Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[O:105]=[C:106]1[CH:110]=[CH:109][C:108](=[O:111])[N:107]1[CH2:112][CH2:113][CH2:114][C:115]([N:117]([CH3:122])[CH2:118][CH2:119][NH:120][CH3:121])=[O:116]>CN(C=O)C>[O:105]=[C:106]1[CH:110]=[CH:109][C:108](=[O:111])[N:107]1[CH2:112][CH2:113][CH2:114][C:115]([N:117]([CH3:122])[CH2:118][CH2:119][N:120]([CH3:121])[C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:116]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: CNCCN(C)C(=O)CCCN1C(=O)C=CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)N(C)CCN(C)C(=O)CCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.6 mg (7.3 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 2000 μl of DMF and then admixed with 5.6 mg (14.7 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 2.6 μl of N,N-diisopropylethylamine and with 4.1 mg (9 μmol) of 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methyl-N-[2-(methylamino)ethyl]butanamide trifluoroacetate. After stirring at RT for 3 h, the same amounts of HATU and N,N-diisopropylethylamine were added once again, and the reaction mixture was then stirred at RT overnight. Subsequently, the solvent was removed under reduced pressure and the remaining residue was purified by means of preparative HPLC. Thus, 4 mg (44% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]([O:13]C)=[O:12])[N:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.[OH-].[Na+]>CO.[Cl-].[Na+].O>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=[O:12])[N:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1
Reactant: COC(=O)c1cc2c(ccn2C)cn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ccc2cnc(C(=O)O)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
In a 500 mL pear flask was added methyl 1-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1B, 14 g, 71 mmol) in methanol (71.0 ml). At 0° C. was added 1N sodium hydroxide solution (140 ml, 140 mmol). This was then stirred at 0° C. for 1 h, when the reaction was complete. Brine (25 ml) was added and methanol was removed in vacuo. The aqueous mixture was washed twice with EtOAc. The aqueous layer was then acidified to pH 4; the resulting precipitate was collected on a fritted glass funnel and dried overnight under a stream of nitrogen to give the desired product 1-methyl-1H -pyrrolo[3,2-c]pyridine-6-carboxylic acid (1C, 10 g, 83% yield) as an off white powder. This was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([B-](F)(F)F)=[CH2:10].[K+].C(N(CC)CC)C>C(O)CC>[Cl:1][C:2]1[N:7]=[C:6]([CH:9]=[CH2:10])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCCO
Solvent: CCN(CC)CC
Product: C=Cc1ccnc(Cl)n1
Temperature: 100 °C

Procedure:
A mixture of 2,4-dichloropyrimidine (4.4 g, 29.5 mmol), potassium vinyltrifluoroborate (4.58 g, 32.5 mmol), PdCl2 (dppf)-CH2Cl2 (1.21 g, 1.48 mmol) and triethylamine (4.12 mL, 29.5 mmol) in nPrOH (148 mL) was purged with nitrogen for 15 min, heated to 100° C. for 5 h, and cooled to room temperature. The mixture was treated with water and extracted with EtOAc (×3). The combined organics were washed with brine, dried (sodium sulfate), concentrated, and purified by flash chromotography to afford 2-chloro-4-ethenylpyrimidine as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.56 (d, J=5.1, 1H), 7.21 (d, J=5.1, 1H), 6.70 (dd, J=10.6, 17.4, 1H), 6.57-6.51 (m, 1H), 5.79 (dd, J=0.8, 10.6, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C(#N)C.Br[CH2:21][CH:22]=[CH2:23]>O>[CH2:23]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C=CCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a mixture of 15 g (0.015 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 15.93 g (0.115 mol)of K2CO3, and 100 ml of acetonitrile is added dropwise 9.07 ml (0.105 mol) of ;b 3-bromopropene. The mixture is stirred overnight at room temperature and then at 65° C. for 2 hours. After cooling, the mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to afford 9.48 g (49%) of title compound as an oil: ir (neat) 2955 and 1090 cm-1 ; NMR (CDCl3) δ5.91 (m, 1H), 5.21 (m, 2H), 3.97 (s, 4H), 3.05 (d, 2H), 2.56 (t, 4H), 1.76 (t, 4H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1
Reactant: COCCN
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Product: COCCNc1cc(C(F)(F)F)cc2nc(NC(=O)c3cccnc3)nn12
Temperature: 120 °C
Yield: 43.2 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and 2-methoxyethylamine (55.0 mg; 0.73 mmol; 5.0 eq), heated at 120° C., to give the title compound as a white solid (23 mg, 40%). HPLC, Rt: 2.70 min. (purity 98.1%). LC/MS, M+(ESI): 380.8, M−(ESI): 378.9.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]1[CH2:36][O:35][C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH2:26][CH2:27]Br)[O:24]1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:27][CH2:26][C:25]3([O:24][CH2:23][CH2:36][O:35]3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCC1(c2ccccc2)OCCO1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCC2(c3ccccc3)OCCO2)CC1
Yield: 99.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (7.2 g) and 3,3-ethylenedioxy-3-phenylpropyl bromide (6.0 g) were reacted and treated in the same manner as in Example 172 to give 9.2 g of 4-amino-5-chloro-N-((1-(3,3-ethylenedioxy-3-phenylpropyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: Cl[O-].[Na+].[Cl:4][C:5]1[C:10]([Cl:11])=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]([Cl:16])[C:6]=1[NH:17][NH:18][CH2:19][CH2:20][C:21]#[N:22].[OH-].[Na+]>C(O)C>[Cl:4][C:5]1[C:10]([Cl:11])=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:8]=[C:7]([Cl:16])[C:6]=1[N:17]1[C:21]([NH2:22])=[CH:20][CH:19]=[N:18]1
Reactant: N#CCCNNc1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CCO
Product: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl
Temperature: 20 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
38 g of sodium hypochlorite solution (prepared by passing about 18 g of chlorine into 220 g of 20% strength sodium hydroxide solution) are added dropwise to 13.5 (0.04 mol) of N-(2,3,6-trichloro-4-trifluoromethylphenyl)-N'-2-cyano-ethylhydrazine in 80 ml of ethanol at 10° C. The mixture is stirred at 20° C. for 16 hours, 0.5 g of solid sodium hydroxide are added and the mixture is subsequently stirred for 6 hours. It is concentrated, the residue is taken up in methylene chloride, the mixture is washed twice with water and concentrated and the residue is distilled. 10 g (76% of theory) of 1-(2,3,6-trichloro-4-trifluoromethylphenyl)-5-amino-pyrazole are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]2)[CH:2]=1.[CH3:13][C:14]([CH3:16])=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OC(C)C)(=O)C>[CH:14]([NH:12][C:10]1[CH:9]=[N:8][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)([CH3:16])[CH3:13]
Reactant: CC(C)=O
Reactant: Nc1cnn(-c2cccnc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1cnn(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1-pyridin-3-yl-1H-pyrazol-4-ylamine (0.6 g, 3.7 mmol) was dissolved in isopropyl acetate (8.5 ml). To the mixture, acetone (0.261 g, 4.5 mmol), trifluoroacetic acid (0.855 g, 7.5 mmol) and sodium triacetoxyborohydride (0.945 g, 4.5 mmol) were added. The reaction was stirred under nitrogen at room temperature for 4.5 hours and then quenched with 10% sodium hydroxide solution until the pH reached ˜9. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated to dryness. The crude material was purified by silica gel chromatography (gradient elution of 5% methanol/dichloromethane) to give the title compound as an off white solid (0.35 g, 46%): mp 105-107° C.; 1H NMR (300 MHz, CDCl3) δ 8.82 (d, J=2.2 Hz, 1H), 8.63 (dd, J=4.8, 1.5 Hz, 1H), 8.13 (d, J=1.8 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 7.94-7.77 (m, 1H), 7.38 (dt, J=15.2, 7.6 Hz, 1H), 6.99 (t, 1H), 3.72 (m, 1H), 1.30 (t, J=10.0 Hz, 6H). ESIMS 214 m/z (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][CH2:22][CH:23]=O>>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][CH2:22][CH:23]1[NH:10][CH2:9][CH2:8][N:3]2[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]12
Reactant: COc1ccc(CCC=O)c(OC)c1
Reactant: Cc1cn(CCN)c(C)n1
Product: COc1ccc(CCC2NCCn3c(C)nc(C)c32)c(OC)c1

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(2,4-dimethoxy-phenyl)-propionaldehyde. LC-MS: tR=0.59 min.; [M+H]+=316 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.O.O.[Sn](Cl)Cl.[NH2:29][C:30]1C=CC(Cl)=CC=1N[C@@H]1CC[C@H](C(NC(C)C)=O)CC1.N#CBr>CCO.C(Cl)Cl>[NH2:29][C:30]1[N:8]([C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:21]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ccc2N)CC1
Agent: Cl[Sn]Cl
Agent: N#CBr
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2c(N)nc3ccc(Cl)cc32)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 123.8 %

Procedure:
To a solution of cis-4-(5-chloro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide (2.27 g, 6.68 mmol) in EtOH (66.8 mL) was added tin(II) chloride dihydrate (6.03 g, 26.7 mmol). The reaction was stirred at 80° C. for 90 minutes. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and 1 N aqueous NaOH. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The cis-4-(2-amino-5-chlorophenylamino)-N-isopropylcyclohexanecarboxamide intermediate (2.07 g, 6.68 mmol) was dissolved in EtOH (20 mL), and cyanogen bromide (1.061 g, 10.02 mmol) was added. The reaction was stirred at RT for 1 hour The reaction was diluted with 200 mL DCM and washed with 1 N aqueous NaOH. The organic layer was concentrated to provide cis-4-(2-amino-6-chloro-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide (2.77 g, 124% yield) as a brown oil. MS, m/z (C17H23ClN4O): calcd, 334.2. found, 334.8 [M+H].
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][OH:24])=[CH:18][CH:17]=1)#[N:15]>CN(C=O)C.CCOC(C)=O>[Si:5]([O:24][CH2:23][CH:22]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:19]1[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:21][CH:20]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)CNC(CO)c1ccc(C#N)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(CO[Si](C)(C)C(C)(C)C)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
t-Butyldimethyl silyl chloride (0.579 g; 3.84 mmol) and imidazole (0.261 g; 3.83 mmol) were added to a solution of tert-butyl 2-(1-(4-cyanophenyl)-2-hydroxyethylamino)acetate (0.709 g; 2.56 mmol) in DMF (10 mL). The reaction mixture was stirred at ambient temperature for 18 hours. The mixture was diluted with EtOAc and washed sequentially with water and brine. The organic phase was poured through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography eluting with iso-hexane/EtOAc (10:1) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.63-7.61 (m, 2H), 7.48 (d, J=8.4 Hz, 2H), 3.86-3.83 (m, 1H), 3.66-3.55 (m, 2H), 3.23 (d, J=16.8 Hz, 1H), 3.06 (d, J=16.8 Hz, 1H), 2.53 (br s, 1H), 1.47 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:4]=1.[H-].[Na+].Cl[CH2:19][C:20]1[CH:38]=[CH:37][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:39][CH3:40])[CH:21]=1>CN(C)C=O>[O:33]1[CH:34]=[CH:35][CH:36]=[C:32]1[C:28]1[O:29][C:30]([CH3:31])=[C:26]([CH2:25][O:24][C:23]2[CH:37]=[CH:38][C:20]([CH2:19][N:2]([CH3:1])[C:3]3[C:7]([CH:8]=[O:9])=[CH:6][N:5]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:4]=3)=[CH:21][C:22]=2[O:39][CH3:40])[N:27]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CNc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CN(C)c2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To a solution of 3-(methylamino)-1-phenyl-1H-pyrazole-4-carbaldehyde (150 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 36 mg) on an ice bath, and the mixture was stirred for 30 min. To the reaction mixture was added 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (227 mg), and the mixture was further stirred at room temperature for 1 hr. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to flash silica gel column chromatography and eluted with ethyl acetate-hexane (1:9 to 6:4, v/v) to give 3-([4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl](methyl)amino)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (170.4 mg, yield 46%). melting point: 101-102° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=1
Reactant: Clc1ncnc2ccccc12
Reactant: OCCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(CCOc2ncnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.4 %

Procedure:
To a solution of 1.1 g of sodium hydride in 50 ml of DMF was added 3.4 g of 2-(4-chlorophenyl)ethanol, and the mixture was stirred at room temperature for one hour. Then 3.6 g of 4-chloroquinazoline in 20 ml of DMF were added, and the mixture was stirred overnight. The mixture was then poured into a mixture of ice in water. Solid was collected and recrystallized from pentane giving 0.149 g of the title product. Yield: 2.4%. M.P. 57°-58° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:4]=[N:3]1.[N+:13]([CH:16]=[C:17](SC)SC)([O-:15])=[O:14]>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][NH:12][C:17]2=[CH:16][N+:13]([O-:15])=[O:14])[CH:4]=[N:3]1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Cn1cc(CNCCCN)cn1
Solvent: CCO
Product: Cn1cc(CN2CCCNC2=C[N+](=O)[O-])cn1
Yield: 70.1 %

Procedure:
A mixture of 16.8 g of N-(1-methyl-4-pyrazolylmethyl)-trimethylenediamine, 16.5 g of 1-nitro-2,2-bis(methylthio)ethylene and 200 ml of ethanol wash heated under reflux until the generation of methylmercaptan ceased. The mixture was cooled, and the precipitated crystals were collected by filtration. Washing with methanol gave 16.6 g of the desired 1-(1-methyl-4-pyrazolylmethyl)2-(nitromethylene)tetrahydropyrimidine as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)=[CH:4][CH:3]=1.[CH2:22]([SH:24])[CH3:23].P(OC#N)(OCC)(OCC)=O.C(N(CC)CC)C>O.C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[S:24][CH2:22][CH3:23])[C:5]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(Oc2ccc(N)nc2C(=O)O)n1
Reactant: CCS
Agent: CCOP(=O)(OC#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCSC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
2.5 g (8.5 mmol) of 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinic acid, 0.64 g (10.3 mmol) of ethylmercaptan, 2.8 g (17 mmol) of diethyl cyano phosphate and 1.73 g (17.1 mmol) of triethylamine were added to a THF solution, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate, followed by separation, washed with water and dried. Then, the solvent was distilled off, and the residual oily product was purified by column chromatography to obtain the desired product as colorless transparent crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].CO.[CH:19](=O)[CH:20]=O>O>[C:11]1([C:9]([C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[N:8]=[CH:20][CH:19]=[N:1]3)=[O:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=CC=O
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Solvent: CO
Solvent: O
Product: O=C(c1ccccc1)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
To a stirred solution of 30 parts of (3,4-diaminophenyl) phenylmethanone in 240 parts of methanol were added 30 parts of an ethanedial solution in water 40%. The reaction mixture was stirred for 3 hours at reflux temperature. After cooling to room temperature, the precipitated product was filtered off, washed with methanol and dried, yielding 20 parts (59.3%) of phenyl (6-quinoxalinyl)methanone; mp. 120° C. (interm. 2).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][C@H:19]([CH3:21])[C@H:18]([C:22]#[N:23])[C@H:17]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:16]1)=O)(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.C(ON1C(=O)CCC1=O)(OC(C)(C)C)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][C@H:19]([CH3:21])[C@H:18]([C:22]#[N:23])[C@H:17]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:16]1
Reactant: C[C@H]1CN(c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1C#N
Agent: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Tert-butyl ((3S,4S,5R)-1-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-cyano-5-methylpiperidin-3-yl)carbamate (1.0 equiv.) was treated with 4 M HCl in dioxane (30.0 equiv.) at rt for 1 hour. The volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2Cl2 (0.05 M), DIEA (5.0 equiv.) and Boc-OSu (1.6 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated to yield tert-butyl (3S,4S,5R)-1-(3-aminopyridin-4-yl)-4-cyano-5-methylpiperidin-3-ylcarbamate in 100% yield. LC/MS (m/z)=332.1 (MH+), Rt=0.59 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44](=[O:46])[CH3:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C[Si](Cl)(C)C>O1CCOCC1.C(O)CCC>[C:44]([N:41]1[CH2:40][CH2:39][N:38]([C:35]2[CH:36]=[CH:37][C:32]([NH:31][C:2]3[N:3]=[C:4]([NH:21][C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([NH2:27])=[O:26])[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:12])=[O:13])[C:6]=4[N:7]=3)=[CH:33][CH:34]=2)[CH2:43][CH2:42]1)(=[O:46])[CH3:45]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(C(N)=O)c4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4cccc(C(N)=O)c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 110 °C
Reaction time: 72 h
Yield: 33.7 %

Procedure:
A mixture of 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzamide (85 mg, 0.19 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (105 mg, 0.480 mmol) and trimethylsilyl chloride (0.030 mL, 0.24 mmol) in dioxane (1 mL) and nBuOH (1 mL) was stirred at 110° C. for 72 h. It was concentrated in vacuo. The residue was purified by HPLC to give 3-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzamide (40 mg).