Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=O)[CH2:8][C:7]=2[CH:13]=1.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:15][CH3:16])[CH2:8][C:7]=2[CH:13]=1
Reactant: CCCNCCC
Reactant: COc1ccc2c(c1)CC(=O)CO2
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C1COc2ccc(OC)cc2C1

Procedure:
A mixture of 11.58 g of 6-methoxy-3,4-dihydro-2H-[1]-benzopyran-3-one, 26 g of dipropylamine, 0.3 ml of trifluoroacetic acid and 160 ml of toluene is refluxed in a Dean-Stark apparatus for 2 hours. The solution concentrated in vacuo and the residue is added to a solution of 8 g of sodium cyanoborohydride in 160 ml of ethanol and 40 ml of acetic acid. After 15 minutes at room temperature most of the solvent is removed in vacuo. The residue is dissolved in 6N hydrochloric acid and washed with ether. The aqueous layer is made basic and the product is extracted with ether. The aqueous layer is made basic and the product is extracted with ether. The ether layer is dried over magnesium sulfate and the solvent is removed in vacuo, to afford 6-methoxy-3,4-dihydro-N,N-dipropyl-2H-[1]-benzopyran-3-amine. The fumaric acid salt melts at 107°-113°.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1)=[O:4].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([O:22][C:23]([C:25]1([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:15]2>CC#N>[Br-:1].[F:13][C:8]1[CH:7]=[C:6]([NH:5][C:3]([CH2:2][N+:14]23[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]2)[C@@H:16]([O:22][C:23]([C:25]2([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[CH2:15]3)=[O:4])[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: O=C(CBr)Nc1cc(F)cc(F)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1cc(F)cc(F)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 17 %

Procedure:
A mixture of 2-bromo-N-(3,5-difluoro-phenyl)-acetamide (42 mg) (Example 35a) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (50 mg) in MeCN (1 mL) was stirred at room temperature for 72 h. The solid precipitate was filtered off, washed with ether and dried at 50° C. under vacuum overnight. The mother liquors were evaporated, treated with ether and the resulting solid was filtered off. The solids were combined and crystallised from hot isopropyl alcohol to give the title compound (15 mg) as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7](N1C=CN=C1)(N1C=CN=C1)=[O:8].CN(C1C=CC=CN=1)C.[CH:28]1([NH:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:32][CH2:31][CH2:30][CH2:29]1>ClCCl.C(OCC)(=O)C>[CH:34]1([N:33]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[C:7]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:8])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: C1CCC(NC2CCCC2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nccs1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1nccs1)N(C1CCCC1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-aminothiazole (50 mg, 0.5 mmol) in dichloromethane was added carbonyldiimidazole (81 mg, 0.5 mmol) and dimethylaminopyridine (3 mg) and the solution stirred 1 h at room temperature. Dicyclopentylamine (77 mg) was then added and the reaction stirred overnight at room temperature. The reaction mixture is then diluted with ethyl acetate (8 mL), washed successively with 10% sodiumhydrogensulphate (3 mL), water (3 mL), dried over magnesium sulphate, concentrated in vacuo, and the residue purified by flash chlomatography (eluant 7 ethyl acetate:3 heptane)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:16][C@@H:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:18][OH:19])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.O.I(O)(=O)(=O)=[O:26].P(O)([O-])([O-])=O.[Na+].[Na+]>C(#N)C.[Cr]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:16][C@@H:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:18]([OH:26])=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CC(C)C[C@@H](CO)N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1
Agent: [Cr]
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)C[C@H](N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentan-1-ol (3.28 g, 8.65 mmol) in acetonitrile (50 mL) containing water (0.375 mL) at 0-5° C. was added, over 20 minutes, a solution of periodic acid and chromium [VI] oxide in acetonitrile (50 mL: prepared by dissolving 11.4 grams of H5IO6 and 23 mg of CrO3 in 100 mL of CH3CN and stirring for 2 hours at room temperature according to the procedure described in Tetrahedron Letters, 1998, vol. 39, p. 5323-5326). The reaction mixture was stirred overnight while warming to room temperature. Disodium phosphate (1.8 g/100 mL water) was added. The reaction mixture was extracted with toluene (150 mL), washed with 1:1 brine/water (50 mL), freshly prepared sodium bisulfite solution (2 g/50 mL water), brine (50 mL), dried over MgSO4, filtered, concentrated in vacuo, and purified on a short plug of silica gel (30% ethyl acetateihexane elution to remove non-polar impurities, then 50% ethyl acetate/dichloromethane elution) to give (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentanoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>C(OCC)(=O)C>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[O:23]([C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1cnc(OC2CN3CCC2CC3)nc1
Reactant: Oc1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc(Oc2cnc(OC3CN4CCC3CC4)nc2)cc1
Yield: 93.3 %

Procedure:
The product of Example 29A (284 mg, 1.0 mmol) was treated with phenol (Aldrich, 188 mg, 2 mmol) according to the procedure of Example 14C. The free base of the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:2, Rf. 0.15) as an oil (42 mg, yield, 14%). The free base of the title compound (42 mg, 0.14 mmol) in ethyl acetate:MeOH (3 mL, 10:1) was treated with fumaric acid (18 mg, 0.15 mmol) at room temperature for 10 hours. The title compound was obtained as a solid (22 mg, 36%). 1H NMR (MeOH-d4, 300 MHz) δ 1.84–2.18 (m, 3H), 2.25–2.38 (m, 1H), 2.50–2.58 (m, 1H), 3.23–3.44 (m, 5H), 3.80–3.88 (m, 1H), 5.32 (m, 1H), 6.69 (s, 2.5H), 7.00–7.06(m, 2H), 7.15–7.20 (m, 2H), 8.39 (s, 2H) ppm. MS (DCl/NH3) m/z 298 (M+H)+. Anal. Calculated for C17H19N3O2.1.26C4H4O4: C, 59.67; H 5.46; N, 9.47. Found: C, 59.43; N, 9.51.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C1COCC1>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([CH2:13][NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNc2nc3ccc(OC)cc3s2)cc1
Reaction time: 48 h
Yield: 50.8 %

Procedure:
To a solution of 2-amino-6-methoxybenzothiazole (2.00 g, 11.1 mmol) in a mixture of dichloroethane (20 mL) and THF (20 mL), were successively added methyl 4-formylbenzoate (1.82 g, 11.1 mmol), sodium triacetoxyborohydride (3.53 g, 16.7 mmol) and acetic acid (1.27 mL, 22.2 mmol). The mixture was stirred over 2 days and was quenched by adding aqueous saturated solution of NaHCO3. The mixture was poured in a separating funnel containing water and was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography using EtOAc/hexane (20:80 to 30:70) to afford the title compound 232 (1.85 g, 51% yield). 1H NMR: (Acetone-d6) δ (ppm): 8.04 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.41 (d, 0.1=8.8 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.94 (dd, J=8.5, 2.7 Hz, 1H), 4.50 (t, J=5.5 Hz, 2H), 3.86 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.Cl.[OH:23][CH:24]1[CH2:27][NH:26][CH2:25]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([N:26]2[CH2:27][CH:24]([OH:23])[CH2:25]2)=[O:21])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2
Reactant: OC1CNC1
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F)N1CC(O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (70 mg, 0.176 mmol) and 3-hydroxyazetidine hydrochloride (23 mg, 0.21 mmol) in DMF (1 mL) was added EDCI (40 mg, 0.21 mmol), HOBt (28 mg, 0.21 mmol) and DIPEA (70 μL, 0.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate then water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated in cyclohexane to give the title compound as a pale tan solid (39 mg, 49%). LCMS (Method A): RT=8.23 min, [M+H]+=453. 1H NMR (DMSO-d6, 400 MHz) 13.17 (1 H, s), 9.55 (1 H, s), 7.63 (1 H, dd, J=10.47, 1.94 Hz), 7.41-7.37 (1 H, m), 7.37 (1 H, s), 7.32 (1 H, d, J=8.69 Hz), 7.05-7.00 (1 H, m), 6.92-6.82 (1 H, m), 5.67 (1 H, d, J=6.13 Hz), 4.44-4.37 (1 H, m), 4.24 (2 H, br, s), 3.83 (2 H, br, s).
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]#[CH:15])[C@@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][OH:5].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:1][N:2]([CH2:13][C:14]#[CH:15])[C@@H:3]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][O:5][S:23]([C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: C#CCN(C)[C@H](CO)Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: C#CCN(C)[C@H](COS(=O)(=O)c1ccc(Br)cc1)Cc1ccccc1
Yield: 47 %

Procedure:
Compound 4c is synthesized by general procedure K from 4b p-bromo-benzene sulfonyl chloride in 47% yield (1.58 g, 1.41 mmol).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([CH3:7])[N:6]=1.IC1NC(C2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=NC=1C.IC1NC(C)=NC=1C>>[CH3:17][C:16]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:4]1[NH:3][C:2]([CH:1]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:6][C:5]=1[CH3:7]
Reactant: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Reactant: Cc1nc(C2CCOCC2)[nH]c1I
Agent: Cc1nc(C)c(I)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCOCC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except 5-iodo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (compound 164.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).
Reaction SMILES: [S:1](=[O:3])=[O:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8](N)=[CH:7][C:6]=1[CH2:12][CH3:13].N([O-])=O.[Na+].[ClH:18]>C(O)(=O)C.O.[Cu]Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:1]([Cl:18])(=[O:3])=[O:2])=[CH:7][C:6]=1[CH2:12][CH3:13]
Reactant: Cl
Reactant: CCc1cc(N)ccc1Cl
Reactant: O=S=O
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(S(=O)(=O)Cl)ccc1Cl

Procedure:
Amounts used: 25 mL of acetic acid was saturated with sulfur dioxide, 700 mg of copper(I) chloride, 4.40 g (28.3 mmol) of 4-chloro-3-ethyl-phenylamine dissolved in a mixture of 9 mL of acetic acid and 9 mL of concentrated hydrochloric acid, 2.20 g of sodium nitrite in 10 mL of water. Flash chromatography on silica using 0-20% ethyl acetate in hexanes afforded 3.4 g of the product as a white solid. LC-MSD spectrum not observed;
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[K+]>CCO.CCOC(C)=O.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Br)cc1F
Yield: 84.4 %

Procedure:
To a solution of 4-bromo-2-fluorobenzylbromide (44.5 g, 166 mmol) in EtOH (118 mL) was added KCN (13.13 g, 182 mmol) and the mixture was stirred at reflux under an argon atmosphere for 18 h. The mixture was allowed to cool and the solvent was concentrated. The residue thus obtained was dissolved in a mixture of EtOAc and H2O and the two phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases dried and concentrated to a crude product. Purification by chromatography on silica gel (hexane-EtOAc, 10%) afforded the title compound as a reddish oil (30.0 g, 84%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]1[O:19][CH2:18][CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]1[CH2:16][CH2:17][CH2:18][O:19][CH:14]1[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: ClCC1OCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NCC1OCCCO1

Procedure:
2,6-Diethylaniline (75 grams), 2-chloromethyl-1,3-dioxane (14 grams), potassium carbonate (34 grams) and dimethylformamide (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 18 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dioxan-2-ylmethyl)-2,6-diethylaniline. EXAMPLE 13
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN1CCCC1=O>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=3)[C:5]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=3)=[N:4][N:3]=2)[CH2:28][CH2:27]1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Reactant: OC1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nnc(N3CCC(O)CC3)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Yield: 85.6 %

Procedure:
10.0 g of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine was dissolved in 50 ml 1-methyl-2-pyrrolidone, then 43.32 g of 4-hydroxypiperidine and 10 ml diisopropylethylamine were added thereto, and the mixture was heated at 170° C. for 8 hr. After cooling, ethyl acetate was added thereto, and the mixture was washed 3 times with water and once with brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The resulting residue was purified by silica gel column chromatography to give 10.1 g of 1-(4-hydroxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([C:13]#[N:14])=[CH:5][NH:6]2.[CH2:15]([O:17][C:18](=[O:38])[CH:19]=[C:20](C1C=CC=C2C=1C(C#N)=CN2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:38])[CH:19]=[C:20]([C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([C:13]#[N:14])=[CH:5][NH:6]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: COc1cc(Br)c2c(C#N)c[nH]c2c1
Product: CCOC(=O)C=C(c1ccccc1)c1cc(OC)cc2[nH]cc(C#N)c12
Yield: 54 %

Procedure:
3-(3-Cyano-6-methoxy-1H-indol-4-yl)-3-phenyl-acrylic acid ethyl ester CXXIX (0.81 g, 54% yield) was prepared from 4-bromo-6-methoxy-1H-indole-3-carbonitrile using the procedure described above for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH2:28][CH3:29])[CH:5]=1.O.[Li+].[OH-]>CO>[CH2:28]([N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:18]([NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1)=[N:19][C:11]=2[NH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:30])=[O:2])[CH3:29]
Reactant: CCn1cnc2c(Nc3cccc(C(=O)OC)c3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1cnc2c(Nc3cccc(C(=O)O)c3)nc(N[C@H]3CC[C@H](O)CC3)nc21

Procedure:
15.8 g (38.5 mmol) of 3-[9-ethyl-2-(trans-4-hydroxy-cyclohexylamino)-9H-purin-6-yl-amino]-benzoic acid methyl ester is suspended in 400 ml of MeOH, 77 ml of H2O and 77 ml of LiOH solution (1M), and stirred for 75 min at 80° C. After completion, the MeOH is removed under reduced pressure and the aqueous layer is washed with EtOAc (2 fold). The aqueous layer is then slowly treated with 1N HCl solution to pH 4-4.5. The precipitate is filtered off and washed to neutral pH to obtain 13.2 g (87% yield) of 3-[9-ethyl-2-(trans-4-hydroxy-cyclohexylamino)-9H-purin-6-yl-amino]-benzoic acid; Rf=0.34; (CH3Cl/MeOH/H2O/CH3COOH 85/13/1.5/0.5); m.p. 317° C.; ESI-MS: 397 (M+H)+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl.C[O:20][C:21](=O)[C:22]([S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])([CH3:34])[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][C:30]([CH3:32])=[C:29]([CH3:33])[CH2:28][CH2:27]1>ClCCl>[C:38]1([S:35]([C:22]([CH3:34])([CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][C:30]([CH3:32])=[C:29]([CH3:33])[CH2:28][CH2:27]2)[CH2:21][OH:20])(=[O:36])=[O:37])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COC(=O)C(C)(CCCN1CCC(C)=C(C)C1)S(=O)(=O)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1=C(C)CN(CCCC(C)(CO)S(=O)(=O)c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
A solution of diisobutylaluminium hydride in toluene (1.0M, 6 ml, 0.6 mmol) was added to a stirred solution of 2-benzenesulfonyl-5-(4,5-dimethyl-3,6-dihydro-2H-pyridin-1-yl)-2-methyl-pentanoic acid methyl ester hydrochloride (60 mg, 0.15 mmol) in dichloromethane at 5° C. The mixture was stirred for 30 min., diluted with dichloromethane (15 ml) and quenched with water (3 drops). The resulting mixture was stirred for 30 min. and solid Na2SO4 was added. The mixture was filtered through a pad of Celite and concentrated. The residue was purified on silica gel (dichloromethane:methanol) to give the title product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[NH2:6][C:5]1[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[C:2]([F:1])=[CH:3][C:4]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(F)ccc1N
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1N
Temperature: -10 °C
Reaction time: 3 h

Procedure:
1.3 g (10 mmol) of 4-fluoro-2-methylaniline were introduced into 10 ml of concentrated sulfuric acid and cooled to -10° C. A cold solution of 0.4 ml (10 mmol) of fuming nitric acid in 2 ml of concentrated sulfuric acid was added slowly dropwise. The resulting mixture was stirred for 3 hours at 0° C. and subsequently poured into ice. The precipitated product was filtered with suction and washed. 0.85 g (50% of the theoretical yield) of product was obtained. The yellow crystalline product had a melting point of 178° C.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1)#C.ClC1C(C#N)=[C:15]([NH:19][C:20]2C=CC=[C:22]([C:26]#C)[CH:21]=2)N=CN=1.C(C1C=C(N2C3C4C(=C(C(O)=O)SC=4N=CN=3)NC2=O)C=CC=1)#C.N1CCCC1.ClCC1C=CC([N+]([O-])=O)=CC=1>>[N:19]1([CH2:15][C:8]2[CH:3]=[CH:4][C:5]([NH2:9])=[CH:6][CH:7]=2)[CH2:20][CH2:21][CH2:22][CH2:26]1
Reactant: C#Cc1cccc(Nc2ncnc(Cl)c2C#N)c1
Reactant: C#Cc1cccc(N)c1
Agent: C#Cc1cccc(N2C(=O)Nc3c(C(=O)O)sc4ncnc2c34)c1
Agent: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: C1CCNC1
Product: Nc1ccc(CN2CCCC2)cc1

Procedure:
Using the procedure of Example 1, 3-ethynyl-phenylamine Compound 54a was used in place of 3-chloro-4-fluoro-phenylamine Compound 1e to prepare 4-chloro-6-(3-ethynyl-phenylamino)-pyrimidine-5-carbonitrile Compound 54b. MS 255 (MH+). Using the procedure of Example 1, Compound 54b was used in place of Compound 1f to prepare 5-(3-ethynyl-phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,6,8-tetraaza-acenaphthylene-2-carboxylic acid Compound 54c. MS 335 (M−). Using the procedure of Example 1, pyrrolidine was used in place of piperidine and combined with 1-chloromethyl-4-nitro-benzene Compound 1i and taken forward to provide 4-pyrrolidin-1-ylmethyl-phenylamine Compound 54e. MS 177 (MH+). Using the procedure of Example 2, Compound 54c was used in place of Compound 40 and Compound 54e was used in place of 3,4-dimethoxy-phenylamine Compound 2c to give Compound 15. MS 495 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([Cl:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1c(Br)ccc2ccc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1c(Br)ccc2ccc(Cl)nc12
Yield: 84 %

Procedure:
A mixture of 7-bromo-8-methoxy-2-quinolinol (4c) (2.22 g, 8.7 mmol) and POCl3 (7 mL) was heated under reflux for 1.5 hours. After neutralization with NaHCO3 and extraction with AcOEt, the residue was dissolved in CHCl3 and filtered through silica gel to remove the brown polar impurities. The product (1.99 g, 84% yield) was obtained as white crystals upon recrystalization from AcOEt-Hexanes. mp 130-132° C.; 1H NMR (400 MHz, CDCl3), 8.06 (d, J=8.8 Hz, 1H), 7.66 (d, J=9.2 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.17 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].[CH3:14][O:15][CH:16]([O:20][CH3:21])N(C)C.Cl[Si](C)(C)C>CN(C=O)C.CO>[CH3:14][O:15][CH:16]([O:20][CH3:21])[CH2:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-])OC
Reaction time: 16 h
Yield: 43.5 %

Procedure:
To a solution of 2,3-dinitrotoluene (3.02 g, 16.6 mmol) in 25 mL of DMF was added dimethylformamide dimethylacetal (6.0 mL, 5.4 g, 45 mmol), and the solution was brought to 140° C. and stirred for 16 hours. The solvent was removed under reduced pressure to afford a dark red solid mass. This crude enamine was dissolved in 40 mL of MeOH and 4.0 mL of chlorotrimethylsilane (3.4 g, 31.7 mmol) was added. The solution was brought to reflux and stirred for 16 hours at reflux. The solvent was removed under reduced pressure and the crude material chromatographed directly to afford the 1-(2,2-dimethoxy-ethyl)-2,3-dinitro-benzene (1.85 g, 44%). 1H NMR (CDCl3) δ 2.96 (2H, d, J=5.2 Hz), 3.35 (6H, s), 4.49 (1H, t, J=5.2 Hz), 7.60 (apparent t, 1H, J=8.0 Hz), 7.76 (d, 1H, J=6.5 Hz), 8.05 (dd, 1H, J=1.3, 8.0).