Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12](O)=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1.C(Cl)(=O)C([Cl:22])=O.CN(C=O)C>ClCCCl>[CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12]([Cl:22])=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(C(=O)O)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(C(=O)Cl)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxylic acid, oxalyl chloride, DMF and DCE was stirred at room temperature for 90 minutes and then treated in the usual way to give 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonyl chloride as a brown solid.
Reaction SMILES: [C:1]1(=[CH:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]([C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1CCCCC1>C(OCC)(=O)C>[O:10]([C:17]1[CH:22]=[CH:21][C:20]([S:23][C:1]2([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Sc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)C=C1CCCC1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: O=C(O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCCC1

Procedure:
A mixture of cyclopentylideneacetic acid (2 mmol) and p-(phenoxy)-thiophenol (2 mmol) was heated at 110° C. under nitrogen in the presence of piperidine (100 μL) for 24 hours. The residue was dissolved in ethyl acetate and washed with dilute hydrochloric acid. The organic layer was separated, dried and evaporated under reduced pressure to give crude 2-[-(4-phenoxyphenylthio)-cyclopent-1-yl]-acetic acid, which can be used in the next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:26]1[N:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29]>CS(C)=O.CCOC(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:26]2[N:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]#[N:29])=[CH:14][CH:13]=1
Reactant: N#Cc1cccnc1F
Reactant: Cn1c(Nc2ccc(O)cc2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cn1c(Nc2ccc(Oc3ncccc3C#N)cc2)nc2ccccc21
Temperature: 80 °C

Procedure:
To a solution of 4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenol (120 mg, 0.5 mmol) in DMSO (1 mL) was added cesium carbonate (196 mg, 0.6 mmol) and 2-fluoronicotinonitrile (61 mg, 0.5 mmol). The resulting mixture was heated to 80° C. for 16 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water and brine several times to remove DMSO. The aqueous layer was back extracted with EtOAc (3×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 5% of MeOH in CH2Cl2, followed by trituration with ether, to provide 2-(4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenoxy)nicotinonitrile as off-white solid. MS (ESI, pos. ion) m/z: 342.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]([F:39])([F:38])[CH:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:35]([CH:32]3[CH2:31][CH2:30][CH:29]([C:28]([F:27])([F:38])[F:39])[CH2:34][CH2:33]3)=[O:36])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)C1CCC(C(F)(F)F)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CCC(C(F)(F)F)CC1

Procedure:
The title compound, white solid (42 mg, 33%), MS (ISP) m/z=505.3 [(M+H)+], mp 190° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-trifluoromethyl-cyclohexanecarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@@H:25]3[CH2:28][C@H:27]([C:29](O)=[O:30])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.F[B-](F)(F)F.O=[C:38]1C=CC=[CH:40][N:39]1OC(N(C)C)=[N+](C)C.C(N(C(C)C)CC)(C)C.CNC>CN(C)C=O>[CH3:38][N:39]([CH3:40])[C:29]([C@H:27]1[CH2:28][C@@H:25]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[CH:9]2)[CH2:26]1)=[O:30]
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@@H](C(=O)O)C1
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 45 mg (0.11 mmol) of cis-3-[4-amino-5-(3benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid in 2 ml of N,N-dimethylformamide is added 36 mg (0.12 mmol) of O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate and 39 μl (0.23 mmol) of diisopropylethylamine. 40 μl of a 5.6 M solution of dimethylamine are added thereto. After stirring the solution for 15 min at RT, working-up is effected by partitioning between water and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated in vacuo to provide cis-3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid dimethylamide. Analytical HPLC: tR=6.81 min (Grad 2); ES-MS: m/eo=442.0.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.[NH4+].[Cl-]>CCOCC.CCCCCC>[Cl:12][C:4]1[CH:3]=[C:2]([B:18]([OH:21])[OH:19])[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=1
Reactant: COB(OC)OC
Reactant: Clc1cc(Br)c2c(c1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cc(Cl)cc2c1OCCO2
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a stirred solution of 5-bromo-7-chloro-2,3-dihydro-benzo[1,4]dioxine (Preparation 28, 1.5 g, 6 mmol) in dry Et2O (45 ml) under nitrogen at −70° C. was added n-butyl lithium (2.63 ml of a 2.5M solution in hexane, 6.6 mmol) and the resultant mixture stirred for 1 hour. Trimethyl borate (0.92 ml, 8 mmol) was then added and the mixture stirred at room temperature overnight. Saturated aqueous NH4Cl was added (60 ml) and the aqueous layer extracted with diethyl ether (3×100 ml). The combined organic extracts were concentrated in vacuo. The residue was taken up in 1M aqueous NaOH and washed with diethyl ether (100 ml). The aqueous layer was then acidified with 2N aqueous HCl (pH 2) and extracted with diethyl ether (3×100 ml). The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a white solid (1.12 g, 87% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[F:37][C:38]([F:58])([F:57])[C:39]([N:41]1[CH2:46][CH2:45][CH:44]([C:47]2[CH:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=2)[CH2:43][CH2:42]1)=[O:40].C(N(CC)CC)C>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][S:53]([C:50]1[CH:51]=[CH:52][C:47]([CH:44]3[CH2:45][CH2:46][N:41]([C:39](=[O:40])[C:38]([F:58])([F:37])[F:57])[CH2:42][CH2:43]3)=[CH:48][CH:49]=1)(=[O:54])=[O:55])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccc(C5CCN(C(=O)C(F)(F)F)CC5)cc4)nc32)[C@H](O)[C@@H]1O
Yield: 77.2 %

Procedure:
The title compound was prepared by a similar method to example 3 using (2R,3R,4S,5R)-2-{2-(aminomethy)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (250 mg, 0.51 mmol), 4-[1-(2,2,2-trifluoroacetyl)-4-pipendinyl]benzenesulfonyl chloride (preparation 20) (157 mg, 0.48 mmol) and triethylamine (155 mg, 1.53 mmol) in tetrahydrofuran (25 ml). This gave the title compound as a solid (300 mg). MS: 811 (MH+)
Reaction SMILES: [CH3:1][NH:2][C:3]1N=C(C(O)=O)C=C(CCC)N=1.[CH2:15]([C:19]1[N:24]=[C:23](S(C)(=O)=O)[N:22]=[C:21]([C:29]([OH:31])=[O:30])[CH:20]=1)[CH:16]([CH3:18])[CH3:17].CNC>>[CH3:1][N:2]([CH3:3])[C:23]1[N:22]=[C:21]([C:29]([OH:31])=[O:30])[CH:20]=[C:19]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:24]=1
Reactant: CC(C)Cc1cc(C(=O)O)nc(S(C)(=O)=O)n1
Reactant: CCCc1cc(C(=O)O)nc(NC)n1
Agent: CNC
Product: CC(C)Cc1cc(C(=O)O)nc(N(C)C)n1

Procedure:
The title compound is obtained as a beige solid (132 mg) in analogy to 2-methylamino-6-propyl-pyrimidine-4-carboxylic acid starting from 6-isobutyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid and 40% aq. dimethylamine; LC-MS: tR=0.78 min, [M+H]+=224.03.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]([NH:23][C:24](=[N:27][CH3:28])SC)#[N:22].O>CN(C)C=O>[C:21]([N:23]=[C:24]([N:27]([CH3:28])[C:24]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1)=[N:23][C:21]#[N:22])[NH:27][CH3:28])#[N:22]
Reactant: Cc1ccnc(-c2sc(N)nc2C)c1
Reactant: CN=C(NC#N)SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=NC#N)N(C)C(=NC#N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Temperature: 100 °C
Reaction time: 12 h
Yield: 14.9 %

Procedure:
To a suspension of 2-amino-4-methyl-5-(4-methylpyridin-2-yl)-thiazole (308 mg) and potassium carbonate (207 mg) in N,N-dimethylformamide (5 ml) was added N-cyano-N′,S-dimethylisothiourea (194 mg), and the mixture was stirred at 100° C. for 12 hours. The mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (2:1, 150 ml×2). The organic layer was washed with brine and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 10 g, 0 to 2% methanol in dichloromethane) to give 2,4-dicyano-1,3-dimethyl-5-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)biguanide (41 mg) as a mixture of regioisomers.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([S:10][CH3:11])[CH:7]=[CH:8][CH:9]=1.S(=O)(O)[O-].[Na+]>ClCCCl>[Cl:3][C:4]1[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:6]([S:10][CH3:11])[CH:7]=[CH:8][C:9]=1[Br:1]
Reactant: CSc1cccc(Cl)c1-c1ccccc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CSc1ccc(Br)c(Cl)c1-c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 3.3 g (20 mmol) of bromine dissolved in 10 mL of 1,2-dichloroethane was added dropwise with stirring to a solution of 4.0 g (17 mmol) of 3-chloro-2-phenyl(methylthio)benzene in 50 mL of 1,2-dichloroethane containing 3.1 g (19 mmol) of ferric chloride. The resulting mixture was allowed to react for another 1.5 hour and then another about 1 g of bromine was added. After 15 min, aqueous sodium bisulfite was added and the mixture was allowed to stand overnight. The organic phase was recovered, washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was chromatographed on silica eluting with a 5:1 mixture of hexane and dichloromethane to obtain 2.7 g (51 percent of theory) of the title compound as a colorless liquid.
Reaction SMILES: ClN1C(=O)CCC1=O.[OH:9][N:10]=[CH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[CH:14][CH:13]=1.[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([C:36]([F:39])([F:38])[F:37])=[CH2:35])[CH:31]=[C:30]([C:40]([F:43])([F:42])[F:41])[C:29]=1[Cl:44].C(=O)(O)[O-].[K+]>CN(C)C=O.O>[Cl:27][C:28]1[CH:33]=[C:32]([C:34]2([C:36]([F:39])([F:37])[F:38])[O:9][N:10]=[C:11]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[CH:14][CH:13]=3)[CH2:35]2)[CH:31]=[C:30]([C:40]([F:41])([F:42])[F:43])[C:29]=1[Cl:44]
Reactant: CC(=O)NCc1ccc(C=NO)c2ccccc12
Reactant: C=C(c1cc(Cl)c(Cl)c(C(F)(F)F)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
N-chlorosuccinimide (0.06 g) was added to N-({4-[(hydroxyimino)methyl]naphthalen-1-yl}methyl)acetamide (0.1 g) in N,N-dimethylformamide (10 ml), and the reaction mixture was stirred at room temperature for 2 hours. 1,2-dichloro-3-(trifluoromethyl)-5-[1-(trifluoromethyl)ethenyl]benzene (0.75 g) and potassium bicarbonate (0.13 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 8 hours. Water was poured into the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with brine, and dried over Magnesium sulfate anhydrous. The solvent was evaporated under the reduced pressure, and the residue was purified with silicagel columnchromatography to get N-[(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}naphthalen-1-yl)methyl]acetamide (0.1 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[S:10](=[O:14])(=[O:13])([OH:12])O.[OH:15][S:16](O)(=[O:18])=[O:17].O=S(=O)=O>>[CH2:1]([C:3]1[CH:4]=[C:5]([S:16]([OH:18])(=[O:17])=[O:15])[C:6](=[CH:8][C:9]=1[S:10]([OH:12])(=[O:14])=[O:13])[NH2:7])[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CCc1cc(S(=O)(=O)O)c(N)cc1S(=O)(=O)O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
121 parts of 4-ethylaniline are added dropwise at 75°-83° C. to 183 parts of 100% sulfuric acid. The mixture is stirred for 15 minutes at 80° C., whereupon a clear solution forms. This sulfuric acid solution is added dropwise over 40 minutes to 320 parts of 66% oleum, while keeping the temperature at 60°-65° C. by cooling with an ice bath. After stirring for 15 minutes at 65° C., no more 4-ethylaniline can be detected. Stirring is continued for 4 hours at 150° C., then the sulfonation mixture is cooled to 80° C. and poured into 900 parts of ice/water. The monopotassium salt of 4-ethylaniline-2,5-disulfonic acid is precipitated by the dropwise addition of 370 parts of a 50% solution of potassium hydroxide and isolated by filtration, affording 350 parts of moist 53.0% 4-ethylaniline-2,5-disulfonic acid, corresponding to a yield of 66%, based on 4-ethylaniline. The purity is >99% (analysis by HPLC).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:24])[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[CH3:24][C:10]1[N:9]([CH2:8][C:4]2[CH:3]=[C:2]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=3)[CH:7]=[CH:6][CH:5]=2)[C:17]2[C:12]([CH:11]=1)=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(-c2cccc(C(F)(F)F)c2)c1

Procedure:
Synthesized as described in Example 310D using 1-[(3-bromophenyl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 318A) and [3-(trifluoromethyl)phenyl]boronic acid: 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.65-7.35 (m, 8H), 6.81 (d, J=7.6 Hz, 1H), 6.68 (s, 1H), 5.44 (s, 2H), 2.48 (s, 3H): MS (ES) m/z 459 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][C:25]1[C:29]([C:30](O)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:30]([C:29]2[C:25]([CH3:24])=[N:26][O:27][C:28]=2[CH3:33])=[O:31])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1noc(C)c1C(=O)O
Product: Cc1noc(C)c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 3,5-Dimethyl-isoxazole-4-carboxylic acid. LC-MS (basic): tR=0.75 min; [M+H]+=456.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[NH2:12][C:13]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17](Cl)[C:14]=1[C:15]#[N:16]>>[NH2:12][C:13]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:14]=1[C:15]#[N:16]
Reactant: COc1ccccc1B(O)O
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1N
Product: COc1ccccc1-c1ccc([N+](=O)[O-])c(N)c1C#N
Yield: 59 %

Procedure:
The title compound was prepared in 59% yield from 2-methoxy-phenylboronic acid and 2-amino-6-chloro-3-nitro-benzonitrile according to the procedure outlined for Example 5A. 1H NMR (400 MHz, CDCl3): δ 8.36 (d, 1H, J=8.8 Hz), 7.42-7.48 (m, 1H), 7.24-7.28 (m, 1H), 7.01-7.10 (m, 2H), 6.82 (br s, 2H), 6.78 (d, 1H, J=8.8 Hz), 3.86 (s, 3H). MS (ES) [m+H] calc'd for C14H11N3O3, 270; found 270.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:24]([O:20][C@@H:5]1[C@@H:4]([O:21][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:3]([O:22][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:2]([CH2:1][O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:7][C@H:6]1[O:8][C@@H:9]1[C@@H:10]([CH2:18][O:19][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:11][CH:12]([O:17][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:13]([O:16][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:14]1[O:15][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)C(OC(=O)c3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
Cellobiose (1.0 g, 2.92 mmol) was dissolved in dry pyridine (20 mL) at 0° C. DMAP (cat.) was added. Benzoyl chloride (2.5 equiv., 58 mmol, 6.8 mL) was added dropwise and the solution stirred at room temperature overnight. The solution was poured onto a mixture of ice-water and DCM. The organic layer was washed with NaHCO3(sat.) (×7), brine, H2SO4 (5%) (×2), followed by brine. The solution was dried (Na2SO4) and the solvent evaporated. The product was passed through a short silica plug to remove the remaining benzoyl chloride and the solvent was evaporated to yield 740 mg (22%) of the white solid product which was reacted on without further purification or characterisation.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C[C:25]([C:33]([OH:35])=O)([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)O)(C)(C)C.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:54]1[C:62]2[C:57](=[CH:58][C:59]([C:63]3[N:67]=[CH:66][N:65](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:64]=3)=[CH:60][CH:61]=2)[C:56]([C:87]2[CH:88]=[C:89](O)[CH:90]=[CH:91][CH:92]=2)=[N:55]1.Cl>O1CCCC1>[NH:65]1[CH:66]=[N:67][C:63]([C:59]2[CH:58]=[C:57]3[C:62](=[CH:61][CH:60]=2)[NH:54][N:55]=[C:56]3[C:87]2[CH:88]=[CH:89][CH:90]=[C:91]([O:35][CH2:33][CH2:25][N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[CH:92]=2)=[N:64]1
Reactant: CC(C)(C)CC(O)(C(=O)O)N1CCNCC1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCN2CCNCC2)cc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 27.1 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), tert-butylcarboxypiperazinylethanol (0.610 g, 2.65 mmol) and diethylazodicarboxylate (0.418 mL) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 1.25 mmol). The mixture was stirred at ambient temperature for 21h and poured into aqueous 6N hydrochloric acid (30 mL). After stirring at ambient temperature for 4h, the mixture was extracted with ethyl acetate (3×). The aqueous fraction was added to aqueous 6N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was stirred with trifluoracetic acid (3.0 mL) at ambient temperature for 70 min. Purification by preparative HPLC (5-70% acetonitrile/water) gave the title compound (0.132 g, 27% yield). ES-MS (m/z) 390 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH2:34][CH:35]([OH:37])[CH3:36])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: CC(O)CN
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(O)CNC(=O)c1cn(C)c(=O)cc1Nc1ccc(I)cc1F
Yield: 36 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (4:1) and treated with 1-amino-2-propanol as for example 34. After workup, the residue was triturated with hexane then dried, affording 4-(2-fluoro-4-iodoanilino)-N-(2-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (36%) as a white solid; m.p. (EtOAc/Hexane) 161-166° C. (glue-liquid). 1H NMR [400 MHz, (CD3)2CO] δ 10.13 (br s, 1H), 8.31 (t, J=1.7 Hz, 1H), 7.73 (br s, 1H), 7.66-7.58 (m, 2H), 7.37-7.31 (m, 1H), 5.75 (dd, J=5.2, 0.9 Hz, 1H), 3.96-3.88 (m, 1H), 3.46-3.39 (m, 1H), 3.42 (s, 3H), 3.25-3.17 (m, 1H), 1.15 (d, J=6.2 Hz, 3H). HRMS (FAB+) calcd for C16H18FIN3O3 446.0377 (M+), found 446.0371. HPLC 96.8% (254 nm).