Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:15][C:16]1[CH:17]=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][C:21]=1[CH3:22]>ClCCCl>[Br:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[O:7])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(C)c(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(Br)c(C)cc1C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-Fluorobenzoyl chloride (1.40 mL, 11.9 mmol) was added dropwise to a suspension of AlCl3 (1.73 g, 13.0 mmol) in 1,2-dichloroethane (30 mL) at room temperature. After 15 min a solution of 3-bromo-4-methylanisole (2.17 g, 10.8 mmol) in 1,2-dichloroethane (3 mL) was added dropwise. The resulting mixture was stirred for 2 h, poured into 200 mL of ice-water, stirred for 20 min and extracted with CHCl3 (3×). The combined organics were washed with 5% aq. NaHCO3, brine, dried (Na2SO4) and concentrated. The residue was subjected to chromatography on silica gel (EtOAc-hexane, 5:95) affording the title compound. 1H NMR (500 MHz, acetone-d6): δ 7.86 (m, 2H), 7.38 (s, 1H), 7.31-7.26 (m, 3H), 3.76 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Cl:22][C:18]1[CH:17]=[C:16]([S:15][C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)[CH:14]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Clc1cccc(Sc2ccnc(Cl)c2)c1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1csc(Nc2cc(Sc3cccc(Cl)c3)ccn2)n1
Yield: 76.7 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (7.007 mL, 4.905 mmol), 2-chloro-4-(3-chlorophenylthio)pyridine (1.382 g, 5.396 mmol), potassium phosphate (1.145 g, 5.396 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.1123 g, 0.1226 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.07805 g, 0.1349 mmol) were reacted in toluene (7 mL) and water (2 mL) to afford 4-(3-chlorophenylthio)-N-(4-methylthiazol-2-yl)pyridin-2-amine (1.256 g, 75.93% yield) as off white solid. 1H NMR (CDCl3) δ 8.11 (d, 1H), 7.51 (t, 1H), 7.38 (m, 2H), 7.30 (m, 1H), 6.58 (dd, 1H), 6.49 (s, 1H), 6.32 (d, 1H), 2.19 (d, 3H); Mass spectrum (esi) m/z=334 (100) (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][NH:3][C:2]1=[S:6].N12CCCN=C1CCCCC2.Br[CH2:19][C:20]1[C:21]([C:30]([F:33])([F:32])[F:31])=[N:22][N:23]([CH3:29])[C:24]=1[O:25][CH:26]([F:28])[F:27].O>C(#N)C>[F:28][CH:26]([F:27])[O:25][C:24]1[N:23]([CH3:29])[N:22]=[C:21]([C:30]([F:33])([F:32])[F:31])[C:20]=1[CH2:19][S:6][C:2]1[O:1][CH:5]=[CH:4][N:3]=1
Reactant: Cn1nc(C(F)(F)F)c(CBr)c1OC(F)F
Reactant: S=c1[nH]cco1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,3-Oxazole-2(3H)-thione (2.960 g, 29 mmol; prepared as described in WO 2003/006442 A) is initially charged in 50 ml of acetonitrile. With ice-bath cooling, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU, 4.81 ml, 32 mmol) is added dropwise. The mixture is stirred at 25° C. for 30 minutes. A solution of 4-(bromomethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole (9.045 g, 29 mmol) dissolved in acetonitrile is added dropwise. The mixture is stirred at 25° C. for a further 4 hours and allowed to stand overnight. For work-up, the reaction mixture is added to water and extracted twice with dichloromethane, and the extracts are then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptan:ethyl acetate, gradient 10:0 to 7:3). This gives 7.6 g of product (74.9% of theory).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=2)[C:10]([O:12]C)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+:18]>C1COCC1>[C:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=2)[C:10]([O-:12])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Li+:18]
Reactant: COC(=O)c1ccnc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])c1ccnc(-c2ccccc2)c1
Reaction time: 8 h

Procedure:
Preparation H1, Step 4: A solution of methyl 2-phenylisonicotinate, N-oxide (397 mg, 1.73 mmol) in THF (6 mL) was treated with 0.5 N aqueous lithium hydroxide (3.65 mL, 1.81 mmol), and the mixture was stirred overnight. The THF was stripped, and the aqueous solution was freeze dried to yield lithium 2-phenylisonicotinate, N-oxide a colorless glass, which was used as-is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:41][CH3:42])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH:16]3[C:35]([O:37]CC)=[O:36])=[O:14])=[CH:8][C:7]=2[CH:40]=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][O:2][C:3]1[C:4]([O:41][CH3:42])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH:16]3[C:35]([OH:37])=[O:36])=[O:14])=[CH:8][C:7]=2[CH:40]=1
Reactant: CCOC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1C(=O)O)=C2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (1.2 g) in methanol (15 ml) are added potassium carbonate (3.0 g) and water (8 ml) and the mixture is stirred at 70° C. for 30 minutes. To the reaction mixture is added water (50 ml). The mixture is washed with ethyl acetate. The aqueous layer is made acid with dilute hydrochloric acid, followed by extraction with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure to give a crude product of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylic acid (1.1 g) as a colorless oily substance. To a mixture of this crude product (0.75 g), triethylamine (0.14 g) and N,N-dimethylformamide (4 ml) is added dropwise, while stirring under ice-cooling, diphenylphosphoryl azide (0.37 g). The reaction mixture is poured into ice-water, followed by extraction with benzene. The organic layer is washed with water and dried, followed by distilling off the solvent under reduced pressure until the whole volume becomes about 20 ml. The resultant solution is heated under reflux for 30 minutes. To the mixture is added methanol (5 ml), followed by heating under reflux for further one hour. The reaction mixture is concentrated under reduced pressure, and the concentrate is purified by means of a silica gel column chromatography (eluent hexane ethyl acetate-acetone=1:1:1) to give crystals, which are recrystallized from ethyl acetate to give 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -2-methoxycarbonylamino-4-(3,4,5-trimethoxybenzoyl)piperazine as colorless crystals (0.6 g), m.p. 143-145° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([O:13][C:14](=O)[C:15]([C:27]#[N:28])=[CH:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[O:25][CH3:26])C>>[C:27]([CH:15]1[C:16]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[O:25][CH3:26])=[C:10]2[C:2](=[C:3]3[CH:4]=[CH:5][N:6]=[C:7]3[CH:8]=[CH:9]2)[O:1][C:14]1=[O:13])#[N:28]
Reactant: CCOC(=O)C(C#N)=Cc1cc(OC)ccc1OC
Reactant: Oc1cccc2[nH]ccc12
Product: COc1ccc(OC)c(C2=c3ccc4c(c3OC(=O)C2C#N)C=CN=4)c1
Yield: 2.6 %

Procedure:
The title compound was prepared from 4-hydroxyindole and 3-(2,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester by a procedure similar to that described for Example 16 in 2.6% yield. 1H NMR (CDCl3): 8.64 (s, 1H), 7.33-7.31 (m, 1H), 7.29-7.24 (m, 1H), 7.10-7.01 (m, 4H), 6.83-6.82 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH2:9][O:10][C:11](=[O:31])[C@@H:12]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:13][CH2:14][O:15]N2C(=O)CCC2=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O>[C:3]1([CH2:9][O:10][C:11](=[O:31])[C@@H:12]([NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:13][CH2:14][OH:15])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCON1C(=O)CCC1=O)C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a mixture of NaBH4 (1.4 g, 37 mmol) in THF (80 mL) and H2O (20 mL) was added a solution of (2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-[(2,5-dioxo-1-pyrrolidinyl)oxy]-butanoic acid phenylmethyl ester (10 g, 24 mmol) in THF at 0° C. After 15 min, the reaction mixture was quenched with NH4Cl (sat.), and extracted with EtOAc, dried over Na2SO4. Concentration in vacuo followed by flash chromatography (hexane-EtOAc, 7:3 to 6:4) afforded the product as colorless oil. LC-MS: 310 (M++1).
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]([C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@@H:14]2[CH3:19])=[N:11][CH:12]=1)([OH:6])[CH3:5].C(N(CC)CC)C.[N+:29]([C:32]1[S:36][C:35]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:33]=1)([O-:31])=[O:30]>C(Cl)Cl>[N+:29]([C:32]1[S:36][C:35]([S:37]([N:16]2[CH2:17][CH2:18][N:13]([C:10]3[N:11]=[CH:12][C:7]([C:4]([OH:6])([CH3:5])[C:3]([F:2])([F:20])[F:21])=[CH:8][N:9]=3)[C@@H:14]([CH3:19])[CH2:15]2)(=[O:39])=[O:38])=[CH:34][CH:33]=1)([O-:31])=[O:30]
Reactant: C[C@H]1CNCCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
The 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol hydrochloride (95 mg, 0.291 mmol) was dissolved in CH2Cl2 (15 mL) was chilled to 0° C. To this solution was added triethylamine (101 μL, 0.727 mmol) followed by 5-nitrothiophene-2-sulfonyl chloride (66.2 mg, 0.291 mmol, Enamine Building Blocks, Kiev, Ukraine). The mixture was warmed slowly to room temperature and stirred for 2 h. Afterwards, the mixture was concentrated onto silica gel and then purified via column chromatography (24 g silica gel, 0 to 10% MeOH in CH2Cl2) to give racemic 2-(2-((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (108 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([CH:11]([C:17]([CH3:19])=O)[C:12](OCC)=[O:13])([CH3:10])[CH3:9].C(Cl)(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[OH:13][C:12]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[C:17]([CH3:19])[C:11]=1[CH:8]([CH3:10])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C(C)=O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccccc2c(O)c1C(C)C
Yield: 21 %

Procedure:
4.56 ml (50 mmol) of aniline and 10.7 ml (60 mmol) of ethyl 2-isopropylacetoacetate were mixed with 50 ml of chloroform. 0.48 g (2.5 mmol) of para-toluenesulfonic acid was added, and the reaction mixture was refluxed with continuous removal of the water produced in the reaction. After 2 d chloroform was removed in vacuum, and the residue was refluxed in 10 ml of phenyl ether. After cooling, the precipitate was filtered and washed with diethyl ether to give 4-hydroxy-3-isopropyl-2-methylquinoline (21%). Following the procedure of Step 3 in Example 1, but substituting 4-hydroxy-3-isopropyl-2-methylquinoline for 9-(10H)acridone, 4-chloro-3-isopropyl-2-methylquinoline (100%) was obtained, which was reacted with 4-(4-methylpiperazin-1-yl)aniline (following the procedure of Step 4 in Example 1), to afford the title compound with 61% yield (overall yield 13%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]([CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5][O:4]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](O)[CH:26]=[CH:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:12]1([C:10](=[O:11])[CH2:9][N:7]2[CH2:6][CH2:5][O:4][C@H:3]([CH2:2][O:1][C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=3)[CH2:8]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: COc1cccc(O)c1
Reactant: O=C(CN1CCO[C@H](CO)C1)N1CCc2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(OC[C@@H]2CN(CC(=O)N3CCc4ccccc43)CCO2)c1
Yield: 78.4 %

Procedure:
Essentially the same procedure was used to make compound 24s as was used for compound 18s (Example 16), with compound 48 (Example 7; 55 mg, 0.2 mmol), 3-methoxyphenol (0.032 ml, 0.3 mmol), triphenylphosphine (78 mg, 0.3 mmol), DEAD (0.05 ml, 0.3 mmol), and THF (1 ml). The crude residue was purified twice by flash column chromatography (silica, DCM/MeOH 1:0 to 8:2) to afford the title compound as a colourless oil (60 mg; 78%). Analyses were performed on the free base, and the free base was converted to the HCl salt for testing.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][C:8]([CH3:16])([C:13](=O)[CH3:14])[C:9]([O:11][CH3:12])=[O:10]>C(Cl)Cl.CN(C=O)C>[Cl:2][C:13](=[CH2:14])[C:8]([CH3:16])([CH3:7])[C:9]([O:11][CH3:12])=[O:10]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(C)C(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(Cl)C(C)(C)C(=O)OC
Temperature: 25 °C
Yield: 38.6 %

Procedure:
To a suspension of PCl5 (270 g, 1.3 mol) in CH2Cl2 (1000 mL) was added dropwise methyl 2,2-dimethyl-3-oxobutanoate (85 g) at 0° C., following by addition of approximately 30 drops of dry DMF. The mixture was heated at reflux overnight. The reaction mixture was cooled to ambient temperature and slowly poured into ice water. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (500 mL×3). The combined organic layers were washed with saturated aqueous NaHCO3 and dried over anhydrous Na2SO4. The solvent was evaporated and the residue was distilled under reduced pressure to give methyl 3-chloro-2,2-dimethylbut-3-enoate (37 g, 23%). 1H NMR (400 MHz, CDCl3) δ 5.33 (s, 1H), 3.73 (s, 3H), 1.44 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13](O)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:34])[NH:26][C:27]([CH3:33])=[CH:28][C:29]=1[CH:30]([CH3:32])[CH3:31].C(O)(C(F)(F)F)=O.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CCOC(C)=O.O.CN(C=O)C>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:11]=[C:12]([C:13]([NH:22][CH2:23][C:24]3[C:25](=[O:34])[NH:26][C:27]([CH3:33])=[CH:28][C:29]=3[CH:30]([CH3:31])[CH3:32])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)C)c(CNC(=O)c2cc(-c3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Yield: 27 %

Procedure:
A DMF solution (6 mL) of 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (288 mg, 1.019 mmol), 3-(aminomethyl)-6-methyl-4-(1-methylethyl)-2(1H)-pyridinone.TFA (300 mg, 1.019 mmol), HOAT (208 mg, 1.529 mmol), EDC (782 mg, 4.08 mmol), and N-methylmorpholine (0.448 mL, 4.08 mmol) was stirred overnight at 40° C. After cooling to room temperature, the reaction mixture was poured into H2O (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAC (2×50 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DMSO and purified by reverse phase (15-40% ACN in H2O, 0.1% TFA). The product fractions were poured into sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a white solid (123 mg, 27% yield). LCMS E-S (M+H)=445.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (m, 6H), 1.56 (m, 6H), 2.17 (s, 3H), 3.17-3.28 (m, 1H), 4.45-4.56 (m, 2H), 5.29-5.43 (m, 1H), 5.99-6.12 (m, 1H), 8.16-8.23 (m, 2H), 8.24-8.29 (m, 1H), 8.40-8.46 (m, 1H), 8.71-8.82 (m, 2H), 8.96-9.04 (m, 1H), 11.53-11.63 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: Oc1ccc(Nc2cnc3cc(Cl)ccc3n2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Nc2cnc3cc(Cl)ccc3n2)cc1

Procedure:
A mixture of 4-[N-(6-chloroquinoxalin-2-yl)amino]phenol (10 mmole), ethyl 2-bromopropionate (10 mmole), anhydrous potassium carbonate (2.0 g) and methyl ethyl ketone (100 ml) was heated under reflux for a period of 12 hours. The mixture was filtered and the solvent was removed by distillation under reduced pressure. The residue was chromatographed over alumina (eluent dichloromethane) to give ethyl 2-{4-[N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate, mp 136° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:19]4/[C:20](=[O:28])[NH:21][C:22]5[C:27]/4=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:15][CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[CH:3][CH:2]=1.B(F)(F)F.CCOCC.OCN1C2C(=CC=C(/C=C3/C(=O)NC4C/3=CC=CC=4)C=2)C(/C=C/C2C=CN=CC=2)=N1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:19]4/[C:20](=[O:28])[NH:21][C:22]5[C:27]/4=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Agent: FB(F)F
Agent: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccncc3)nn(CO)c2c1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A dry-round bottom was charged with (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (906 mg, 1.83 mmol), and CH2Cl2 (100 mL) under an atmosphere of N2. Boron trifluoride etherate (2.3 mL, 18.3 mmol) was added dropwise and the reaction was stirred for 4 hours at which time LC-MS indicated complete conversion to the partially de-protected material (E)-3-((1-(hydroxymethyl)-3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)-indolin-2-one. The CH2Cl2 was removed in vacuo, and then 150 mL of a 2:1 mixture of EtOH/2M HCl was added and the reaction heated to 50° C. for 3 hours at which time LC-MS indicated complete conversion to the title compound. The reaction was cooled with an ice-bath and neutralized with NH4OH to pH˜8, the EtOH was removed and the suspension filtered washing with water. The dried solid was collected and then titurated and filtered several times with 90:10 CH2Cl2/MeOH which gave, after drying, the title compound (353 mg, 53%) as an orange solid. 1H NMR (400 MHz, d6-DMSO) δ 13.57 (s, 1H), 10.64 (s, 1H), 8.57 (d, J=5.16 Hz, 2H), 8.38 (d, J=8.13 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J=16.7 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J=5.16 Hz, 2H), 7.62-7.53 (m, 3H), 7.23 (t, J=8.29 Hz, 1H), 6.91-6.82 (m, 2H); MS ESI 365.1 [M+H]+, calcd for [C23H16N4O+H]+ 365.14.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:25]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1)([CH3:27])[CH3:26]>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:33][CH2:32][C:31]3[CH:30]=[CH:29][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:35][CH:34]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)c1ccc(CN)cc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2ccc(C(C)C)cc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (4-isopropylbenzyl)amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.08 (d, J=15.04 Hz, 1H), 1.17 (d, J=6.72 Hz, 6H), 1.24-1.31 (m, 4H), 1.60 (s, 1H), 1.68 (t, J=11.95 Hz, 4H), 1.87 (s, 3H), 2.22 (s, 3H), 2.84 (t, J=13.90, 6.88 Hz, 1H), 3.89 (d, J=7.52 Hz, 1H), 4.48 (d, J=5.37 Hz, 2H), 7.14-7.28 (m, 4H), 7.55 (d, J=7.52 Hz, 1H), 8.06 (s, 1H), 12.69 (bs, 1H); MS (ESI) m/z 353.0 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:6][CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH2:4][NH2:5])[CH3:2].N[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[NH:5][CH2:4][C:3]([CH2:1][CH3:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])[CH3:24]
Reactant: CCOC(N)=O
Reactant: CCN(CC)CCC(CC)(CN)c1ccccc1
Product: CCOC(=O)NCC(CC)(CCN(CC)CC)c1ccccc1

Procedure:
From 2-ethyl-2-phenyl-4-diethylamino-butylamine in analogy to 3a. The urethane was further reacted in a pure state.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:23]4[CH:24]=[N:19][CH:20]=[N:21][CH:22]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: OB(O)c1cncnc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2cncnc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, off-white solid (13 mg, 17%), MS (ISP) m/z=304.5 [(M+H)+], mp 277° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available pyrimidin-5-ylboronic acid (40.3 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[NH:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[F:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[N:9]([NH:12][CH3:13])[CH:8]=[C:7]([C:14]([OH:16])=[O:15])[C:6]2=[O:17]
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: C1CSCCN1
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCSCC3)cc21

Procedure:
6-Fluoro-1,4-dihydro-1-methylamino-4-oxo-7-(4-thiomorpholinyl)-3-quinolinecarboxylic acid [I; R=CH3NH, R"=H, Z=N=4-thiomorpholinyl] was prepared from 3.5 g of 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid (Preparation 4A) and 6.5 ml of thiomorpholine in 80 ml of pyridine according to the procedure of Example 1. There was obtained 2 g of product, pale yellow solid, m.p. 260°-261° C. when recrystallized from dimethylformamide.