Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].COC([CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[N:13]([C:19]1[C:24]([NH2:25])=[CH:23][N:22]=[C:21]([Cl:26])[N:20]=1)[CH:14]1C[CH2:17][CH2:16][CH2:15]1)=O>C(O)(=O)C>[Cl:26][C:21]1[N:22]=[CH:23][C:24]2[NH:25][C:1](=[O:3])[CH:2]3[CH:14]([CH2:15][CH2:16][CH2:17]3)[N:13]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:8]3)[C:19]=2[N:20]=1
Reactant: COC(=O)C1CCCC1N(c1nc(Cl)ncc1N)C1CCCC1
Reactant: CCO
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)C2CCCC12

Procedure:
A mixture of 150 mL of ethanol, 3.0 mL of acetic acid and 2.85 g (0.0084 mole) of (rac)-2-[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-cyclopentanecarboxylic acid methyl ester (V-68) from the previous step, combined with material from a separate experiment was heated at reflux overnight and then concentrated under reduced pressure to give 2.49 g of (rac)-6-chloro-4-cyclopentyl-2,3,3a,4,9,10a-hexahydro-1H-4,5,7,9-tetraaza-benzo[f]azulen-10-one (VI-68), which was used without further purification.
Reaction SMILES: COC([O:7][CH3:8])N(C)C.C[C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13].P([O-])([O-])([O-])=O>CN(C=O)C.C1COCC1>[CH:8]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13])=[O:7]
Reactant: Cc1cccc([N+](=O)[O-])c1C#N
Reactant: COC(OC)N(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1c(C=O)cccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (13.56 mL, 102 mmol) was added to a solution of 2-methyl-6-nitrobenzonitrile (15.0 g, 92.5 mmol) in anhydrous DMF (60 mL) under nitrogen and was heated at 130° C. for 15 h. Ice water (300 mL) was added, and the resultant dark precipitate was collected by filtration and dried under vacuum. Phosphate buffer (pH 7, 350 mL) and then NaIO4 (40 g, 187 mmol) were added to a solution of the dark precipitate in THF (350 mL) and stirred at rt for 3 h. The mixture was extracted with EtOAc, the combined extract was washed with brine and dried with MgSO4. The filtrate was concentrated and the residue was purified by chromatography on silica using the solven gradient hexanes→EtOAc, to give 3.07 g (19%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (t, J=8.4 Hz, 1H), 8.41 (dd, J=1.2, 7.6 Hz, 1H), 8.62 (dd, J=1.2, 8.4 Hz, 1H), 10.25 (s, 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[CH:28]=[CH:27][C:15]2[C:16](=[O:26])[C:17]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:18]=3[CH2:19][CH2:20][C:14]=2[CH:13]=1>O1CCCC1>[CH3:11][C:12]1[CH:28]=[CH:27][C:15]2[CH:16]([OH:26])[C:17]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:18]=3[CH2:19][CH2:20][C:14]=2[CH:13]=1
Reactant: Cc1ccc2c(c1)CCc1cc(C)ccc1C2=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)CCc1cc(C)ccc1C2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisobutylaluminium hydride (5.5 ml of a 1M solution in tetrahydrofuran) was added dropwise to 10,11-dihydro-2,8-dimethyl-5H-dibenzo[a,d]cyclohepten-5-one (European Patent, 1993, 0 589 322 A1) (1.2 g) in tetrahydrofuran (20 ml) at-78 ° C. After 1 hour the cooling bath was removed and the reaction was stirred at r.t. for 2 hours. The reaction was quenched with brine and methanol. After 0.5 hours the reaction was partitioned between ethyl acetate and water. The ethyl acetate solution was washed with water, brine, dried (MgSO4) and evaporated. Purification was by chromatography eluting with toluene. Yield 1.2 g. Used directly in step (ii)
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:29])[N:6]([CH2:16][CH2:17][C@@:18]([CH3:28])([S:24]([CH3:27])(=[O:26])=[O:25])[C:19]([O:21]CC)=[O:20])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1.CO.O>[F:3][C:4]1[C:5](=[O:29])[N:6]([CH2:16][CH2:17][C@@:18]([CH3:28])([S:24]([CH3:27])(=[O:25])=[O:26])[C:19]([OH:21])=[O:20])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)[C@@](C)(CCn1ccc(-c2ccccc2)c(F)c1=O)S(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@](CCn1ccc(-c2ccccc2)c(F)c1=O)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Potassium hydroxide (120 mg, 2.14 mmol) was added to a solution of ethyl (2R)-4-(3-fluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (131 mg, 0.33 mmol) in THF:methanol:water (2:2:1, 10 mL) and the reaction was stirred at RT overnight. The reaction was concentrated, and the residue was dissolved in aqueous 1N sodium hydroxide (20 mL), washed with ethyl acetate (3×20 mL), acidified using concentrated HCl, and extracted with ethyl acetate (3×50 mL). The combined organics were dried (MgSO4), filtered, and concentrated to afford the title compound as a white solid (88.4 mg, 72.7%). LC-MS m/z 383.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 (s, 3H) 2.13-2.30 (m, 1H) 3.17 (s, 3H) 3.93-4.23 (m, 2H) 6.43 (t, J=6.93 Hz, 1H) 7.44-7.56 (m, 3H) 7.57-7.66 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][CH2:31][CH2:32][Cl:33]>C(O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:30][CH2:31][CH2:32][Cl:33])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: ClCCCBr
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCCl)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (WO 99/29661) (0.48 g) in ethanol (5 ml) was added caesium carbonate (0.977 g) and reaction mixture heated to 85° C. for 10 min. before addition of 1-bromo-3-chloropropane (0.74 ml). Heating was continued for 24 h before cooling to room temperature and concentration under reduced pressure. The residue was dissolved in ethyl acetate and washed with water(twice), then with KHSO4 solution and brine. The organics were dried (MgSO4), concentrated and the residue purified by silica gel chromatography (eluting with 20% ethyl acetate in isohexanes) to deliver the sub-title compound as a pale yellow foam (0.50 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([N:26]([CH2:28][C:29]([C:32](=[O:34])[NH2:33])([CH3:31])[CH3:30])[CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.C1C=CC(P([N:56]=[N+:57]=[N-])(C2C=CC=CC=2)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([N:26]([CH2:28][C:29]([CH3:31])([CH3:30])[C:32]([N:33]=[N+:56]=[N-:57])=[O:34])[CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN(CC(C)(C)C(N)=O)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(CC(C)(C)C(=O)N=[N+]=[N-])C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of 1-02 [see step 4 SC-174] (110 mg, 0.223 mmol) in dry toluene (4 mL) was added Et3N (62 μL, 0.446 mmol) and DPPA (63 μL, 0.290 mmol). The reaction mixture was stirred overnight and concentrated in vacuo to give the desired product as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[C:24]1([CH:30]([NH2:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:37][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 59 %

Procedure:
The title compound was prepared in a yield of 59% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and diphenylmethylamine.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.[NH2:13][NH2:14].O>CO>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:13][NH2:14])=[O:2])=[CH:5][CH:6]=1)#[N:11]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: N#Cc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-cyano-benzoic acid methyl ester (1.0 g, 13 mmol) in 30 mL of MeOH was added 3 mL of H2NNH2.H2O. The mixture was stirred at ambient temperature for 16 h. The solid was collected and washed with CH3OH to give 4-cyano-benzoic acid hydrazide 9 as a solid. Yield: 0.8 g, 80%.
Reaction SMILES: O1C=CC(C2C(OC)=C(C(CS(C3C=CC=CC=3)(=[N:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=O)=CC=2)C(OC)=O)=C1.[C:34]1([S:40]([CH2:42][C:43]2[C:48]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[C:47]([O:56][CH3:57])[C:46]([C:58]3[CH:62]=[CH:61][O:60][CH:59]=3)=[CH:45][CH:44]=2)=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[O:60]1[CH:61]=[CH:62][C:58]([C:46]2[C:47]([O:56][CH3:57])=[C:48]([C:43]([CH2:42][S:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[N:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[O:41])=[CH:44][CH:45]=2)[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[CH:59]1
Reactant: COC(=O)c1c(CS(=O)(=NC(=O)C(F)(F)F)c2ccccc2)ccc(-c2ccoc2)c1OC
Reactant: COc1c(-c2ccoc2)ccc(CS(=O)c2ccccc2)c1C(=O)OC(C)(C)C
Product: COc1c(-c2ccoc2)ccc(CS(=O)(=NC(=O)C(F)(F)F)c2ccccc2)c1C(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 215, starting from t-butyl 6-(benzenesulphinylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 221).
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH:13]([S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH3:14])[CH2:7][C:6]1=[O:26])(=O)[CH2:2][CH3:3].Cl.[CH2:28]([O:30][NH2:31])[CH3:29].C(N(CC)C1C=CC=CC=1)C.O>C(OCC)(=O)C>[CH2:28]([O:30][NH:31][C:1](=[C:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH:13]([S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=2)[CH3:14])[CH2:7][C:6]1=[O:26])[CH2:2][CH3:3])[CH3:29]
Reactant: CCON
Reactant: CCC(=O)C1C(=O)CC(CC(C)Sc2ccc(C(F)(F)F)cc2)CC1=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCONC(CC)=C1C(=O)CC(CC(C)Sc2ccc(C(F)(F)F)cc2)CC1=O
Temperature: 25 °C

Procedure:
0.27 Gram of 2-propionyl-5-[2-(4-trifluoromethylphenylthio)propyl]cyclohexane-1,3-dione was dissolved in 10 ml of ethyl acetate, and 0.08 g of ethoxyamine hydrochloride and 0.1 g of N,N-diethylaniline were added to the resulting solution which was then refluxed for 5 hours. The reaction solution was cooled to room temperature, poured into water, weakly acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid and water subsequently and dried over anhydrous magnsium sulfate. After removing ethyl acetate, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.13 g of 2-(1-ethoxyaminopropylidene)-5-[2-(4-trifluoromethylphenylthio)propyl]cyclohexane-1,3-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:17][CH2:16][CH2:15]2)=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>>[Cl:26][C:20]1[N:19]=[C:18]([C:14]2([C:12]3[C:7]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=4)[CH2:9][CH2:10][N:11]=3)[CH2:17][CH2:16][CH2:15]2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CCNC(=O)C2(c3ccccn3)CCC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2

Procedure:
N-[2-(4-methoxyphenyl)ethyl]-1-(pyridin-2-yl)cyclobutanecarboxamide (679 mg, 1.969 mmol) was reacted with phosphorusoxychloride (2.7 ml, 29.5 mmol) in the microwave at 140° C. for 60 min. The reaction mixture was poured on ice water. After 10 min 10% aqueous sodium hydroxide solution was added until pH 8 was reached. The aqueous layer was extracted with dichloromethane. The combined extracts were dried (MgSO4), concentrated in vacuo and the crude product was purified by flash chromatography (silica, dichloromethane, methanol). Yield: 560 mg (1.71 mmol, 87%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[CH:23]=O)=[CH:19][C:14]3=[N:13][CH:12]=2)[CH:8]=[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:6]=1)([CH3:3])[CH3:2].[CH2:34]([NH2:36])[CH3:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH2:34]([NH:36][CH2:23][C:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]3[C:11]([C:9]4[CH:8]=[C:7]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:6]=[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])[CH:10]=4)=[CH:12][N:13]=[C:14]3[CH:19]=2)[CH:27]=[CH:26][CH:25]=1)[CH3:35]
Reactant: CCN
Reactant: CC(C)Nc1cc(-c2cnc3cc(-c4cccc(C=O)c4)ccn23)cc(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNCc1cccc(-c2ccn3c(-c4cc(NC(C)C)nc(-c5ccccc5)c4)cnc3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-[3-(2-isopropylamino-6-phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridin-7-yl]-benzaldehyde (Ex. 1.186) (1 eq, 0.055 mmol, 30 mg) in MeOH (2 ml) is added ethyl amine (10 eq, 0.55, 0.27 ml) and acetic acid (2 eq, 0.11 mmol, 6.59 mg) and the reaction mixture is stirred at room temperature for 30 min. After this time sodium triacetoxyborohydride (5 eq, 0.27 mmol, 58.2 mg) is added to the reaction mixture and is stirred for a further 2 h. The reaction is diluted with CH2Cl2 and the organic phase is washed with NaHCO3. The aqueous layer is further extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield {4-[7-(3-ethylaminomethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-6-phenyl-pyridin-2-yl}-isopropyl-amine as a light yellow solid; [M+H]+=462
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27]O)[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:1]([O:4][CH2:27][CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: OCCCCNCCCCc1cccc(OCc2ccccc2)c1
Solvent: O
Product: CC(=O)OCCCCNCCCCc1cccc(OCc2ccccc2)c1
Temperature: 80 °C
Yield: 88 %

Procedure:
To 10 ml of anhydrous acetic acid was added 2.7 g (8.2 mmol) of 4-[(3-benzyloxyphenyl)butylamino]-1-butanol and the mixture was stirred with heating at 80° C. for 1 hour. The reaction mixture was poured into 150 ml of water and subjected to extraction with ethyl acetate. Washing was performed with a saturated sodium bicarbonate solution and then with a saturated saline solution. Drying over anhydrous sodium sulfate and concentration were performed. The residue was purified by silica gel column chromatography to give 2.68 g of a colorless oily matter (yield: 88.0%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:20]=[C:19]([NH2:29])[N:18]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>C1COCC1>[NH2:29][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([O:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:31]([F:30])=[CH:32][CH:33]=4)[CH:8]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=1
Reactant: NCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Product: Nc1nc(Nc2ccc(Oc3ccnc(CNC(=O)c4ccc(F)cc4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.7 %

Procedure:
N4-(4-{[2-(Aminomethyl)pyridin-4-yl]oxy} phenyl)-6-phenylpyrimidine-2,4-diamine (50 mg, 0.13 mmol, Example 39) and 4-fluorobenzoyl chloride (20.6 mg, 0.13 mmol) were suspended in THF (1 mL) and stirred at rt for 24 h. TLC and LC-MS indicated the reaction was completed. The mixture was extracted with EtOAc and washed with 1N aqueous sodium hydroxide solution (2×) and H20 (3×). The organic layer was dried and concentrated to give 68 mg of the crude product. The residue was purified by Prep-TLC (CH3OH:EtOAc=2:8) to obtain 38 mg (58%) of the title product as a yellowish oil. 1H NMR (CD3OD) δ 8.34 (d, 1H), 7.82 (m, 4H), 7.78 (d, 2H), 7.44 (m, 3H), 7.15 (t, 2H), 7.02 (d, 2H), 6.85 (d, 1H), 6.82 (s, 1H), 6.42 (s, 1H), 4.59 (s, 2H); MS ES 507 (M+H)+, calcd 507, RT=2.50 min; TLC (MeOH/EtOAc=20/80) Rf=0.57.
Reaction SMILES: C([O:3][CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](OCC)=O)C.[NH2:16][NH2:17].[OH-].[Na+]>CCO>[OH:3][C:4]1[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][NH:17][N:16]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c[nH]nc1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of diethyl (ethoxymethylene)malonate (20 g, 92.5 mmol) in 200 mL of EtOH is treated with hydrazine (2.9 mL, 92.5 mmol) by dropwise addition. After 10 min, 100 mL of 1 N NaOH is added (slightly exothermic), and the reaction mixture is stirred for a further 30 min. The EtOH is removed in vacuo, and the aqueous solution is diluted with a little more water and extracted with EtOAc. The aqueous phase is cooled to 0° C. and acidified to pH=5 with conc. HCl. The resulting precipitate is collected by vacuum filtration and dried in vacuo to give the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]([O:12]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl-].[NH4+]>O1CCCC1>[O:17]=[S:16]1(=[O:18])[CH2:15][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[CH2:19]1
Reactant: COC(=O)[C@H](CCS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCS(=O)(=O)CC1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of (S)-methyl 2-(tert-butoxycarbonylamino)-4-(methylsulfonyl)butanoate (2 g, 6.78 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C., to which potassium bis(trimethylsilyl)amide (1.0 M, toluene solution, 15 ml) was added dropwise, and the mixture was stirred at −78° C. for 2 hours and at room temperature for another 2 hours. An aqueous solution of ammonium chloride (1 M) was added, and the mixture was stirred. The reaction mixture was subjected to liquid separation. The resultant organic layer was then washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the formed solid was collected by filtration to obtain the title compound. The water layer separated previously was extracted twice with ethyl acetate. The resultant organic layers were combined, washed with water and brine, and dried over anhydrous magnesium sulfate. The ethyl acetate extracts were combined, dried and then concentrated under reduced pressure to obtain the title compound. The combined product was purified by flash column chromatography (ethyl acetate:petroleum ether, 3:1) to afford the title compound (55 mg, yield 22%) as a yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:8]=[N:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=1.N([O-])=[O:16].[Na+]>O.C(OCC)(=O)C>[OH:16][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[N:9][CH:8]=1
Reactant: O=N[O-]
Reactant: N#Cc1ccc(N)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(O)cn1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Concentrated sulfuric acid (21.0 mL) was added to a suspension of 3-amino-6-cyanopyridine (5.00 g, 42.0 mmol) in water (75.0 mL), and then a 1.6 M aqueous solution of sodium nitrite (29.0 mL, 46.4 mmol) was slowly added dropwise thereto under ice water cooling. This suspension was stirred for 6 hours at 100° C. The reaction mixture was cooled to room temperature, and then was diluted with ethyl acetate (100 mL). The organic layer was washed sequentially with water and saturated brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→1:1, v/v). Thus, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[C:23]1[CH:28]=[CH:27][N:26]=[N:25][CH:24]=1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][N:26]=[N:25][CH:24]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: Brc1ccnnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Cl)c(-c2ccnnc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
[2-Chloro-5-(trifluoromethyl)phenyl]boronic acid (0.410 g, 1.83 mmol), caesium carbonate (1.1 g, 3.38 mmol) and 4-bromopyridazine hydrobromide (Preparation 20, 0.35 g, 1.46 mmol) were dissolved in 1,4-dioxane (3.5 mL) and water (1 mL). The mixture was heated to 80° C. under nitrogen then palladium tetrakis triphenylphosphine (0.085 g, 0.074 mmol) was added. The reaction was stirred for three hours before it was left to cool to room temperature. The mixture was subsequently filtered through Arbocel®, then diluted in ethyl acetate (15 mL) and washed twice with a saturated solution of aqueous brine (15 mL). The organic layer was collected, dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ISCO™, 0-50% ethyl acetate in heptane gradient elution, 12 g SiO2) to give title compound as a green solid (0.23 g, 61%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Br:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ncnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 12.62 mmol) in 50 mL N,N-dimethylformamide at 0° C. was added 95% sodium hydride (0.351 g, 13.89 mmol). The mixture was stirred at 0° C. for 30 minutes, benzenesulfonyl chloride (1.772 mL, 13.89 mmol) was added, and the mixture was stirred at 0° C. for an additional 2 hours. The mixture was quenched with 20 mL saturated ammonium chloride and diluted with water (100 mL). The resulting suspension was stirred for 5 minutes, filtered, and dried under-vacuum to give the title compound. MS (ESI+) m/z 340.0 (M+H)+.