro-3-cyanopyridine (3.38 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 1.07 g) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (5.55 g, 74%) of 6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 124-125° C.
Reaction SMILES: [CH3:1][CH:2]([C@@:4]1([NH:26][C:27]([C@H:29]2[CH:44]=[C:43]3[C@@H:32]([CH2:33][C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][C:41]=53)[NH:36][CH:35]=4)[N:31]([CH3:45])[CH2:30]2)=[O:28])[O:17][C@:16]2([OH:18])[N:7]([C@@H:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]([N:11]3[C@H:15]2[CH2:14][CH2:13][CH2:12]3)=[O:10])[C:5]1=[O:6])[CH3:3].[CH3:46][S:47]([OH:50])(=[O:49])=[O:48].C(OCC)C>C(O)C>[CH3:3][CH:2]([C@@:4]1([NH:26][C:27]([C@@H:29]2[CH:44]=[C:43]3[C@H:32]([CH2:33][C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][C:41]=53)[NH:36][CH:35]=4)[N:31]([CH3:45])[CH2:30]2)=[O:28])[O:17][C@:16]2([OH:18])[N:7]([C@H:8]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:9]([N:11]3[C@H:15]2[CH2:14][CH2:13][CH2:12]3)=[O:10])[C:5]1=[O:6])[CH3:1].[CH3:46][S:47]([OH:50])(=[O:49])=[O:48]
Reactant: CC(C)[C@@]1(NC(=O)[C@H]2C=C3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)O[C@@]2(O)[C@@H]3CCCN3C(=O)[C@H](Cc3ccccc3)N2C1=O
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)[C@@]1(NC(=O)[C@@H]2C=C3c4cccc5[nH]cc(c45)C[C@@H]3N(C)C2)O[C@@]2(O)[C@@H]3CCCN3C(=O)[C@@H](Cc3ccccc3)N2C1=O

Procedure:
Ergocristinine (1.25 g; 0.05 mmoles) was dissolved in absolute ethanol (25 ml), containing methanesulfonic acid (0.15 ml; 2.31 mmoles). After clarifying, the solution was slowly poured into absolute diethylether (350 ml) while stirring. The precipitated salt was filtered off and dried in vacuo. Ergocristinine methanesulfonate (1.40 g; 96.4% of the theory) with a melting point of 170°-180° C. was obtained.
Reaction SMILES: [N:1]1([CH2:6]/[C:7](/[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:8]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CO.[Pd]>[N:1]1([CH2:6][CH:7]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(/C=C(/Cn2ccnc2)c2nccs2)cc1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CC(Cn2ccnc2)c2nccs2)cc1-c1ccccc1
Reaction time: 6 h
Yield: 25 %

Procedure:
A suspension of methyl 4-[(Z)-3-(imidazol-1-yl)-2-(thiazol-2-yl)-prop-1-enyl]-2-phenyl-benzoate (see this Example, compound a), step B) (1.2 g; 3 mmol) and 10% Pd/C (0.3 g) in MeOH (10 ml) was hydrogenated for 6 hours. After filtration of the catalyst and evaporation to dryness the residue was purified by flash chromatography eluting with CH2Cl2/EtOH (98/2) to give methyl 4-[3-(imidazol-1-yl)-2-(thiazol-2-yl)-propyl]-2-phenyl-benzoate. Yield=25%.
Reaction SMILES: NC1C=CC=CN=1.C(=O)CCCC.[CH3:14][C:15]1C(N)=C[C:29]2[C:17](=N[C:19]3[CH:24]=[CH:23][C:22]([N:25](C)C)=C[C:20]=3[N:28]=2)[CH:16]=1.Cl.C([BH3-])#N.[Na+]>CO.O.C(O)(=O)C>[CH2:29]([NH:28][C:20]1[CH:19]=[CH:24][CH:23]=[CH:22][N:25]=1)[CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: Cc1cc2nc3ccc(N(C)C)cc3nc2cc1N
Agent: Cl
Agent: Nc1ccccn1
Agent: [BH3-]C#N
Solvent: O
Solvent: CCCCC=O
Solvent: CO
Product: CCCCCNc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Acetic acid was added dropwise to 100 ml of a methanol solution containing 2-aminopyridine (3.0 g, 31.9 mmol), valeraldehyde (4.4 ml, 41.7 mmol) and a crystal of Neutral Red until the solution becomes red. After 15 min, a solution of 4.9 g sodium cyanoborohydride in 20 ml MeOH was added and the mixture was stirred at room temperature overnight. Another portion of sodium cyanoborohydride (0.5 g) was added and the mixture was stirred for a further 2 h. Water was added to the reaction mixture which was then extracted with dichloromethane. The organic phase was dried, concentrated and the residue was purified by column chromatography (silica gel, CH2Cl2/MeOH 95/5) to give 4.9 g (95%) of 2-(n-pentylamino)pyridine. A mixture of 2-(n-pentylamino)pyridine (3.39 g, 20.2 mmol), triethylorthoformate (4.0 ml, 24.0 mmol) and diethyl phosphite (13.0 ml, 101 mmol) was heated to 150° C. for 17 h in a flask equipped with a condenser. Heating was discontinued and the reaction mixture was concentrated at reduced pressure. The residue was submitted to several purifications by column chromatography (silica gel, CHCl3/AcOEt 9/1, CH2Cl2/MeOH 95/5 and CH2Cl2/AcOEt/MeOH 7/2/1) and the purified fractions gave 1.5 g (17%) of an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:12][C:3]=12.C(N(CC)CC)C.[NH2:28][CH2:29][C@@H:30]([OH:32])[CH3:31]>C1COCC1>[CH3:9][S:8][C:6]1[N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:12][C:3]2=[C:2]([NH:28][CH2:29][C@H:30]([OH:32])[CH3:31])[N:7]=1
Reactant: C[C@H](O)CN
Reactant: CSc1nc(Cl)c2cnn(COCC[Si](C)(C)C)c2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1nc(NC[C@@H](C)O)c2cnn(COCC[Si](C)(C)C)c2n1
Reaction time: 4 h
Yield: 107.4 %

Procedure:
4-Chloro-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine (391 mg, 1.182 mmol) was dissloved in 5 mL of dry THF. Triethylamine (239 mg, 2.363 mmol) was added, and the reaction mixture was stirred for four hours. (S)-1-Amino-propan-2-ol (93 mg, 1.241 mmol) was then added, and the reaction mixture was stirred for 64 hours. The reaction mixture was quenched by addition to water, and was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure to give (R)-1-[6-Methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (469 mg). Mass Spec. M+H=370.
Reaction SMILES: [Br:1][C@@H:2]1[CH2:9][O:8][C@@H:4]([C:5]([OH:7])=O)[CH2:3]1.ON1C2C=CC=CC=2N=N1.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>O.CN(C)C=O.C(Cl)Cl>[C:21]1([CH2:20][O:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:5]([C@@H:4]3[O:8][CH2:9][C@@H:2]([Br:1])[CH2:3]3)=[O:7])[CH2:32][CH2:31]2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)[C@H]1C[C@H](Br)CO1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(C(=O)[C@H]2C[C@H](Br)CO2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A mixture of 0.941 g of product from Example 150, 0.652 g of 1-hydroxybenzotriazole, 1.17 g of 1-benzyloxycarbonyl piperazine, 1.39 g of dicyclohexylcarbodiimide and 8 ml of dry methylene chloride is stirred at room temperature for 1 hour. Five ml of dimethylformamide is added and the stirring continued overnight at room temperature. The reaction mixture is diluted with water and extracted with chloroform. The organic layer is dried, concentrated in vacuo and the residue purified by chromatography (silica gel: 10-80% ethyl acetate/hexane) to give 1.1 g of the desired product.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:33])[C:7]([CH3:32])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][NH:21][C:20](=[O:23])[N:19]2[CH3:24])=[CH:11][CH:10]=1)[CH3:4].Br[CH2:35][C:36]1[CH:49]=[CH:48][C:39]([C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:41])=[CH:38][CH:37]=1>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:33])[C:7]([CH3:32])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:35][C:36]3[CH:37]=[CH:38][C:39]([C:40](=[O:41])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)=[CH:48][CH:49]=3)[C:20](=[O:23])[N:19]2[CH3:24])=[CH:13][CH:14]=1)[CH3:4]
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(=O)c4ccccc4)cc3)C(=O)N2C)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 10.9 %

Procedure:
To a cooled (0° C.) suspension of NaH (45 mg, 1.1 mmol, 60% w/w in mineral oil) in DMF (0.5 ml) is added a solution of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (320 mg, 0.75 mmol) in DMF (1.5 ml). After 5 minutes, the reaction mixture is removed from the cooling bath and stirred while warming to ambient temperature over 30 minutes. The solution is cooled again to 0° C., and 4-(bromomethyl)benzophenone (188 mg, 0.68 mmol) is added in a single portion, the cooling bath removed, and the mixture stirred for one hour. The reaction mixture is quenched with 1N HCl and extracted with ethyl acetate (2×). The organic extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil. The crude product is purified by flash chromatography on a Biotage silica cartridge (gradient elution, 2:1 hexanes:ethyl acetate to 1:2 hexanes:ethyl acetate) to provide an oil (46 mg, 10%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[F:18][C:19]([F:33])([F:32])[CH2:20][C:21]1[N:22]=[C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[S:24][CH:25]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:29]1[CH2:30][CH2:31][N:26]([C:23]2[S:24][CH:25]=[C:21]([CH2:20][C:19]([F:33])([F:18])[F:32])[N:22]=2)[CH2:27][CH2:28]1)=[O:9])([CH3:2])[CH3:3]
Reactant: FC(F)(F)Cc1csc(N2CCNCC2)n1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(CC(F)(F)F)cs2)CC1
Yield: 28 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[4-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a white crystalline solid (yield 28%). MS (m/e): 492.1 (M+H+, 100%).
Reaction SMILES: [OH:1][CH:2]([C:5]1[C:6]2[N:7]([N:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH2:3][CH3:4].C(N(CC)CC)C>CS(C)=O>[CH3:12][O:11][C:8]1[N:7]2[N:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=[C:6]2[C:5]([C:2](=[O:1])[CH2:3][CH3:4])=[CH:10][CH:9]=1
Reactant: CCC(O)c1ccc(OC)n2nc(C(F)(F)F)cc12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)c1ccc(OC)n2nc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
The compound of Example 135 (32.1 g) was dissolved in DMSO (780 mL) in an argon atmosphere. To this solution, triethylamine (163 mL) and sulfur trioxide-pyridine complex (93.1 g) were sequentially added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into ice water and the resulting solid product was collected by filtration. The product was washed with water and dissolved in ethyl acetate. The solution was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the title compound as a colorless powder (24.0 g).
Reaction SMILES: C[O:2][C:3](=[O:42])[C@H:4]([CH2:24][C:25]1[N:29]=[CH:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=2[N+:39]([O-:41])=[O:40])[CH:26]=1)[NH:5][C:6](=[O:23])[C@@H:7]([CH2:15][S:16]([C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>O1CCOCC1>[C:19]([S:16]([CH2:15][C@@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]([NH:5][C@H:4]([C:3]([OH:42])=[O:2])[CH2:24][C:25]1[N:29]=[CH:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=2[N+:39]([O-:41])=[O:40])[CH:26]=1)=[O:23])(=[O:18])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)[C@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)C(=O)O
Yield: 78.4 %

Procedure:
20.5 g (34.07 mmol) of N-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamoyl]-1-(2,4-dinitrophenyl)-L-histidine methyl ester are dissolved in 180 ml of dioxan, treated with 85 ml (170.34 mmol) of 2N hydrochloric acid and subsequently heated to 80° for 2.5 hours. Usual working-up and crystallization from ether/hexane yields 15.7 g (78%) of N-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamoyl]-1-(2,4-dinitrophenyl)-L-histidine in the form of a pale yellow amorphous solid, Rf value 0.2 in a 5:1 mixture of methylene chloride and methanol, MS: 588 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[CH:10][N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[C:16]2=[N:15][C:14]=1[CH3:28].[CH2:29]1[CH2:33]OC[CH2:30]1.C([Mg]Br)CC.C(OCC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[CH:10][N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([C:22]([OH:26])([CH2:30][CH2:29][CH3:33])[CH2:23][CH2:24][CH3:25])[C:16]2=[N:15][C:14]=1[CH3:28]
Reactant: CCCC(=O)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3Cl)c(C)nc12
Reactant: C1CCOC1
Agent: CCC[Mg]Br
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCC(O)(CCC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3Cl)c(C)nc12
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of 1-{3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazin-8-yl}-butan-1-one (0.15 g, 0.36 mmol) and THF (5 mL) is cooled to 0° C., and a 2.0 M propyl magnesium bromide solution in diethylether (0.22 mL, 0.43 mmol) is added. The reaction is warmed to ambient temperature, diluted with ethyl acetate (30 mL), and washed with a sat. NH4Cl solution (30 mL). The organic layer is dried over MgSO4, filtered, and concentrated. The residue is purified by ISCO flash chromatography (20%-40% EtOAc gradient) to furnish the title compound (0.016 g, 0.017 mmol, 47%). 1H-NMR (CDCl3), δ 0.90 (t, J=7.4 Hz, 6H), 1.12-1.29 (m, 2H), 1.37-1.54 (m, 2H), 1.86-2.04 (m, 4H), 2.50 (s, 3H), 2.54 (s, 3H), 4.15 (s, 3H), 6.11 (bs, 1H), 6.73 (s, 1H), 7.48 (s, 1H), 7.90 (s, 1H) ppm. LC/MS (m/z): calcd. for C22H27ClN6OS (M+H)+: 459.2; found: 459.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([N:23]2[CH2:37][C:26]3=[C:27]4[N:32]([N:33]=[C:25]3[CH2:24]2)[C:31]([CH3:34])=[C:30]([Cl:35])[C:29]([CH3:36])=[N:28]4)=[O:22])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][C:30]1[C:29]([CH3:36])=[N:28][C:27]2[N:32]([N:33]=[C:25]3[CH2:24][N:23]([C:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][C@H:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)=[O:22])[CH2:37][C:26]3=2)[C:31]=1[CH3:34]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1O[C@H]1CCCN(C(=O)OC(C)(C)C)C1)C3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1O[C@H]1CCCNC1)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of (S)-3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (270 mg; 0.51 mmol; 1 eq.) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 1 hour then concentrated in vacuo. The residue was taken up in water, the pH made basic with 5M NaOH and extracted with DCM (2×). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (176 mg, 81%) as white foam. 1H NMR (CDCl3) δ 7.41-7.33 (m, 2H), 7.08-6.98 (m, 2H), 5.02-5.01 (m, 2H), 4.67 (br s, 2H), 4.33 (br s, 1H), 3.11-3.06 (m, 1H), 2.91 (s, 2H), 2.85 (s, 1H), 2.84-2.72 (m, 3H), 2.69 (s, 1H), 2.62 (s, 2H), 1.98-1.91 (m, 1H), 1.80-1.69 (m, 3H), 1.50-1.40 (m, 1H). HPLC (max plot) 98.9%, Rt 2.85 min. UPLC/MS: (MS+) 426.4 ([M+H]+).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Fc1cccc(Br)c1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3cccc(F)c3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 1-bromo-3-fluorobenzene
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[O:24][CH2:23][C:13]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:22])[C:11]=2[CH:12]=1)(=[O:5])=[O:4].[OH-].[Na+].Br[CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>CN(C)C=O.C(OCC)(=O)C>[F:26][C:2]([F:1])([F:25])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[O:24][CH2:23][C:13]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:30][C:31]4[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)[C:14]3=[O:22])[C:11]=2[CH:12]=1)(=[O:5])=[O:4]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2ccccc2C12COc1ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1ccc(OS(=O)(=O)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
To a mixture of 2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yl trifluoromethanesulfonate (0.42 g, 1.10 mmol) and sodium hydroxide (0.07 g, 1.65 mmol) in N,N-dimethylformamide (5.00 mL) was added 2-(bromomethyl)-5-(trifluoromethyl)furan (0.50 g, 2.20 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h and diluted with ethyl acetate (200 mL). After washing with aqueous saturated sodium chloride (2×20.0 mL), the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/3) to give the title compound (0.47 g, 80%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.34 (t, 1H), 7.18-6.94 (m, 5H), 6.74 (dd, 1H), 6.55 (dd, 1H), 6.40 (d, 1H), 5.09-4.72 (m, 4H); MS (ES+) m/z 534.4 (M+1).