Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22](I)[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22]([C:5]#[C:4][CH2:3][NH:2][CH3:1])[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#CCNC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1cc(C(C)=O)c[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargylamine (43.6 mg, 0.66 mmol) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (100 mg, 0.25 mmol) (Example 90B) using (Ph3P)4Pd (30.1 mg) and CuI (6.0 mg) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 89° C. for 5 h to yield (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].Cl>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH:10]([CH3:11])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: CCC(=O)c1ccc(SC)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CC(C)C(=O)c1ccc(SC)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of potassium hexamethylsilazane (0.158 mole) in toluene (254 ml) and THF (160 ml) at -78° C. was added dropwise the ketone from Step A of this Example (25.8 g) in THF (90 ml). The reaction mixture was stirred 30 minutes at -78° C. Methyl bromoacetate (16.2 ml) in THF (25 ml) was added dropwise. After stirring 1.5 hours at -78° C. the reaction mixture was poured into 1N HCl (400 ml). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4 and evaporated to give a yellow oil which was purified on a flash silica gel column (1 kg) using hexane/EtOAc (10:2) as eluant to give the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Hg](C#N)C#N.[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@@H:22]1Br)(=[O:19])[CH3:18]>>[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:22]1[S:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: FC(F)(F)c1ccc(S)cc1
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C(F)(F)F)cc2)SC[C@H]1OC(C)=O
Yield: 40 %

Procedure:
If the procedure described in Preparation I is followed starting from 5.58 g (32.10-3 mol) of 4-tri-fluoromethylbenzenethiol, 8.87 g (35.10-3 mol) of mercuric cyanide, Hg(CN)2, and 12.3 g (35.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 6.2 g (yield: 40%) of the expected product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1.CC(=O)OCC>C(#N)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: NCCc1ccc(Br)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=S(=O)(O)CCCNCCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 4-Bromophenethylamine (4 g, 20 mmol) and 1,3-propane sultone (2.56 g, 21 mmol) in acetonitrile (30 mL) was heated at reflux for 2.5 hours. The mixture was cooled to room temperature. The solid was collected by filtration, rinsed with acetonitrile (2×5 mL) air-dried for 15 minutes (9.57 g), and further dried for 15 minutes in vacuo (8.02 g). The solid was suspended in ethanol (40 mL) and the suspension was heated at reflux for 1 hour. The mixture was then cooled to room temperature. The solid was collected by suction filtration, rinsed with ethanol (2×5 mL), air-dried for 15 minutes, and further dried in a vacuum oven at 60° C. for 18 hours. Compound EA was obtained as a white solid (6.04 g, 18.8 mmol, 94% yield). 1H NMR (500 MHz, DMSO) δ 1.95 (t, J=6.3 Hz, 3H), 2.63 (t, J=6.1 Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 3.09 (t, J=6.3 Hz, 2H), 3.15 (t, J=7.8 Hz, 2H), 7.25 (2, J=7.8 Hz, 2H), 7.53 (2, J=7.8 Hz, 2H), 8.63 (br s, 2H). 13C NMR (125 MHz, DMSO) δ 21.8, 31.0, 46.7, 47.2, 48.8, 119.9, 131.0, 131.4, 136.5. ES-MS 324 (M+1).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH2:24][OH:25])[CH2:4][CH3:5])[CH3:2].C=O.[CH3:28]C1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[C:8]=1[CH2:24][O:25][CH2:28][N:14]2[C:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: CCC(CC)Oc1cc(C)nc2c1COCN2c1c(C)cc(C)cc1C
Yield: 97.3 %

Procedure:
A mixture of [4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol (79 mg, 0.231 mmol), 37% aqueous formaldehyde (0.1 ml) and p-TsOH (22 mg, 0.116 mmol) in 10 ml of toluene was heated at reflux using a Dean-Stark apparatus for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 100 mg of the crude material. The crude material was purified through silica gel column chromatography using 2% methanol in chloroform as eluent to give 40 mg (50%) of the title compound as a clear oil. 1H NMR (CDCl3) δ 6.90(s,2H), 6.04(s,1H), 4.87(2 sets of s, 4H), 4.16(m,1H), 2.28(s,3H), 2.19(s,3H), 2.14(s,6H), 1.67(m,4H), 0.94(t,6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.C(N(CC)CC)C.[Br:14][CH:15]([CH3:19])[C:16](Br)=[O:17]>C(Cl)(Cl)Cl>[Br:14][CH:15]([CH3:19])[C:16]([NH:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1)=[O:17]
Reactant: Nc1ccon1
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)Nc1ccon1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−40° C.) stirring solution of 3-aminoisoxazole (0.88 ml, 11.9 mmol) and triethylamine (1.99 ml, 14.3 mmol) in chloroform (6 ml) is added slowly, 2-bromopropionyl bromide (1.37 ml, 13.1 mmol) in chloroform (6 ml). The reaction mixture is stirred at −40° C. for 30 minutes, and then allowed to warm to room temperature. The mixture is then partitioned between 1M aqueous hydrochloric acid and ethyl acetate. The organic extract is washed with saturated sodium hydrogen carbonate, dried over Na2SO4 and the solvent removed in vacuo to afford the titled compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]([OH:23])[CH3:22])=[N:6][CH:7]=1.[C:24]([C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1)([O:26][CH3:27])=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]([O:23][C:31]2[CH:32]=[CH:33][C:28]([C:24]([O:26][CH3:27])=[O:25])=[CH:29][CH:30]=2)[CH3:22])=[N:6][CH:7]=1
Reactant: CC(O)c1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OC(C)c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1

Procedure:
Prepared from 1-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}ethanol (INTERMEDIATE B6.1) and 4-carbomethoxyphenol using a similar procedure as described in the preparation of example B2.1. MS: M+H=485.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]2[C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[S:15][C:16]=2[CH2:17][OH:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CS(Cl)(=O)=O>[CH3:1][S:2]([O:18][CH2:17][C:16]1[S:15][C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[C:12]=1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: OCc1sc2ccccc2c1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1sc2ccccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
Methanesulfonyl chloride (127 μL, 1.63 mmol) was added dropwise to a solution of (3-phenylbenzo[b]thiophen-2-yl)methanol (356 mg, 1.48 mmol) and DIPEA (322 μL, 1.85 mmol) in anhydrous DCM (10 mL) at 0° C. Stirring at 0° C. was continued for 15 min, then the mixture was slowly warmed to RT. After 2.5 h stirring at RT, additional methanesulfonyl chloride (1 drop) was added and stirring was continued for 1 h. The reaction mixture was diluted with DCM and the organic layer was washed with water, then dried (Na2SO4) and concentrated in vacuo affording (3-phenylbenzo[b]thiophen-2-yl)methyl methanesulfonate as a yellow oil (408 mg, 87%). 1H NMR (DMSO, 400 MHz): δ 8.07-8.02 (1H, m), 7.62-7.56 (2H, m), 7.55-7.37 (6H, m), 4.96 (2H, s), 3.33 (3H, s).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9][CH2:8][CH2:7][C:6]2=1.[CH:25](N(C(C)C)CC)(C)C.CI.Cl>C1COCC1>[ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([N:16]([CH3:25])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9][CH2:8][CH2:7][C:6]2=1
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3NCCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCc1ccccc1)C1CCCc2c1[nH]c1ccc(Br)cc21
Reaction time: 12 h

Procedure:
6-Bromo-N-methyl-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared from 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt (0.05 g, 0.12 mmol), diisopropylethyl amine (0.04 mL, 0.25 mmol) and methyl iodide (0.008 mL, 0.12 mmol) in THF (2.0 mL). The reagents were added to a round bottom flask and allowed to stir for 12 hrs. at room temperature under inert atmosphere. The solvent was evaporated, ethyl acetate was added (10 mL), the organics were washed with water (2.0 mL) and sat. NaCl (2.0 mL), dried over Na2SO4, filtered and evaporated to leave an oily residue. Purification by flash chromatography with gradient 10-50% ethyl acetate/hexanes eluent afforded a clear oil that was converted to the HCl salt to give a white solid (0.01 g, 20%). 1H-NMR (CDCl3): δ 8.30 (s, 1H), 7.53 (d, 2H), 7.38-7.10 (m, 5H), 6.89 (d, 1H), 4.09 (m, 1H), 3.04-2.95 (m, 1H), 2.90-2.80 (m, 2H), 2.70-2.55 (m, 3H), 2.48 (s, 3H), 2.11-1.99 (m, 2H), 1.70-1.60 (m, 2H).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:43][C:38]1[CH:37]=[C:36]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH2:21]2)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: COc1ccccc1CC(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: COc1ccccc1CC(=O)N1CC[C@@](CCN2CCC(N3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(2-methoxyphenyl)acetyl]pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[N:10]=[N:11][NH:12][N:7]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(-c2nn[nH]n2)cc1
Yield: 76 %

Procedure:
4-Bromobenzonitrile (20 g, 110 mmol), sodium azide (7.9 g, 121 mmol) and NH4Cl (6.5 g, 121 mmol) in DMF (340 mL) were heated at 90° C. under argon. After 2 days the reaction mixture was concentrated and then diluted with water (300 mL). After adding enough 1M NAOH to render the mixture basic (litmus paper) it was washed with ether (4×25 mL). The aqueous portion was acidified to pH 3 with 1N HCl, the precipitated product was collected by suction filtration and then washed with water. The crude product was recrystallized from ethanol to give crystalline 5-(4-bromophenyl)-2H-tetrazole (19.2 g. 83.6 mmol) in 76% yield, mp. 271°-273° C.
Reaction SMILES: [Se](=O)=O.[OH:4][CH2:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)C>CC(O)C>[C:8]([C:7]1[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=1[CH:5]=[O:4])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OCc1ccccc1C(O)c1ccccc1
Agent: O=[Se]=O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=Cc1ccccc1C(=O)c1ccccc1

Procedure:
A mixture of 1 g. of selenium dioxide and 1 g. of 2-hydroxymethylbenzhydrol in 5 ml. of acetic acid was refluxed for 41/2 hours. The solution was cooled, filtered from selenium and the filtrate was poured into ice water and made alkaline with sodium hydroxide. Extraction with ether gave a yellow oil to which petroleum ether was added. White prisms were obtained which melted at 64°-67°. Ultraviolet maximum (2-propanol) at 226/7 mμ (ε = 15,750) and 251/2 mμ (ε = 18,500), inflexion at 294 mμ (ε = 2600); infrared absorption (CHCl3) at 1665 cm-1 and 1705 cm-1
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[C:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[CH3:25]>>[F:22][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH3:23])=[CH:14][C:13]=1[C@@H:11]([C:8]1[N:6]2[N:7]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([C:24](=[O:26])[CH3:25])[CH2:28][CH2:29]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: CC(=O)N1CCNCC1
Reactant: C[C@@H](c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Product: CC(=O)N1CCN(c2ccc3ncc([C@@H](C)c4cc5cnn(C)c5cc4F)n3n2)CC1

Procedure:
The title compound was prepared analogy to Example 38 using 6-chloro-3-[(S)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate E) (50 mg, 0.153 mmol) and 1-acetylpiperazine (39.2 mg, 0.306 mmol) (tR 3.67 min (conditions 5), MH+=421, 1H-NMR in DMSO-d6: 7.93 (s, 1H); 7.81 (d, 1H); 7.52 (d, 1H); 7.50 (s, 1H); 7.47 (d, 1H); 4.75 (m, 1H); 3.95 (s, 3H); 3.42 (m, 6H); 2.00 (s, 3H); 1.70 (d, 3H)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:19]([OH:21])=O)[N:15]=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:46][O:47][C:48]([C:50]1[C:58]2[N:57]=[C:56]([NH2:59])[NH:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.CCN(C(C)C)C(C)C>[CH3:46][O:47][C:48]([C:50]1[C:58]2[N:57]=[C:56]([NH:59][C:19]([C:14]3[N:15]=[CH:16][C:17]4[C:12]([CH:13]=3)=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:18]=4)=[O:21])[NH:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49]
Reactant: O=C(O)c1cc2ccc(OCc3ccccc3)cc2cn1
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2[nH]c(NC(=O)c3cc4ccc(OCc5ccccc5)cc4cn3)nc12
Yield: 88.4 %

Procedure:
0.70 g (2.5 mmol) of 7-benzyloxy-isoquinoline-3-carboxylic acid synthesized above, 1.0 g (2.7 mmol) of HBTU in a mixture of 7.5 ml of DMF and 1.7 mL of DIEA was reacted with 0.48 g (2.5 mmol) of 2-Amino-3H-benzoimidazole-4-carboxylic acid methyl ester (Intermediate A) as described in general procedure A. 2-[(7-Benzyloxy-isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester (1.0 g, 88%) was isolated after column chromatography using 1:1 ethyl acetate and hexane as an eluents. LCMS: 453 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])O[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[C:14]([CH2:16]C(OCC)=O)#[N:15].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:13]=[C:6]2[C:5]([C:10]([OH:11])=[C:16]([C:14]#[N:15])[C:8](=[O:12])[NH:7]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC#N
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1c(O)c2ccc(F)cc2[nH]c1=O

Procedure:
A mixture of 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (515 mg, 2.8 mmol) (commercially available through AstaTech™, Inc.), ethyl 2-cyanoacetate (303 μL, 2.8 mmol), and triethylamine (793 μL, 5.7 mmol) in DMF (1.4 mL) was stirred at 120° C. for 6 h. The reaction mixture was then concentrated. Upon addition of 1M HCl a precipitate formed, which was isolated by filtration and dried under vacuum, affording 7-fluoro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile. Mass Spectrum (ESI) m/e=205 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[N:30]=[C:31]=[O:32]>O1CCOCC1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[NH:30][C:31](=[O:32])[N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CNc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: C1COCCO1
Product: CN(C(=O)Nc1c(Cl)cccc1Cl)c1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-methyl-N′-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine (428.0 mg, 1.5 mmol), 2,6-dichlorophenyl isocyanate (310.2 mg, 1.65 mmol) in dry dioxane (5 mL) is shaken for 1.5 h at 80° C. After evaporation of the solvent in vacuo, the residue is purified by flash chromatography (CH2Cl2/CH3OH). The combined pure fractions are evaporated, the residue triturated with CH2Cl2 and the solid filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][O:11][C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:14][C:12]([O:11][CH3:10])=[O:13]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)c1
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1cccc(Br)c1
Yield: 82.1 %

Procedure:
To a mixture of 3-bromobenzaldehyde (10 g) and methoxy-carbonylmethylenetriphenylphosphine (20 g) was added toluene (150 ml), and the mixture was refluxed under nitrogen atmosphere for 2 hours. The solvent was evaporated, and the organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give methyl 3-bromocinnamate (10.7 g) as colorless crystals. 1H-NMR(δ ppm, CDCl3): 3.82 (3H, s), 6.44 (1H, d, J=16.0 Hz),
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O-:9])=[O:8])[C@@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.C[C@@H]([NH3+])C1C=CC=CC=1.Cl.CCO>O>[OH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[C@@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: O=C([O-])[C@@H]1CC[C@H](O)[C@H]1c1ccc(F)cc1
Agent: C[C@@H]([NH3+])c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CC[C@H](O)[C@H]1c1ccc(F)cc1

Procedure:
The salt from Step A was dissolved in water and acidified with 2N HCl and was extracted with 3 portions of EtOAc. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to give a white solid. [α]D (EtOH)=-19.9 (c=0.675).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11]>ClCCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([OH:8])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: O=[N+]([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: ClCCCl
Product: O=[N+]([O-])c1cc(Cl)c(F)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
4-chloro-3-fluorophenol (2.38 g, 16.2 mmol) was dissolved in DCE (32 mL) and tetrabutylammonium bromide (0.524 g, 1.62 mmol) was added. HNO3 70% (2.1 mL, 32 mmol) was diluted with H2O (18.9 mL) to make a 7% HNO3 solution. This solution was added to the reaction mixture which was then stirred at rt for 4 h at which time the reaction was judged complete by TLC. The reaction was poured into H2O and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step A (2.29 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (br. s., 1H), 8.18 (d, J=8.1 Hz, 1H), 7.10 (d, J=10.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[CH:12]([OH:22])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40](B4OC(C)(C)C(C)(C)O4)=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:38]=[CH:39][C:40]([C:2]4[N:3]=[CH:4][C:5]5[C:10]([C:11]=4[CH:12]([OH:22])[CH2:13][CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:9][CH:8]=[CH:7][CH:6]=5)=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]
Reactant: OC(CCCc1ccccc1)c1c(Cl)ncc2ccccc12
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4ncc5ccccc5c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-(3-chloro-isoquinolin-4-yl)-4-phenyl-butan-1-ol and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.