Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH:38]3OCC(C)(C)C[O:39]3)[CH2:32][CH3:33])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O.CCOC(C)=O>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:32][CH3:33])[CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=[O:39])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CCN(CCCCC1OCC(C)(C)CO1)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CCCCC=O)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[[4-(5,5-dimethyl-1,3-dioxan-2-yl)butyl](ethyl)amino]-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (20 mg, 0.0286 mmol) in THF (3 mL) and water (1 mL) was added p-toluene sulfonic acid (excess). The reaction was stirred at room temperature for 16 hours, and then brought to reflux and stirred for 24 hours. The mixture was diluted with EtOAc (20 mL) and washed with saturated NaHCO3 solution and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (35% EtOAc/hexanes) afforded 5-[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](ethyl)amino]pentanal. Rf=0.24 (35% EtOAc/hexanes). LCMS=615.2 (M+1)+. 1H NMR (CDCl3, 500 MHz), 9.72 (s, 1H), 7.89 (s, 1H), 7.79 (s, 2H), 7.19-7.12 (m, 3H), 5.73 (d, J=8.2 Hz, 1H), 4.73 (d, J=16.3 Hz, 1H), 4.53 (d, J=16.0 Hz, 1H), 4.04-4.00 (m, 1H), 2.95-2.85 (m, 4H), 2.42 (t, J=7.1 Hz, 2H), 1.61-1.37 (m, 4H), 0.98 (t, J=7.1 Hz, 3H), 0.67 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH:15]=O)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[Br-:19].[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])([OH:22])=[O:21]>C(O)C.C1(C)C=CC=CC=1>[Br-:19].[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1/[CH:34]=[CH:15]/[C:9]1[C:10](=[O:14])[O:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[C:4]([N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])[CH:13]=2)([OH:22])=[O:21]
Reactant: CCN(CC)c1ccc2cc(C=O)c(=O)oc2c1
Reactant: Cc1cccc[n+]1CCCCCC(=O)O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(CC)c1ccc2cc(/C=C/c3cccc[n+]3CCCCCC(=O)O)c(=O)oc2c1

Procedure:
0.2 mmol 7-diethylamino-2-oxo-2H-chromen-3-carbaldehyde and 0.2 mmol 1-(5-carboxy-pentyl)-2-methyl-pyridinium bromide are converted according to the general directions above. Column chromatography: SiO2, eluent: ethanol/toluene.
Reaction SMILES: [CH3:1][N:2](C=O)C.CI.CN(C)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[C-]#N.[K+]>O.C1COCC1>[N+:20]([C:16]1[CH:15]=[C:14]2[C:19]([C:11]([CH2:10][C:1]#[N:2])=[CH:12][NH:13]2)=[CH:18][CH:17]=1)([O-:22])=[O:21]
Reactant: CN(C)Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: N#CCc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Yield: 36 %

Procedure:
To a mixture of DMF (35 mL) and MeI (74.6 g, 0.53 mol) in water (35 mL) and THF (400 mL) was added dimethyl-(6-nitro-1H-indol-3-ylmethyl)-amine (23 g, 0.105 mol). After the reaction mixture was refluxed for 10 min, potassium cyanide (54.6 g, 0.84 mol) was added and the mixture was kept refluxing overnight. The mixture was then cooled to room temperature and filtered. The filtrate was washed with brine (300 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (6-nitro-1H-indol-3-yl)-acetonitrile (B-9-a) (7.5 g, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19](=[CH2:21])[CH3:20]>CN(C)C=O>[CH3:18][C:19](=[CH2:21])[CH2:20][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:7][C:6]([CH3:10])=[CH2:5]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COC(=O)c1cc(Cl)ccc1OCC(=C)C

Procedure:
When this reaction was repeated employing 2.77 Kg of 5-chloro-2-hydroxybenzoic acid, 7.6 liters of dimethylformamide, 5.55 Kg of potassium carbonate, and 3.96 liters of methallyl chloride, the cooled reaction mixture was filtered and divided into two portions. Each portion was poured separately into a mixture of 2.8 liters of hexane, 1.4 liters of ethyl acetate and 7 liters of water. The layers were separated and the aqueous layer in each case extracted again with a mixture of 1.4 liters of hexane and 0.7 liters of ethyl acetate. The organic fractions were combined and washed with 4.1 liters of water followed by a sodium chloride solution of 800 grams of sodium chloride in 4.1 liters of water. The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 4.21 Kg of the desired intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:16]=1)[NH:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1.O.NN>CO.O.[Ni]>[Br:1][C:2]1[CH:16]=[C:6]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=2)[C:5]([NH2:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1cncc(F)c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc(Br)cc1NCc1cncc(F)c1
Temperature: 50 °C

Procedure:
To a solution of Example 12A (1.777 g, 5.45 mmol) in methanol (30 mL) was added hydrazine hydrate (0.74 g, 15.26 mmol), followed by 50% Raney® nickel in water (200 mg) and the mixture was heated at 50° C. for 60 minutes. After cooling, diatomaceous earth was added and the slurry was filtered through diatomaceous earth with dichloromethane. Concentration provided the crude title compound which was used without further purification. MS (ESI) m/z 295.9 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH:5]1([NH:9][N:10]=[CH:11][C:12](=[O:14])[CH3:13])[CH2:8][CH2:7][CH2:6]1>O>[OH:14][C:12]1[C:11]([C:1](=[O:2])[CH3:3])=[N:10][N:9]([CH:5]2[CH2:8][CH2:7][CH2:6]2)[CH:13]=1
Reactant: CC(=O)C=NNC1CCC1
Reactant: O=CC=O
Solvent: O
Product: CC(=O)c1nn(C2CCC2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A 40% aqueous solution of glyoxal (1.13 mL, 9.84 mmol) was added to 2-oxopropanal cyclobutylhydrazone (1.38 g, 9.84 mmol) in H2O (70 mL). The mixture was then heated at reflux. After 1 hour, the mixture was cooled to room temperature and extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford 1.53 g (86%) of 1-(4-hydroxy-1-cyclobutyl-1H-pyrazol-3-yl)ethanone as a yellow oil. The crude product was then used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17].[OH-].[Na+].Br[CH2:33][C:34]([OH:36])=[O:35].Cl>CCO.O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:33][C:34]([OH:36])=[O:35])[CH2:21][CH2:20]1)=[O:17]
Reactant: O=C(O)CBr
Reactant: COc1ccc(C(=O)NC2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)NC2CCN(CC(=O)O)CC2)cc1OCCc1ccc(Cl)cc1Cl

Procedure:
To 360 mg 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-yl-benzamide hydrochloride and 162 mg NaOH in 20 ml EtOH/H2O 1:1 142 mg bromo acetic acid was added at RT. After stirring over night the reaction mixture was acidified with half concentrated HCl. After evaporation of the solvent the residue was coevaporated with toluene. The waxy brown solid was subjected to the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 51.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 3-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.036 g (51%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.C(N(CC)CC)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([CH3:27])[CH:21]=1>C1COCC1.C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:1]=[O:2])=[C:22]([CH3:27])[CH:21]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(F)ccc1N
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1N=C=O
Reaction time: 2 h

Procedure:
20% Phosgene in toluene (0.25 mL, 0.48 mmol) and triethylamine (0.11 mL, 0.76 mmol) were added to a solution of 4-fluoro-2-methyl-benzenamine (12 mg, 0.095 mmol) in a mixture of THF (0.30 mL) and DCM (0.10 mL). The reaction was stirred for two hours, then solvents were removed in vacuo and the product used without further purification in the next step.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13](O)(=[O:15])=[O:14])[CH:8]=1.S(Cl)([Cl:20])=O>CN(C)C=O>[CH3:2][O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([Cl:20])(=[O:15])=[O:14])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)O)c1
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Yield: 97 %

Procedure:
To the sodium salt of 3-(3-sulfophenyl)acrylic acid methyl ester (2) (0.670 g, 2.53 mmol) benzene (2 mL), thionyl chloride (1.508 g, 0.9 mL, 12.67 mmol) and 3 drops of dimethylformamide were added and the resultant suspension was stirred at reflux for one hour. The reaction mixture was evaporated, the residue was dissolved in benzene (3 mL), filtered and the filtrate was evaporated to give the title compound (0.640 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:21])[CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OCC)=O)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[BrH:22]>O>[BrH:22].[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:21])[CH2:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC(CC(=O)c2cccc(Cl)c2)CC1
Agent: Br
Solvent: O
Product: O=C(CC1CCNCC1)c1cccc(Cl)c1
Yield: 90 %

Procedure:
A mixture of 19 parts of ethyl 4-[2-(3-chlorophenyl)-2-oxoethyl]-1-piperidinecarboxylate and 120 parts of a hydrobromic acid solution 48% in water is stirred and refluxed for 2 hours. The reaction mixture is evaporated and the solid residue is boiled in 2-propanol. The product is filtered off after cooling, washed with 2-propanol and dried in vacuo, yielding 17.5 parts (90%) of 1-(3-chlorophenyl)-2-(4-piperidinyl)ethanone hydrobromide; mp. 214.1° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([F:25])=[C:17]([CH:23]=[CH2:24])[CH:18]=2)[C:13]=1[O:26][S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([F:25])=[C:17]([CH2:23][CH3:24])[CH:18]=2)[C:13]=1[O:26][S:27]([C:30]([F:32])([F:33])[F:31])(=[O:29])=[O:28])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1cc2cc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(OS(=O)(=O)C(F)(F)F)c2cc1F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(CC)c(F)cc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 4 h

Procedure:
A mixture of (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate (23 mg, 0.050 mmol) and 10% Palladium on carbon (5 mg) in ethanol (2.0 mL) was stirred under a hydrogen atmosphere for 4 hours, then filtered through a pad of Celite. Filtrate was concentrated to give a thin film (23 mg) that was used in the next step without further purification.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C@@H:14](O)[CH2:13][N:12]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:39]=[N+:40]=[N-:41].[Na+]>ClCCl.CCOC(C)=O>[N:39]([C@H:14]1[CH2:15][C@H:10]([O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][N:12]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13]1)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=N[C@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of (3S,5R)-benzyl 3-(benzoyloxy)-5-hydroxypiperidine-1-carboxylate (1 eq) in 20 mL of dichloromethane was added triethyl amine (3 eq) and methanesulfonyl chloride (1.5 eq) at 0° C. The reaction mixture was allowed to stir at room temperature for 2 hours. The crude mixture was diluted with 120 mL of EtOAc, washed with sat. aq. sodium bicarbonate, brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was dissolved in 25 mL of NMP. Sodium azide (2.2 eq) was added and the resulting suspension was stirred at 80° C. overnight. The reaction mixture was diluted with 200 mL of EtOAc and 100 mL of hexanes, washed with water, brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:2) to yield (3S,5S)-benzyl 3-azido-5-(benzoyloxy)piperidine-1-carboxylate (88%). LC/MS (m/z): 381.0 (MH+). HPLC: Rt: 4.41 min.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[C:10]([F:26])=[C:11]([C:19]3[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=3)[CH:12]=[CH:13][C:14]=2[CH:15]2[CH2:18][CH2:17][CH2:16]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O.O1CCOCC1>[NH2:25][C:22]1[N:23]=[CH:24][C:19]([C:11]2[C:10]([F:26])=[C:9]([C:14]([CH:15]3[CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:12]=2)[O:8][C:5]2[N:4]=[CH:3][C:2]([C:35]3[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=3)=[CH:7][N:6]=2)=[N:20][CH:21]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Nc1cnc(-c2ccc(C3CCC3)c(Oc3ncc(Br)cn3)c2F)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1cnc(-c2ccc(C3CCC3)c(Oc3ncc(-c4cnc(N)nc4)cn3)c2F)cn1
Temperature: 25 °C

Procedure:
5-(3-((5-Bromopyrimidin-2-yl)oxy)-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine (60 mg, 0.14 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (32 mg, 0.14 mmol) were added to a sealable microwave vial equipped with a stir-bar. 1,4-Dioxane (0.58 mL) and Na2CO3 (2 M, 0.14 mL) were added And the mixture sparged with Ar for 10 min before adding Pd(dppf)Cl2.CH2Cl2 (5 mg, 0.007 mmol) and heating the reaction mixture at 80° Celsius for 15 hours. The reaction was then cooled to rt, diluted with water (5 mL), and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by HPLC to give the title compound. MS (ESI): mass calcd. for C22H19FN8O, 430.17; m/z found, 431.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.83 (s, 2H), 8.67 (s, 2H), 8.23 (s, 1H), 8.16 (s, 1H), 7.82-7.74 (m, 1H), 7.30 (d, J=8.3, 1H), 3.68 (p, J=8.9, 1H), 2.31-2.08 (m, 4H), 2.07-1.92 (m, 1H), 1.92-1.76 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10](=[O:34])[CH2:11][N:12]([S:20]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=2)[CH:24]=1)(=[O:22])=[O:21])[CH2:13][CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][N:9]1[C:10](=[O:34])[CH2:11][N:12]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[CH2:13][CH:14]1[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C=CCN(CC(=O)NNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A solution of methyl 4-[[2-(N′-tert-butoxycarbonylhydrazino)-2-oxoethyl](6-chloro-naphthalene-2-sulfonyl)amino]-2-butenoate (500 mg) in THF (25 ml) was combined with potassium t-butoxide (22 mg) and stirred at 70° C. for 15 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water and brine, dried and concentrated to obtain the title compound (500 mg) as a colorless amorphous material.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH2:23][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22])[C:6]=2[CH:7]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)[C:29](=O)[N:30]2CCCCC>>[O:22]=[C:9]1[C:8]2([C:6]3[CH:7]=[C:2]([C:29]#[N:30])[CH:3]=[CH:4][C:5]=3[O:24][CH2:23]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCN1C(=O)C2(COc3ccc(Br)cc32)c2ccccc21
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Product: CCCCCN1C(=O)C2(COc3ccc(C#N)cc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 30, and making non-critical variations using 5-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, the title compound was obtained (78%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.51 (dt, 1H), 7.34 (dt, 1H), 7.12-6.91 (m, 5H), 5.01 (d, 1H), 4.76 (d, 1H), 3.86-3.63 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.32 (m, 4H), 0.92 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.2, 164.1, 142.6, 134.8, 131.4, 130.8, 129.6, 127.8, 123.9, 123.5, 118.8, 111.5, 109.1, 104.7, 80.6, 57.3, 40.6, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 333.5 (M+1).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.Cl.[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]([CH3:50])[CH3:49])=[CH:44][CH:43]=1.C(N(CC)CC)C>>[CH3:49][N:48]([CH3:50])[C:45]1[CH:46]=[CH:47][C:42]([CH2:41][NH:40][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:43][CH:44]=1
Reactant: CN(C)c1ccc(CN)cc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(N(C)C)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and (4-aminomethylphenyl)-dimethylamine dihydrochloride in the presence of two equivalents of triethylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound in 37% yield, m.p. 148-150° C. MS [(+)ESI, m/z]: 585 [M+H]+
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:11][C:12]1[CH:16]=[CH:15][S:14][CH:13]=1.O>CN(C=O)C>[O:7]([CH2:11][C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(OCc2ccsc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A solution of phenol (13.16 g) in DMF (10 ml) was added in portions over 10 minutes to a stirred suspension of sodium hydride (3.12 g) in DMF (100 ml). After 2 hours, a solution of 3-(chloromethyl)thiophene (14.50 g) in DMF (30 ml) was added in one portion and the resulting mixture was stirred at room temperature for 3 hours then poured into water and extracted with ether. The extracts were washed successively with water, dilute aqueous sodium hydroxide, and aqueous sodium chloride, then dried and concentrated to give 3-(phenoxymethyl)thiophene (18.86 g, 91% yield) as a white solid. An analytical sample, recrystallised from methanol, had mp 49°-50° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[N+:16]([O-])=O>[C].[Pd].C(O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH2:16]
Reactant: COc1ccc([N+](=O)[O-])c(NCC2OCCO2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(NCC2OCCO2)c1
Temperature: 40 °C
Reaction time: 0.67 h

Procedure:
To 100 mL of an ethanol suspension containing 4.5 g of N-(1,3-dioxolan-2-ylmethyl)-5-methoxy-2-nitroaniline, 1.3 g of 10% palladium-carbon was added at room temperature, and the mixture was stirred at 40° C. for 3 hours and 40 minutes under a hydrogen atmosphere. The insoluble material filtered off, and the solvent was removed under reduced pressure to obtain 3.5 g of a violet oily substance, 2-(1,3-dioxolan-2-ylmethyl)amino-4-methoxyaniline.
Reaction SMILES: C(O)(=O)C(O)=O.C([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:21]([CH2:36][C:37]1[CH:42]=[C:41]([Br:43])[C:40]([O:44][CH3:45])=[C:39]([Br:46])[CH:38]=1)[NH:20][CH2:19][CH2:18]2)C1C=CC=CC=1.[OH-].[Na+].C(Cl)[Cl:50].Cl>CO>[ClH:50].[Br:46][C:39]1[CH:38]=[C:37]([CH:42]=[C:41]([Br:43])[C:40]=1[O:44][CH3:45])[CH2:36][CH:21]1[C:22]2[C:17](=[CH:16][C:15]([OH:14])=[C:24]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:23]=2)[CH2:18][CH2:19][NH:20]1
Reactant: ClCCl
Reactant: COc1c(Br)cc(CC2NCCc3cc(OCc4ccccc4)c(NS(=O)(=O)c4ccc(C)cc4)cc32)cc1Br
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: COc1c(Br)cc(CC2NCCc3cc(O)c(NS(=O)(=O)c4ccc(C)cc4)cc32)cc1Br

Procedure:
N-[6-benzyloxy-1-(3,5-dibromo-4-methoxy-benzyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-4-methyl-benzenesulfonamide oxalate (0.48 g, 0.00062 mol) was neutralized in a mixture 1N NaOH-methylene chloride. A free base was dissolved in a methanol—conc. HCl mixture (20 mL of each). The reaction mixture was refluxed for 1 h and evaporated. A residue was crystallized from methanol—ethyl ether mixture.