Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH:19]2[O:31][CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[O:31][CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCOCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: c1ccc(COCCCc2ccc(C3CCNCC3OCc3ccc4ccccc4c3)cn2)cc1

Procedure:
In an analogous manner to that described in Example 125 (h), from tert-butyl (3'RS,4'RS)-6-(3-benzyloxy-propyl)-3'-(naphthalen-2-ylmethoxy)-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained (3'RS,4'RS)-6-(3-benzyloxy-propyl)-3'-(naphthalen-2-ylmethoxy)-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine in the form of a colourless oil; MS: 467 (M+H)+.
Reaction SMILES: CS(C)=O.F[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[OH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>O>[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[CH2:17][CH2:16]1
Reactant: N#Cc1cccc(F)c1
Reactant: OC1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cccc(N2CCC(O)CC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A dimethylsulfoxide (30 mL) solution of 3-fluorobenzonitrile (9.73 g, 80.0 mmol) and 4-hydroxypiperidine (8.15 g, 81 mmol) was heated to 100° C. and stirred for 5 hours. The solution was cooled to room temperature and added dropwise to water (500 mL). The mixture was extracted with ethyl acetate (2×300 mL) and washed with water (2×200 mL), brine (200 mL), dried (magnesium sulfate) and concentrated in vacuo to afford the crude product. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=[C:6]([O:18][CH:19]([CH3:21])[CH3:20])[CH:5]=1.[OH-].[Na+]>C1COCC1.CO>[CH:19]([O:18][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=1)[C:3]([OH:22])=[O:2])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(OCCc2ccsc2)cc(OC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 3-isopropoxy-5-(2-thiophene-3-yl-ethoxy)-benzoic acid methyl ester (9.5 mmol) in a mixture of THF/MeOH 1/1 (40 ml) is added at 0° C. NaOH 1N (28.6 ml). Then the reaction mixture is stirred at room temperature for 6 h and the solvents are concentrated in vacuo. The residue is diluted with water (100 ml), the aqueous phase is extracted with ethyl ether (2×50 ml), acidified to pH 3 with conc. HCl and extracted with ethyl acetate (2×100 ml). The combined organic layer is washed with brine (50 ml), dried over MgSO4 and the solvent removed in vacuo. The residue is triturated with ethyl ether and pentane then filtered. 3-Isopropoxy-5-(2-thiophene-3-yl-ethoxy)-benzoic acid is obtained as white powder in a yield of 90%; MS: 307.1 (M+H+);
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[C:5]([C:13]([F:16])([F:15])[F:14])=[N:4]1)[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([C:13]([F:15])([F:14])[F:16])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1cc(C(=O)O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
Ethyl 1-ethyl-3-trifluoromethylpyrazole-4-carboxylate (2.17 g) was dissolved in ethanol and potassium hydroxide (1.06 g) in water was added. The reaction was stirred at room temperature overnight. Ethanol was removed under reduced pressure and the resulting residue partitioned between water and ether. The aqueous layer was separated, acidified with hydrochloric acid (2M) and extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo to give 1-ethyl-3-trifluoromethylpyrazole-4-carboxylic acid as a white solid (1.86 g). NMR (CDCl3) δ1.45(t,3H), 4.20(q,2H), 7.95(s,1H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:32])([CH3:31])[C:18]([NH:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[O:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:3][CH2:2]1.F[C:39](F)(F)[C:40](O)=[O:41]>>[NH2:23][CH2:22][CH2:21][N:20]([CH2:39][CH2:40][OH:41])[C:18](=[O:19])[C:17]([S:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:6]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[N:7][C:8]=2[CH:13]=1)(=[O:15])=[O:16])([CH3:32])[CH3:31]
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)NCCNC(=O)OC(C)(C)C)ccc2n1CC1CC1
Reactant: O=C(O)C(F)(F)F
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)N(CCN)CCO)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of 1,1-dimethylethyl {2-[(2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoyl)amino]ethyl}carbamate (Step A, 217 mg, 0.406 mmol) and trifluoroacetic acid (4 mL) was stirred at room temperature for 1 h. After the mixture was concentrated under reduced pressure, the residue was diluted with dichloromethane. The mixture was washed with 2 mol/L sodium hydroxide aqueous solution and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by HPLC (ODS, gradient elution with acetonitrile/0.01% aq. NH3=4:96 to 96:4, by volume; flow rate 40 mL/min) to afford the title compound (127 mg, 71%) as an amorphous.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].Cl>CC(O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCCC(=O)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCCC(O)c1ccc(CC(C)C)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
To a solution of 4'-isobutylhexanophenone (10.5 g) in 2-propanol (60 ml) was added sodium borohydride (2.05 g), and the mixture was stirred at 50° C. for 6 hours. The mixture was poured into ice water and acidified with 6N hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to give 1-(4-isobutylphenyl)hexan-1-ol (9.32 g) as a colorless oil.
Reaction SMILES: C([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19]([F:23])[C:20]=3[CH3:22])[C:15](=[O:25])[C:14]([C:26]([O:28]CC)=[O:27])=[CH:13]2)[C:9]([F:31])=[CH:8][C:7]=1[F:32])(C)(C)C>Cl>[NH2:5][C:6]1[N:11]=[C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19]([F:23])[C:20]=3[CH3:22])[C:15](=[O:25])[C:14]([C:26]([OH:28])=[O:27])=[CH:13]2)[C:9]([F:31])=[CH:8][C:7]=1[F:32]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(C)c(F)c(F)cc2c1=O
Agent: Cl
Product: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c12
Yield: 83.6 %

Procedure:
To 2.5 g of ethyl 1-(6-t-butylamino-3,5-difluoropyridin-2-yl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate was added 10 mL of 36% hydrochloric acid, followed by heating under reflux overnight. After the reaction mixture was allowed to cool down, the resulting precipitate was collected by filtration. The precipitate was washed with ethanol and then with diethyl ether, whereby 1.7 g of the title compound was obtained as a pale yellow powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:19][C:20]#[N:21])[N:7]([CH3:18])[C:8]=1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[CH3:22]I.O>COCCOC>[Cl:3][C:4]1[CH:5]=[C:6]([CH:19]([CH3:22])[C:20]#[N:21])[N:7]([CH3:18])[C:8]=1[C:9](=[O:17])[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: Cn1c(CC#N)cc(Cl)c1C(=O)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C#N)c1cc(Cl)c(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 1 h

Procedure:
To a suspension of 12.2g. of 50% sodium hydride (mineral oil) in 1,2-dimethoxyethane is added 70 g. (0.24 mole) of 4-chloro-5-(p-chlorobenzoyl)-1-methylpyrrole-2- acetonitrile in 1,2-dimethoxyethane over a period of one half hour at room temperature. After the addition is complete, the whole is stirred for one hour and then 35 g. (0.25 mole) of methyl iodide is added. The reaction mixture is stirred for an additional 3 hours and is concentrated in vacuo; the residue is diluted with water and extracted with chloroform. After the extract is dried the chloroform is removed, leaving a brown solid residue which, upon trituration with cold water, yields 4-chloro-5- (p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetonitrile.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([CH2:15][CH3:16])[CH2:8]2)(=[O:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([NH:4][C:5]1[C:6]([Br:17])=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([CH2:15][CH3:16])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC1Cc2cc(NC(C)=O)ccc2C1=O
Solvent: CN(C)C=O
Product: CCC1Cc2c(ccc(NC(C)=O)c2Br)C1=O
Temperature: 60 °C
Yield: 93.1 %

Procedure:
A solution of 5-(acetylamino)-2-ethyl-1-indanone (2.32 g, 10.7 mmol) in anhydrous N,N-dimethylformamide (10.7 mL) was treated with N-bromosuccinimide (2.00 g, 11.21 mmol). The mixture was placed under a N2 atmosphere, stirred, and heated in an oil bath at 60° C. for 100 minutes. After cooling to room temperature, the mixture was partitioned between EtOAc (200 mL) and water (200 mL). The organic phase was washed with water (4×200 mL) and brine (100 mL), dried over MgSO4, filtered, and evaporated under vacuum to afford crude 5-(acetylamino)-4-bromo-2-ethyl-1-indanone as a yellow solid (2.95 g).
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)=O.CC(C)=O.[H-].[Na+].[C:32](N1C=CN=C1)(N1C=CN=C1)=[S:33]>O1CCCC1>[S:33]=[C:32]1[N:12]2[C:13]3[N:14]([C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[CH:4]=4)=[CH:10][CH2:11]2)[N:15]=[CH:16][C:17]=3[C:18](=[O:19])[NH:20]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(C2=CCn3c(=S)[nH]c(=O)c4cnn2c43)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.00 g of 4,5-dihydro-7-(3-methyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared as described in Example 4) in dry tetrahydrofuran cooled to -78° C. (dry ice-acetone) is added sodium hydride (60% dispersion in mineral oil). The reaction mixture is stirred at -78° C. for 30 minutes then 1,1'-thiocarbonyldiimidazole is added. The mixture is allowed to slowly warm to room temperature and is stirred for 36 hours. Then reaction mixture is quenched with water, neutralized with 5% aqueous hydrochloric acid and extracted with chloroform. Evaporation of the solvent in vacuo gives 4,5-dihydro-5-thioxo-8-(3-methylphenyl)-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH2:16]O)[CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1.S(Cl)([Cl:22])=O.C1(C)C=CC=CC=1>ClCCl>[Cl:22][CH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:8][N:7]=1
Reactant: OCc1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Oc2cccc(CCl)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
[3-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyl]-methanol from Step 1 (4.68 g, 17.4 mmol), in dichloromethane (46 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (1.40 mL, 19.1 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 30 min. Toluene (10 mL) was added and the mixture was concentrated by evaporation to form a residue. The residue was evaporated again from toluene and dried under high vacuum to afford the desired product (4.88 g, 98% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.60 (s, 2H) 7.03 (d, J=8.70 Hz, 1H) 7.11 (ddd, J=8.09, 2.35, 0.94 Hz, 1H) 7.20 (t, J=2.03 Hz, 1H) 7.26-7.31 (m, 1H) 7.42 (t, J=7.88 Hz, 1H) 7.91 (dd, J=8.67, 2.53 Hz, 1H) 8.44 (dd, J=1.51, 0.90 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[Cl:6][C:7]1[C:8]([F:38])=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:36][CH3:37])=[C:21]([CH2:24][N:25]([CH3:35])[C:26]4([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:1]([N:29]1[CH2:30][CH2:31][C:26]([N:25]([CH2:24][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][C:20]=2[O:36][CH3:37])[N:17]=[CH:16][N:15]=[C:14]3[NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=2[F:38])[CH3:35])([C:32]([NH2:34])=[O:33])[CH2:27][CH2:28]1)(=[O:3])[CH3:2]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Acetyl chloride (7 μl, 0.094 mmol) was added to a stirred solution of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide hydrochloride (0.05 g, 0.085 mmol, prepared as described in Example 64) and triethylamine (53 μl, 0.38 mmol) in dichloromethane (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, concentrated and purified by column chromatography on silica eluting with increasingly polar mixtures of dichloromethane/methanol (100/0-90/10) to give the title product (0.039 g, 91%) as a pale yellow solid; 1H NMR Spectrum: (DMSO-d6) 1.75-1.98 (m, 2H), 2.05 (m, 5H), 2.19 (s, 3H), 3.32-3.75 (m, 6H), 3.94 (s, 3H), 7.20 (s, 1H), 7.26 (m, 2H), 7.34 (t, 1H), 7.51-7.57 (m, 2H), 8.38 (s, 1H), 8.46 (s, 1H), 9.80 (s, 1H); Mass Spectrum: (M+H)+ 515.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8](=[S:28])[NH:9][C:10]=2[C:11]2[C:20]([F:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.F[B-](F)(F)F.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([N+]#N)=[CH:37][CH:36]=1.CS(C)=O>C(Cl)Cl>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:28][C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[C:20]([F:21])=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:18]4)=[CH:13][CH:12]=3)[N:9]=2)=[CH:37][CH:36]=1
Reactant: N#[N+]c1ccc(Br)cc1
Reactant: Nc1nccn2c(=S)[nH]c(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Product: Nc1nccn2c(Sc3ccc(Br)cc3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Reaction time: 0.5 h

Procedure:
Into a round bottom flask was added 8-amino-1-(8-fluoro-2-phenyl-quinolin-7-yl)-2H-imidazo[1,5-a]pyrazine-3-thione (21 mg, 0.000053 mol), 4-bromobenzenediazonium tetrafluoroborate (0.018 g, 0.000064 mol) and dimethyl sulfoxide (0.1 mL, 0.002 mol) and the reaction mixture was stirred in ice for 30 min. The reaction mixture was cooled, dissolved in DCM and washed with water. Purification by Gilson HPLC eluting with 10→90% acetonitrile: H2O afforded the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=7.13-7.17 (m, 2H), 7.23 (d, J=5.05 Hz, 1H), 7.42 (d, J=8.59 Hz, 2H), 7.49-7.59 (m, 3H), 7.61 (d, J=5.05 Hz, 1H), 7.75-7.78 (m, 2H), 8.05 (d, J=8.59 Hz, 1H), 8.22-8.27 (m, 2H), 8.32 (dd, J=8.72, 1.39 Hz, 1H). MS (ES+): m/z 544.15 (100)[MH+]. HPLC: tR=2.69 min (Open Lynx polar—5 min).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18](Cl)[C:9]=2[C:8]1=[O:22].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1OB(O)O>>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][CH3:32])[C:9]=2[C:8]1=[O:22]
Reactant: COc1ccccc1OB(O)O
Reactant: CSc1nc(Cl)c2c(n1)NCCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Product: COc1ccccc1-c1nc(SC)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 88.6 %

Procedure:
In a similar manner to Reference Example 10, 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 7; 2.43 g) was reacted with 2-methoxyphenylboric acid (912 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (2.47 g, 89%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)OC(C)(C)C)=[C:5]([NH:17][C:18](=[O:27])/[CH:19]=[CH:20]/[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH:4]=1>O1CCOCC1.C(OCC)C>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([F:2])=[CH:4][C:5]=1[NH:17][C:18](=[O:27])/[CH:19]=[CH:20]/[C:21]1[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=1
Reactant: Cn1cc(/C=C/C(=O)Nc2cc(F)ccc2NC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cn1cc(/C=C/C(=O)Nc2cc(F)ccc2N)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
Protecting group removal was effected by addition of a 4M solution of HCl in dioxane (2.5 mL) to a solution of (E)-tert-butyl (4-fluoro-2-(3-(1-methyl-1H-pyrazol-4-yl)acrylamido)phenyl)carbamate (0.10 g, 0.28 mmol) in dioxane (2.5 mL). The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with diethyl ether (20 mL) and the hydrochloride salt of (E)-N-(2-amino-5-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)acrylamide precipitated was filtered. It was suspended in a saturated sodium bicarbonate solution and the mixture was stirred. The solid was filtered and washed with water then dried under vacuum to give the pure product (58 mg) as an off-white solid. ES+(M+H)+261.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([CH3:19])[O:10]2)[C@H:6]1[O:20][C:21](=[O:23])[CH3:22])(=[O:3])[CH3:2].[N:24]([CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35])=[N+:25]=[N-:26].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.CCN(CC)CC>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@H:6]([O:20][C:21](=[O:23])[CH3:22])[C@@H:7]([NH:8][C:9](=[O:10])[CH3:19])[C@H:11]([O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][N:24]=[N+:25]=[N-:26])[O:12][C@@H:13]1[CH2:14][O:15][C:16](=[O:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H]2OC(C)=N[C@@H]2[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: [N-]=[N+]=NCCOCCOCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1[C@H](OCCOCCOCCN=[N+]=[N-])O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
This protocol was modified to synthesis 5β exclusively. Briefly, compound 2 (1.0 g, 3.03 mmol) and alcohol 4 (1.60 g, 9.11 mmol) were dissolved in anhydrous DCM (20 mL), followed by addition of dried 4 A° MS (0.4 g) and reaction mixture stirred at room temperature for 20 minutes under N2. CSA (camphor sulphonic acid, 0.615 g, 9.0 mL, 9.1 mmol) was added at room temperature and 8 hours, followed by heating to 45° C. for 24 hours. The reaction mixture was cooled to room temperature, neutralized with Et3N (0.2 mL, pH 7.5), diluted with DCM (100 mL) and extracted using saturated NaHCO3 solution. The organic layer was washed with water, brine and dried over Na2SO4. Solvents were evaporated under reduced pressure and the residue purified by silica gel column chromatography using DCM:EtOAc:MeOH (8.0:1.5:0.5) to obtain compound 5β (1.15 g, 85%). The spectral data matched with above compound 5β.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH:8]=[CH:7][N:6]=1.CC1CCCO1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:42]S(C2C=CC=CC=2)(=O)=O)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][CH:29]=1)#[N:27]>O>[C:37]([O:36][C:35](=[O:41])[N:34]([C:31]1[CH:30]=[CH:29][C:28]([C:26]#[N:27])=[CH:33][CH:32]=1)[CH2:42][C:13]1[C:14](=[O:17])[CH2:15][CH2:16][C:12]=1[NH:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:4]([F:3])([F:18])[F:19])[CH:10]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C1C=C(Nc2ccnc(C(F)(F)F)c2)CC1
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2ccnc(C(F)(F)F)c2)CCC1=O)c1ccc(C#N)cc1

Procedure:
Sodium hydride (60% in mineral oil, 895 mg, 22.4 mmol) is added in portions to a mixture of 3-(2-(trifluoromethyl)pyridin-4-ylamino)cyclopent-2-enone (intermediate 17, 4.52 g, 18.7 mmol) and 2-methyltetrahydrofuran (30 mL). After 30 min tert-butyl (4-cyano-phenyl)(phenylsulfonyl)methylcarbamate (6.90 g, 18.5 mmol) is added, and mixture is stirred at room temperature for 30 min Water is added, and the phases are separated. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. Yield: 9.20 g; ESI mass spectrum [M+H]+=473; Retention time HPLC: 1.09 min (Z018_504).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH3:15][CH:16]([NH2:18])[CH3:17]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:18][CH:16]([CH3:17])[CH3:15])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC(C)N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 865 mg, 3.15 mmol) and propan-2-amine (3.725 g, 63.0 mmol) in DMF (3 mL) was heated at 120° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with water. The precipitated product was filtered, washed with water and dried in vacuo to obtain the title compound as a white solid (893 mg, 95% yield). HPLC (condition B): retention time=3.28 min. LCMS MH+ m/z 297.00. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (1 H, s), 7.86 (1 H, d, J=1.76 Hz), 7.02 (1 H, d, J=1.76 Hz), 4.24-4.53 (1 H, m), 1.29 (6 H, d, J=6.16 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27](O)=[O:28]>>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:28]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1cc2ccccc2o1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cc5ccccc5o4)cc23)CC1
Yield: 83.5 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 24.0 mg (0.15 mMol) benzofuran-2-carboxylic acid, 15.6 mg (84%) of the title compound were recovered.