Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]1[CH:6]=[CH:7][C:8]([CH3:24])=[C:9]([NH:11][C:12]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[S:13])[CH:10]=1)[CH2:2][CH3:3].BrBr>C(Cl)(Cl)(Cl)Cl.O>[C:20]1([CH3:21])[CH:19]=[C:18]([CH3:22])[CH:17]=[C:16]([CH3:23])[C:15]=1[NH:14][C:12]1[S:13][C:10]2[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:25][CH2:26][CH3:27])=[CH:6][CH:7]=[C:8]([CH3:24])[C:9]=2[N:11]=1
Reactant: CCCN(CCC)c1ccc(C)c(NC(=S)Nc2c(C)cc(C)cc2C)c1
Agent: BrBr
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCN(CCC)c1ccc(C)c2nc(Nc3c(C)cc(C)cc3C)sc12
Yield: 39.2 %

Procedure:
To a mixture of 1-(5-dipropylamino-2-methylphenyl)-3-mesitylthiourea (100 mg, 0.261 mmol) in carbon tetrachloride (10 ml) was added dropwise bromine (0.015 ml, 0.287 mmol) in carbon tetrachloride (5 ml) over 30 min. The mixture was refluxed for 18 h and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water and brine and concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 39 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:16])C2C=CC=CC=2Cl)[CH:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[O:19][CH3:20].CC(C)([O-:24])C.[K+].O>COCCOC>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[O:19][CH3:20])[C:8]([OH:16])=[O:24]
Reactant: CC(C)(C)[O-]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)cc(Br)c1OC
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCc1cc(C(=O)O)cc(Br)c1OC
Reaction time: 6 h
Yield: 73.5 %

Procedure:
At ambient temperature, to a stirred mixture containing 2-bromo-4-(2-chlorobenzoyl)-6-ethylanisole (10.0 g, 28.2 mmol) and potassium t-butoxide (31.7 g, 0.283 mol) in ethylene glycol dimethyl ether (157 mL) was added H2O (1.52 mL). After 6 h, the reaction solids were collected by filtration and washed with ether (2×). The crude product was dissolved in H2O (200 mL), acidified with 2N HCl (pH <2) and stirred for 7 h. The precipitate was collected by filtration, washed with H2O (2×) and dried to give 5.37 g (73%) of the title compound. 1H NMR: consistent. mass spectrum (EI) m/z 258 (M+).
Reaction SMILES: [C:1]1([CH2:13][CH2:14][NH:15][S:16]([CH2:19][C:20]([O:22]C)=O)(=[O:18])=[O:17])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[NH2:24][OH:25]>>[OH:25][NH:24][C:20](=[O:22])[CH2:19][S:16]([NH:15][CH2:14][CH2:13][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1)(=[O:18])=[O:17]
Reactant: NO
Reactant: COC(=O)CS(=O)(=O)NCCc1ccc(-c2ccccc2)cc1
Product: O=C(CS(=O)(=O)NCCc1ccc(-c2ccccc2)cc1)NO

Procedure:
In a manner similar to Example 1 (b), methyl 2-({[2-(biphen4-yl)ethyl]amino}sulfonyl)acetate was reacted with hydroxylamine to give the title compound as a colourless solid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1.[CH2:15]([N:17]([CH2:28][CH3:29])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21](O)=O)[CH3:16]>>[CH2:28]([N:17]([CH2:15][CH3:16])[C:18]1[CH:19]=[C:20]([C:21]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=3)[N:14]=2)[CH:24]=[C:25]([CH3:27])[N:26]=1)[CH3:29]
Reactant: CCCOc1ccc(C(=N)NO)cc1
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Product: CCCOc1ccc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc1

Procedure:
The title compound is prepared in analogy to Example 5 starting from N-hydroxy-4-propoxy-benzamidine and 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=1.41*min; [M+1]+=367.09.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:21][C:22]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:23]=1[O:24][CH2:25][C:26](O)=[O:27].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C>O1CCCC1>[Cl:21][C:22]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:23]=1[O:24][CH2:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])=[O:27]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cc1ccc(OC)c(N)c1)OC(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1NC(=O)COc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 8.2 %

Procedure:
30 mg of Ethyl 3-(3-amino-4-methoxyphenyl)-2-isopropoxypropanoate and 20 mg of 2,4-dichlorophenoxyacetic acid were dissolved in 0.5 ml of tetrahydrofuran, and 30 mg of carbonyldiimidazole and 0.05 ml of triethylamine were added, and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was then partitioned between water and ethyl acetate, and the organic layer was concentrated. The residue was dissolved in 0.6 ml of ethanol, and 0.12 ml of 5N sodium hydroxide was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by HPLC using a reverse-phase column and a water-acetonitrile-trifluoroacetic acid elution solvent, to give 3.4 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=2)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(Cl)c(F)c1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(Cl)c(F)c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-chloro-3-fluorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 206.8-207.4° C. 1H NMR (acetone-d6/300 MHz) 7.92 (s, 1H), 7.74 (s, 1H), 7.59 (m, 1H), 7.16 (m, 1H), 6.99 (m, 1H), 6.83 (s, 1H), 5.86 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz)-79.4 (d, 3F, J=6.5 Hz), −113.8 (m, 1F). Anal. Calc'd for C17H8Cl2F4O4: C, 48.25; H, 1.91; Cl, 16.76. Found: C, 48.20; H, 1.97; Cl, 16.92.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:25][C:26]([N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36](Cl)[C:31]=2[CH:30]=[CH:29]1)=[O:27].C(Cl)(=O)C.[NH2:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46]([NH2:48])=[O:47]>C(O)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:25][C:26]([N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36]([NH:42][C:43]3[CH:51]=[CH:50][CH:49]=[C:45]([C:46](=[O:47])[NH2:48])[CH:44]=3)[C:31]=2[CH:30]=[CH:29]1)=[O:27]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=O)n1ccc2c(Cl)ncnc21
Reactant: NC(=O)c1cccc(N)c1
Solvent: CC(=O)Cl
Solvent: CCCCO
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=O)n1ccc2c(Nc3cccc(C(N)=O)c3)ncnc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 59.9 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-phenyl}-amide resin (50 mg, 0.05 mmol), prepared as in reference 2, in n-butanol (2 mL) is mixed with acetyl chloride (17.8 μL, 0.25 mmol) and 3-aminobenzamide (34 mg, 0.25 mmol), and shaken at 80° C. for 24 hours. The resulting mixture is filtered and the resin is treated with TFA/CH2Cl2/H2O (45/50/5) (600 μL) for 30 minutes before filtering and washing with CH2Cl2 (3×2 mL), MeOH (3×2 mL). The washes are then combined together and concentrated. The residue is purified by preparative HPLC-MS to give 4-(3-carbamoyl-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-phenyl}-amide (18.5 mg, yield, 60%); 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 10.31 (s, 1H), 9.99 (s, 1H), 8.60 (s, 1H), 8.52 (d, J=1.71 Hz, 1H), 8.23 (s, 1H), 8.12 (d, J=7.59 Hz, 1H), 8.00 (s, 1H), 7.98 (d, J=8.02 Hz, 2H), 7.87 (d, J=3.89 Hz, 1H), 7.59 (dd, J=17.87, 9.00 Hz, 2H), 7.49 (d, J=7.98 Hz, 2H), 7.47 (s, 1H), 7.38 (s, 1H), 7.29 (d, J=8.48 Hz, 1H), 7.11 (d, J=3.89 Hz, 1H), 3.75 (s, 2H), 3.43-2.79 (m, 8H), 2.50 (s, 3H), 2.49 (s, 3H); ESIMS m/z 618.20 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([NH2:11])[CH:3]=1.[N:12]([O-])=O.[Na+].O.O.Cl[Sn]Cl>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([NH:11][NH2:12])[CH:3]=1
Reactant: COc1cc(C)c(Cl)cc1N
Reactant: O=N[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(C)c(Cl)cc1NN
Yield: 33.2 %

Procedure:
The title compound was prepared by the general procedure described above for Preparations 2a-i using 4-chloro-5-methyl-2-aminoanisole (10.26 g), NaNO2 (4.5 g), and SnCl2.2H2O (30 g). Workup gave 3.7 g (33%) of (5-chloro-4-methyl-2-methoxyphenyl)hydrazine.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([Cl:17])=[O:14])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Product: O=C(Cl)c1ccc(Br)c2ccccc12
Temperature: 40 °C
Reaction time: 16 h

Procedure:
4-Bromonaphthalene-1-carboxylic acid (9.80 g) was suspended in thionyl chloride (80 mL) and stirred at 40° C. for 16 hours and evaporated under vacuum. Solid was dissolved in DCM (20 mL) and evaporated under vacuum, giving 4-bromonaphthalene-1-carbonyl chloride (13.8 g, crude) as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][C:11](Cl)=[N:12][CH:13]=[C:8]2[C:7]([NH:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])=[N:6]1)[CH2:2][CH:3]=[CH2:4].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(C(F)(F)F)=O>O1CCOCC1>[CH2:1]([N:5]1[C:9]2=[N:10][C:11]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:12][CH:13]=[C:8]2[C:7]([NH:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])=[N:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCn1nc(Nc2c(C)cccc2C)c2cnc(Cl)nc21
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: C=CCCn1nc(Nc2c(C)cccc2C)c2cnc(Nc3ccccc3)nc21

Procedure:
A solution of 815 mg (2.5 mmol) of 1-(but-3-enyl)-6-chloro-N-(2,6-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-amine 32 (Example 1, Step D) in 17 mL of 1,4-dioxane was treated sequentially with 280 μl (3.1 mmol) of aniline and 415 μl (5.6 mmol) of TFA. The resulting orange solution was heated at reflux for 6 h, and then was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 3:1) to give the title compound 33. 1H-NMR (DMSO-d6) δ 2.24 (s, 6H), 2.45-2.52 (m, 2H), 4.08 (t, J=6.8 Hz, 2H), 4.94 (d, J=10.2 Hz, 1.1 Hz, 1H), 5.02 (dd, J=17.2 Hz, 1.6 Hz, 1H), 5.78-5.88 (m, 1H), 6.95 (t, J=7.3 Hz, 1H), 7.06-7.14 (m, 3H), 7.28 (t, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 8.10 (s, 1H), 8.39 (s, 1H), 9.66 (s, 1H). Mass Spectrum (ESI) m/e=385.2 (M+1).
Reaction SMILES: [CH:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([Li])CCC.[O:17]1[CH:19]([CH3:20])[CH2:18]1.B(F)(F)F.CCOCC>C1COCC1>[OH:17][CH:19]([CH3:20])[CH2:18][C:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC1CO1
Reactant: CCCCOS(=O)(=O)C1CC1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCOS(=O)(=O)C1(CC(C)O)CC1
Reaction time: 0.5 h

Procedure:
A solution of butyl cyclopropanesulfonate 2 (1.2 g, 6.7 mmol) in THF (24 mL) was cooled to −78° C. and n-butyllithium (1.6M in n-hexane, 5.0 mL, 8.1 mmol) was added within 5 min. The mixture was stirred for 30 min and epoxypropane derivative 1 or 8 (8.1 mmol) was added followed by addition of boron trifluoride diethyl etherate (0.84 mL, 6.7 mmol). The solution was stirred for 1 h at −78° C., the cooling bath was removed and stirring was continued for 2 additional hours. For aqueous work-up diluted hydrochloric acid (10%, 0.8 mL), water (10 mL) and ethyl acetate (20 mL) were added. The organic layer was is concentrated at 40° C. to afford the corresponding butyl 1-[2-hydroxypropyl]cyclopropanesulfonate 3.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.Cl>C(O)C.O>[Cl:8][C:7]1[C:2]([NH2:1])=[C:3]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[N:4]=[CH:5][N:6]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: c1ccc2c(c1)CCN2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)ncnc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a stirring slurry of 5-amino-4,6-dichloropyrimidine (3 g, 18.29 mmol) and indoline (2.057 mL, 18.29 mmol) in ethanol (7 mL) and water (43 mL) was added concentrated aqueous HCl (600 μL) and the mixture was refluxed for 3 h and left to stir at room temperature overnight. The reaction mixture was extracted with ethyl acetate, washed with water, brine, dried over MgSO4 and solvent evaporated. The resulting residue was triturated in 25% ethyl acetate in hexanes for 1 h then filtered to afford title compound 105 (1.55 g, 34%) as a tan solid. LRMS (ESI): (calc) 246.07. (found) 247.2 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13].[C-:14]#[N:15].[Na+]>CO.O>[C:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13])#[N:15]
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CC#N)c(F)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 56.7 %

Procedure:
To a solution of methyl 4-(bromomethyl)-3-fluorobenzoate (18 g, 73 mmol) in MeOH (150 ml) was added the solution of NaCN (7.2 g, 146 mmol) in H2O (40 ml). The mixture was stirred at 65° C. for 5 hours. Most of MeOH was evaporated and additional water was added and extracted by EtOAc (200 ml×3), dried with anhydrous Na2SO4, filtered and evaporated to give the crude product. Purification by column chromatography (PE/EtOAc=50/1 to 10/1) gave the product (8 g, 63.8%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:17][O-:18].[Na+]>CS(C)=O>[ClH:2].[CH3:17][O:18][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: C[O-]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNC1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(S(=O)(=O)C2CCNC2)cc1

Procedure:
A solution of 15.5 g (0.060 mole) of 3-[(4-chlorophenyl)sulfonyl]pyrrolidine hydrochloride and 9.0 g (0.167 mole) of sodium methoxide in 200 ml of dimethylsulfoxide was stirred at 100° C. for 2 hours. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and water. The methylene chloride solution was dried over magnesium sulfate and the solvent was removed in vacuo to give an oil, the free base of the title compound. The hydrochloride salt was prepared, recrystallizing from methanol-diethyl ether to give 9.1 g (55%) of white crystalline solid, m.p. 181°-182° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:10][O:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(C=O)cc1
Temperature: 60 °C
Yield: 47.9 %

Procedure:
4-Hydroxybenzaldehyde (300 g) and 2-chloroethyl methyl ether (279 g) were dissolved in DMF (3 L) and potassium carbonate (408 g) was added. The mixture was stirred with heating at 60° C. for 16 hr. After the reaction, the reaction mixture was poured into water and liberated oil was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. After drying, the residue was concentrated under reduced pressure to give 4-(2-methoxyethoxy)benzaldehyde as an oil (212 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:7]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=3)[CH2:36]2)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(C#N)(CCCCCCl)Sc2ccc(C)cc2)cc1OC
Product: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 56.9 %

Procedure:
The procedure of Example 3 is repeated using 4.65 g of α-(5-chloropentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 4.25 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. This affords 3.67 g of the desired product as a light brown gum. MS(Hi res): m/z Calcd for C33H40N2O4S 0.5H2O 560.2209 Found 561.2287(M+H). Calcd for C33H40N2O4S 0.5H2O: C=69.77, H=7.17, N=4.58, S=5.33 Found C=69.56, H=7.25, N=4.92, S=5.63
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH:6]([CH2:8][C:9](O)=O)[CH2:5][C:4]([CH3:13])([CH3:12])[NH:3]1.[NH:15]([C:17](=[S:19])[NH2:18])[NH2:16].O=P(Cl)(Cl)Cl>>[CH3:1][C:2]1([CH3:14])[CH2:7][CH:6]([CH2:8][C:9]2[S:19][C:17]([NH2:18])=[N:15][N:16]=2)[CH2:5][C:4]([CH3:13])([CH3:12])[NH:3]1
Reactant: CC1(C)CC(CC(=O)O)CC(C)(C)N1
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CC(Cc2nnc(N)s2)CC(C)(C)N1
Temperature: 78 °C
Reaction time: 72 h
Yield: 22.5 %

Procedure:
A stirred mixture of 2-(2,2,6,6-tetramethylpiperidin-4-yl)acetic acid (410 mg, 2.057 mmol) and hydrazinecarbothioamide (281 mg, 3.09 mmol) was cooled under nitrogen in an ice bath. POCl3 (0.575 mL, 6.17 mmol) was added drop-wise and the mixture was heated at 78° C. for 3 hours. The reaction mixture was cooled in an ice bath and quenched by addition of ice water (20 mL). The resulting mixture was sonicated for 20 minutes and the resulting suspension was stirred at room temperature for 72 hours. The resulting solution was basified by addition of NaOH (pellets added portion-wise over ˜15 minutes). The resulting suspension was stirred at room temperature for 1 hour before filtering under vacuum and rinsing with water to afford the title compound as a pale brown solid (118 mg, 22% yield). LC-MS: Rt 0.44 min; MS m/z 255.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.98 (s, 2H), 2.66 (d, J=7.07 Hz, 2H), 2.03 (br. s., 1H), 1.49 (d, J=10.61 Hz, 2H), 1.08 (s, 6H), 0.99 (br. s., 6H), 0.78 (t, J=12.13 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:13]/[C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])/[C:5](=[O:12])[NH:6]2.Cl.[CH:21](N)=N>C(O)C>[CH3:19][C:15]1[N:16]=[CH:17][NH:18][C:14]=1/[CH:13]=[C:4]1\[C:5](=[O:12])[NH:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:11][CH:21]=[N:1][C:2]=3[C:3]\1=2
Reactant: N=CN
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21
Agent: Cl
Solvent: CCO
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc3[nH]cnc3c21
Temperature: 25 °C

Procedure:
A mixture of (Z)-4,5-diamino-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (30 mg, 0.1175 mmol) (from Example 45 above) and formamidine hydrochloride (95 mg, 1.18 mmol) (Aldrich) in ethanol (1.5 mL) was heated at reflux for 1 h. The mixture was cooled to r.t., and the reaction was quenched with water. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Mg2SO4 and concentrated under reduced pressure. The crude oily residue was triturated with ether and the resulting yellow precipitate was collected by suction filtration. (First crop; yield 5 mg, 16%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[C:17]1([CH2:23][C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CC(N(C)C)=O>[O:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][N:2]1[NH:1][C:24](=[O:25])[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
To a 4 mL vial was added the product from Example 11B (20 mg in DMA), phenylacetic acid [1.5 equivalents in dimethyl acetamide, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 2 equivalents in dimethyl acetamide) and triethylamine (3 equivalents, neat). The vial was capped and microwaved at 150° C. for 30 minutes. The reaction was checked by LC/MS and concentrated to dryness upon completion. The residue was dissolved in 1:1 MeOH:DMSO and purified by reverse phase HPLC [Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min [0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A]. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.89-11.91 (bs, 1H), 8.43 (dd, J=8.0, 1.3 Hz, 1H), 8.12-8.15 (m, 1H), 7.96-8.08 (m, 2H), 7.32-7.42 (m, 4H), 7.26-7.30 (m, 1H), 3.73 (s, 2H); MS (ESI+) M/Z 348 (M+H)+, 365 (M+NH4)+.
Reaction SMILES: [CH3:1][NH2:2].[CH:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8](OC)=[O:9])=[O:4].C[Al](C)C.C1(C)C=CC=CC=1>C1COCC1>[CH:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([NH:2][CH3:1])=[O:9])=[O:4]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(C=O)c1
Temperature: -50 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A 2M solution of methylamine in THF (44 mL, 5 eq, 87.5 mmol) was added to methyl 3-formylbenzoate (2.875 g, 1 eq, 17.5 mmol) in dry THF (65 ml). The reaction mixture was cooled to −50° C. under nitrogen and a 2M solution of trimethylaluminium in toluene (22 ml, 2.5 eq, 43.75 mmol) was added slowly over 15 mins. The reaction mixture was allowed to warm slowly to room temperature and stirred for 18 h. The reaction mixture was quenched with a 20% w/v solution of potassium sodium tartrate in water (50 ml). This was extracted with ethyl acetate (2×100 ml) and washed with water (50 ml), saturated sodium chloride solution (50 ml), dried over MgSO4 and evaporated under reduced pressure to give a gum. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 2.5% methanol in DCM. Pure fractions were combined and evaporated to afford 3-formyl-N-methylbenzamide (1.6502 g, 58%) as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8](Br)[CH2:7][CH2:6]1.[Cl:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][SiH:26](Cl)[CH2:25][CH2:24]2)=[CH:16][C:15]=1[F:30]>>[Cl:13][C:14]1[C:15]([F:30])=[CH:16][C:17]([O:21][CH2:22][C@H:23]2[CH2:24][CH2:25][Si@H:26]([C@H:8]3[CH2:9][CH2:10][C@H:5]([CH2:4][CH2:3][CH:2]([CH3:12])[CH3:1])[CH2:6][CH2:7]3)[CH2:27][CH2:28]2)=[CH:18][C:19]=1[F:20]
Reactant: CC(C)CCC1CCC(Br)CC1
Reactant: Fc1cc(OCC2CC[SiH](Cl)CC2)cc(F)c1Cl
Product: CC(C)CC[C@H]1CC[C@H]([Si@H]2CC[C@H](COc3cc(F)c(Cl)c(F)c3)CC2)CC1

Procedure:
The general procedure of Example 36 was repeated using 4-(3-methylbutyl)cyclohexyl bromide and 4-(4-chloro-3,5-difluorophenyloxyrnethyl)-1-chloro-1-silacyclohexane, thereby obtaining the intended product.