Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@:9]([NH:31][C:32](=[O:44])[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:45]1(B(O)O)[CH2:47][CH2:46]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:45]1([C:2]2[CH:3]=[C:4]([C@@:9]([NH:31][C:32](=[O:44])[C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]([F:42])([F:41])[F:43])[CH:34]=3)([C:17]3[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:20]=[C:19]([F:30])[CH:18]=3)[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH2:47][CH2:46]1
Reactant: OB(O)C1CC1
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(Br)c1)c1ccc(F)c(C(F)(F)F)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C2CC2)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 30 %

Procedure:
To a mixture of (S)—N-(1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide, prepared as described in Procedures 3, 62, 5, 6 and 7, (50 mg, 0.07 mmol), (50 mg, 0.07 mmol), cyclopropylboronic acid (6 mg, 0.07 mmol), palladium (II) acetate (1 mg, 0.004 mmol) and tricyclohexylphosphine (2 mg, 0.007 mmol) in toluene (2 mL) was added K3PO4 (0.072 mL, 0.22 mmol). The reaction mixture was heated at 100° C. under microwave irradiation for 15 min. The reaction mixture was filtered, concentrated and the resulting residue was purified by preparative HPLC (Sunfire-S5-C18 18×50 mm column, eluting with 10-90% MeOH/H2O gradient over 8 min, with flow rate 20 mL/min and UV detection at 220 nm) to yield (R)—N-(1-(3-cyclopropyl-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 309, 14 mg, 30% yield). LCMS: RT=4.37 min [M+H] 656.38 (Waters Sunfire-S5-C18 4.6×50 mm, eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (500 MHz, CDCl3) δ ppm 7.90 (1H, dd, J=6.60, 1.92 Hz), 7.81-7.84 (1H, m), 7.22-7.30 (5H, m), 7.16 (2H, t, J=7.56 Hz), 6.93-7.00 (4H, m), 6.77-6.81 (1H, m), 6.68 (2H, d, J=7.42 Hz), 6.62 (1H, s), 6.54 (1H, dd, J=6.87, 2.47 Hz), 5.88 (1H, t, J=52.73 Hz), 4.08 (1H, d, J=13.20 Hz), 3.66 (1H, d, J=13.20 Hz), 2.03 (1H, ddd, J=13.75, 8.52, 5.22 Hz), 0.92-0.96 (2H, m), 0.52-0.56 (1H, m), 0.43-0.47 (1H, m).
Reaction SMILES: [F:1][C:2]([F:16])([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:2]([F:1])([F:16])[C:3]([F:4])([F:5])[F:6])=[CH:15][CH:14]=2)=[CH:20][CH:19]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc(F)cc1)c1ccc(C(F)(F)C(F)(F)F)cc1
Yield: 99.3 %

Procedure:
A solution of 4-pentafluoroethyl-benzoic acid (500 mg, 2.08 mmol), 2-(4-fluorophenyl)ethylamine (319 mg, 2.29 mmol), 4-methylmorpholine (632 mg, 6.24 mmol), and HBTU (1.19 g, 3.12 mmol) in DMF (38 mL) was stirred at RT for 16 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (746 mg, 99%). White solid, MS (ISP) 362.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:17](O)[CH3:18])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.CN(C=O)C.C1(P([N:45]=[N+:46]=[N-:47])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1CCCCC1.O>[N:45]([CH:17]([C:7]1[N:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[C:9]2[C:5]([N:6]=1)=[C:4]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:3]=[C:2]([Cl:1])[N:10]=2)[CH3:18])=[N+:46]=[N-:47]
Reactant: CC(O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-[2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethanol (0.37 g, 1.01 mmol) was dissolved in anhydrous toluene (5.6 mL) and DMF (0.9 mL) and the solution was cooled in ice. Diphenylphosphoryl azide (0.56 mL, 2.54 mmol) was added, followed by dropwise addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL, 2.54 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with ethyl acetate followed by water and the phases were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue, together with crude product from a reaction performed similarly on a smaller scale (0.10 g, 0.27 mmol of 1-[2-chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethanol), was subjected to flash chromatography (SiO2) gradient 0-50% ethyl acetate in cyclohexane to give 8-(1-Azido-ethyl)-2-chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purine as two separated pairs of diastereomers (0.25 g and 0.27 g, total 0.52 g, 100%). LCMS RT=4.05 min, [M+H]+=393/395. LCMS RT=4.16 min, [M+H]+=393/395
Reaction SMILES: [NH2:1][C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[C:3]1=[O:24].CCN(C(C)C)C(C)C.Cl.Cl.[NH2:43][C:44]([CH3:52])([CH3:51])[CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH3:48].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(N(CC)CC)C>[NH2:1][C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:19](=[O:21])[NH:43][C:44]([CH3:52])([CH3:51])[CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])=[CH:22][CH:23]=2)[C:3]1=[O:24]
Reactant: CCN(CC)CC(C)(C)N
Reactant: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2Cc1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2Cc1ccc(C(=O)NC(C)(C)CN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
A solution of 0.896 g of the compound obtained in step B of EXAMPLE 262 in 10 ml of DCM is cooled to 0° C. and 0.36 ml of DIPEA is added, followed by 0.445 g of 2-amino-1-(diethylamino)-2-methylpropane dihydrochloride and then by 1.14 ml of triethylamine and 0.906 g of BOP. The mixture is stirred for 1 hour at RT and concentrated under vacuum. The residue is taken up with AcOEt, the organic phase is washed with a 5% solution of potassium carbonate, with water and with a saturated solution of NaCl and dried over sodium sulfate fate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using AcOEt and then an AcOEt/MeOH mixture (80/20; v/v) as the eluent to give 0.12 g of the expected product after crystallization from a DCM/hexane mixture. M.p.=59° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[NH2:11].C(N(CC)CC)C.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26](O)=[O:27].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26]([NH:11][C@H:3]1[C@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1([CH3:12])[CH3:1])=[O:27]
Reactant: CC1(C)[C@@H](N)[C@@H]1c1ccccc1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)N[C@H]1[C@H](c2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of trans-2,2-dimethyl-3-phenyl-cyclopropylamine (1.04 g, 6.5 mmol) in DCM was added triethylamine (1.435 g, 14.3 mmol), followed by 5-chloro-2-methoxybenzoic acid (1.446 g, 7.44 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (2.696 g, 8.45 mmol). The resulting mixture was stirred at room temperature overnight, then poured into water and extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by flash chromatography (0% to 15% of EtOAc in hexane) to give 1.71 g (86% yield) of trans-5-chloro-N-(2,2-dimethyl-3-phenyl-cyclopropyl)-2-methoxy-benzamide, MS=330 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[C:4]([F:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=2)[C:27]([O:29][CH3:30])=[O:28])O1>>[F:13][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=2)[C:27]([O:29][CH3:30])=[O:28])[CH:7]=[CH:6][C:5]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Reactant: COC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)c(F)c2)c1

Procedure:
According to General Method 1A, 8.0 g (30.9 mmol) of 4-bromo-2-fluoro-1-(trifluoromethoxy)benzene and 20.13 g (77.22 mmol) of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate were reacted. Yield: 8.02 g (69% of theory)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:9]3[C:10]([C:17]4([CH2:21][O:20][C:19]([NH2:22])=[N:18]4)[C:4]=2[CH:3]=1)=[N:11][C:12]([Cl:16])=[CH:13][C:14]=3[F:15].[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[Cl:16][C:12]1[N:11]=[C:10]2[C:17]3([C:4]4[CH:3]=[C:2]([C:29]5[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:7]=[CH:6][C:5]=4[O:8][C:9]2=[C:14]([F:15])[CH:13]=1)[CH2:21][O:20][C:19]([NH2:22])=[N:18]3
Reactant: NC1=NC2(CO1)c1cc(Br)ccc1Oc1c(F)cc(Cl)nc12
Reactant: OB(O)c1cccnc1F
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC1=NC2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(Cl)nc12
Temperature: 105 °C

Procedure:
A mixture of 8-bromo-2-chloro-4-fluoro-5′H-spiro[chromeno[3,2-b]pyridine-10,4′-oxazol]-2′-amine (27.0 mg, 0.070 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ii) (2.486 mg, 3.51 μmol), 2-fluoropyridine-3-boronic acid (10.8 mg, 0.077 mmol) and potassium phosphate (29.8 mg, 0.140 mmol) in a 2:1 mixture of dioxane and water (1.2 mL) was heated at 105° C. in the microwave for 35 min. The reaction mixture was purified by column chromatography (SiO2, CH2Cl2 to CH2Cl2/EA=2:1 to 1:1 to 3:4 to 1:2 to 1:3 to pure EA) to give 2-chloro-4-fluoro-8-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[3,2-b]pyridine-10,4′-oxazol]-2′-amine as an off white solid.
Reaction SMILES: [Br:1]/[C:2](=[CH:10]/[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:3]([O:5]C(C)(C)C)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[Br:1]/[C:2](=[CH:10]/[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)/[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)/C(Br)=C\CCC#Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C(O)/C(Br)=C\CCC#Cc1ccccc1
Yield: 76 %

Procedure:
A solution of t-butyl 2-bromo-7-phenyl-(2E)-hepten-6-ynoate (1.5 g, 4.48 mmol) and 4-toluenesulphonic acid (0.1 g) in dry benzene (15 ml) was heated under reflux under dry nitrogen for 2 hours. The cooled mixture was diluted with ether and the organic phase was extracted with aqueous sodium bicarbonate. The aqueous phase was acidified and extracted with ether. The organic phase was washed with brine and dried over magnesium sulphate. The solvents were removed to give 0.95 g (76% of theory) of 2-bromo-7-phenyl-(2E)-hepten-6-ynoic acid as a colourless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([C:26]1[CH:31]=[C:30]([OH:32])[N:29]=[C:28]([CH3:33])[N:27]=1)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:30]4[CH:31]=[C:26]([CH2:24][CH3:25])[N:27]=[C:28]([CH3:33])[N:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(O)nc(C)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)nc(C)n1
Yield: 12.6 %

Procedure:
4-[4-(6-Ethyl-2-methyl-pyrimidin-4-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (10 mg, 13%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.18 mmol) with 4-ethyl-6-hydroxy-2-methylpyrimidine (Synchem Inc., Des Plaines, Ill., USA; 25 mg, 0.18 mmol) in the presence of potassium carbonate (54 mg, 0.39 mmol). Mass spectrum MH+=440.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][N:27]=[N:26][CH:25]=1)CCC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:24]3[CH:29]=[CH:28][N:27]=[N:26][CH:25]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]([CH3:14])=[CH:7]1)([CH3:13])[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnnc2)cc2c1c(C)cn2C(C)C
Temperature: 105 °C

Procedure:
To a 50 ml round bottom flask was added; methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate (150 mg, 0.484 mmol), PdCl2(dppf)-CH2Cl2 adduct (39.5 mg, 0.048 mmol) and 1,4-Dioxane (4836 μl) followed with 4-(tributylstannyl)pyridazine (179 mg, 0.484 mmol) and a magnetic stir bar. The flask was equipped with a reflux condenser and an exhaust bubbler and heated to 105° C. The reaction solution changed to a dark brown at 30 minutes. LCMS (105 C-3 h) showed the reaction to be complete. The reaction solvent was removed in-vacuo and the remaining residue taken up with DMSO. (1.5 ml). The DMSO solution was purified by reverse phase HPLC using a Phenomenex Gemini 100×30 mm column, neutral acetonitrile and 0.1% formic acid in water, 40-70%, 10 min gradient. The desired fractions were dried in a Genovac EZ-2 evaporator and the solid residues combined. The product, methyl 1-isopropyl-3-methyl-6-(pyridazin-4-yl)-1H-indole-4-carboxylate, was obtained as a white solid. 1H NMR (400 MHz, METHANOL-δ4) δ 9.68 (δ, J=1.26 Hz, 1H), 9.19 (d, J=5.56 Hz, 1H), 8.20 (d, J=1.52 Hz, 1H), 8.13 (dd, J=2.53, 5.56 Hz, 1H), 7.98 (d, J=1.52 Hz, 1H), 7.48 (s, 1H), 4.96 (dt, J=6.60, 13.33 Hz, 1H), 4.00 (s, 3H), 2.39 (s, 3H), 1.56 (d, 6H). MS(ES) [M+H]+ 310.2.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.CN(C=O)C.C1C(=O)N([Br:25])C(=O)C1>O>[Br:25][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1])[NH2:6]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Cl)c(Cl)c(Br)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.2 %

Procedure:
The procedure of Mitchell and Williams, J. Org. Chem. 44:4733 (1979) was modified to obtain the title compound. A mixture of 4,5-dichloro-2-nitroaniline (1.59 g, 7.68 mmol, Aldrich), DMF (30 mL, dist. at reduced pressure) and NBS (1.51 g, 8.48 mmol, Aldrich) was stirred at room temperature (25° C.) for two days. The dark brown solution was poured into deionized water (200 mL) and allowed to set for 30 minuets. The mixture was filtered and the solids washed with deionized water giving 1.81 g (82.4%) of the crude bromide as a yellow powder. The powder was crystallized from ethanol/water (5:1) giving 1.74 g (79.2%) of the title compound as bright yellow needles, mp. 132°-4° C., pure by 1H NMR. 1H NMR (CDCl3) 6.82 (s, 2H), 8.32 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24]I)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.Cl.CNC1CCOCC1.CCN(CC)CC.[Na+].[Cl-]>CC(N(C)C)=O.C1(C)C=CC=CC=1.[OH-].[Na+].C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24][N:27]([CH3:26])[CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCI)CC1
Reactant: CNC1CCOCC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 4 %

Procedure:
A solution of 0.100 g (0.20 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one (example 9B) in 3.1 ml of DMA was treated with free methyl-(tetrahydro-pyran-4-yl)-amine in 1 ml of toluene [0.035 g (0.22 mmol) methyl-(tetrahydro-pyran-4-yl)-amine hydrochloride were dissolved in 0.8 ml of 0.5 N NaOH was extracted with toluene (2 ml). The organic phase was dried over Na2SO4] and stirred for 22 h at RT, 0.06 ml (0.40 mmol) of Et3N was added and stirring was continued for 18 h at 50° C. Again methyl-(tetrahydro-pyran-4-yl)-amine in 1 ml of CH2Cl2 [0.035 g (0.22 mmol) methyl-(tetrahydro-pyran-4-yl)-amine hydrochloridewere dissolved in 0.5 ml aqueous 10% NaCl solution/0.4 ml of 1 N NaOH was extracted with CH2Cl2 (1 ml). The organic phase was dried over Na2SO4] was added and heated for 9 h at 50° C. The reaction was extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4), concentrated and evaporated. Purification by catridges, Si-Amine, 70 ml, 20 g (n-heptane/EtOAc 1:4 to 1:9) gave 0.004 g (4%) of the title compound as a light yellow semisolid. MS: 482.3 (MH+, 2Cl).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].CN.[Cl:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[S:21][C:22]4[CH2:28][C:27](=O)[CH2:26][CH:25]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[C:23]=4[N:24]=3)=[CH:15][C:14]=2[O:37][CH3:38])[CH:12]=1>CO>[Cl:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[S:21][C:22]4[CH2:28][CH:27]([NH:2][CH3:1])[CH2:26][CH:25]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[C:23]=4[N:24]=3)=[CH:15][C:14]=2[O:37][CH3:38])[CH:12]=1
Reactant: COc1cc(Nc2nc3c(s2)CC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CO
Product: CNC1Cc2sc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.7 %

Procedure:
Sodium cyanoborohydride (37 mg, 0.59 mmol) and methylamine (170 μL, 0.34 mmol) were added to a solution of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(4-fluorophenyl)-4,5-dihydrobenzo[d]thiazol-6(7H)-one (50 mg, 0.107 mmol, from example 75) in MeOH (1.1 mL). The mixture was stirred at rt for 4 hours. The crude reaction mixture was purified using preparatory HPLC (Column: Phenomenex Luna C18 30×100 mm, Solvent A=10 mM Ammonium Acetate in 95:5 water/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 water/ACN. Flow rate: 40 ml/mM, 30-95% B, 20 min to afford 5.0 mg (9% yield) of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(4-fluorophenyl)-N6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine. LC-MS (M+H)+ 484.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O=S(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccccc3)c2c([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 6,7-dimethoxy-5-nitro-3H-quinazolin-4-one (1.0 g, 3.98 mmol) (from Example 1, Step A, supra) in SOCl2 (20 mL) (Aldrich) were added a few drops of DMF. The reaction mixture was then heated with stirring at 90° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (30 mL), then aniline (0.36 mL, 3.98 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:1:0.05) as eluent to give the desired (6,7-dimethoxy-5-nitro-quinazolin-4-yl)-phenyl-amine as a yellow solid. (Yield 0.9 g, 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH:18]=[O:19])=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([CH2:18][OH:19])=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2c(cc1OCc1ccccc1)CCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1cc2c(cc1OCc1ccccc1)CCO2
Temperature: -65 °C
Reaction time: 1 h

Procedure:
A flamed dried, N2 purged 1-liter, 3-neck flask equipped with a dropping funnel mechanical stirrer, and thermometer was charged with 5-benzyloxy-2,3-dihydrobenzofuran-6-carboxaldehyde (30.00 g, 0.12 moles) and anhydrous toluene (150 ml). The resultant yellow solution was cooled to -65° C. and with efficient stirring a diisobutylaluminum hydride solution in toluene (77 ml of a 25 wt. %) was added dropwise over 30 minutes. Upon complete addition, the reaction mixture was allowed to warm to room temperature and stirred 1 hour more. The reaction mixture was poured slowly into 2N HCl (300 ml) and crushed ice (400 ml) with rapid stirring. The quenched mixture was extracted sequentially with Et2O (2×300 ml) and EtoAC (2×200 ml). The combined organic layers were washed with brine (2×300 ml), dried over MgSO4, filtered, and the filtrate concentrated in vacuo to afford 5-benzyloxy-6-hydroxymethyl-2,3-dihydobenzofuran as a white precipitate (30.0 g, 97.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[N:12][C:11]=2[C:22]([O:24]CC)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>>[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:22]([C:11]1[N:12]=[N:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:15][C:10]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:24]
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Product: CN(C)CCNC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 92.8 %

Procedure:
A mixture of ethyl 4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxylate (1.0 g) and 2-dimethylaminoethylamine (0.75 g) was heated for 30 minutes at 90° C. with stirring. After allowing to cool at ambient temperature, the resulting precipitates were collected by filtration, recrystalized from diethyl ether to give 3-(2-dimethylaminoethylcarbamoyl)-4-(3-nitrophenyl)-6-phenylpyridazine (1.04 g).