Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([NH:14][C:15]1[C:20]([CH2:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:23][CH3:24])=[NH:13])[CH3:2].[Cl:25][CH:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([NH:14][C:15]1[C:20]([CH2:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:23][CH3:24])=[N:13][CH2:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][Cl:25])[CH:28]=1)[CH3:2]
Reactant: Cc1cccc(C(Cl)Cl)c1
Reactant: CCc1cccc(CC)c1NC(=N)Nc1c(CC)cccc1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1NC(=NCc1cccc(CCl)c1)Nc1c(CC)cccc1CC
Yield: 32.5 %

Procedure:
9.7 g (0.03 mole) of N,N'-bis-(2,6-diethylphenyl) guanidine, 5.7 g (0.033 mole) of α,α-dichloro-m-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of toluene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and then concentrated for the purpose of recovering the solvent and unreacted raw materials to obtain a slightly yellow crystal. The crystal was then recrystallized from benzene to obtain 4.5 g of white powder.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24]([O:25][CH3:26])=[N:23][C:22]3[C:17]2=[N:18][C:19]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[N:20][C:21]=3[NH2:27])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClC[C:42]1[CH:49]=[CH:48][C:45]([CH2:46][OH:47])=[CH:44][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:27][C:21]1[N:20]=[C:19]([O:28][CH2:29][CH2:30][O:31][CH3:32])[N:18]=[C:17]2[C:22]=1[N:23]=[C:24]([O:25][CH3:26])[N:16]2[CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][C:42]2[CH:49]=[CH:48][C:45]([CH2:46][OH:47])=[CH:44][CH:43]=2)[CH2:13][CH2:12]1
Reactant: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Reactant: OCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(Cc4ccc(CO)cc4)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
To the compound (0.84 g, 1.86 mmol) obtained in Example 9, Step (i) was added trifluoroacetic acid (12 ml), and the mixture was stirred at room temperature for 20 minutes. Trifluoroacetic acid was evaporated by an evaporator, and DMF (15 ml), 4-(chloromethyl)benzyl alcohol (0.32 g, 2.04 mmol), and potassium carbonate (1.28 g, 9.30 mmol) were added thereto, and the mixture was stirred at room temperature for 18 hours. The carbonate was removed by filtration, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted three times with chloroform/ethanol=3/1. The resultant was dried over magnesium sulfate, concentrated, and purified by silica gel column (chloroform/methanol=20/1) to give the subtitle compound (0.52 g, 1.11 mmol) as a white solid. Yield: 60%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21])(=[O:12])=[O:11])([O-])=O.O.O.Cl[Sn]Cl.[OH-].[K+]>CCOC(C)=O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21])(=[O:12])=[O:11]
Reactant: Cc1ccc(C)c(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(NS(=O)(=O)c2ccccc2N)c1
Temperature: 25 °C

Procedure:
2-nitro-N-(2,5-dimethyl-phenyl)-benzenesulfonamide (6.1 g, 20 mmol) in EtOAc (60 mL) is treated with SnCl2.2H2O (22.5 g, 100 mmol). The reaction mixture is heated to reflux for 30 minutes and then allowed to cool to room temperature. 2 N KOH (250 mL, 500 mmol) is added and the resulting mixture stirred vigorously until all solids dissolve. The aqueous layer is separated and extracted 2×100 mL EtOAc. The combined organic layers are washed with sat. brine, dried over MgSO4, filtered, and concentrated to a solid, which is recrystallized from hot EtOAc/hexanes to provide 2-amino-N-(2,5-dimethyl-phenyl)-benzenesulfonamide.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][SH:4].F[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14].C(N(CC)CC)C>O1CCCC1>[CH2:3]([S:4][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH:2]=[CH2:1]
Reactant: C=CCS
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCSc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A solution of 2.3 g (0.031 mole) of allylthiol in 25 ml of tetrahydrofuran was added to 5.0 g (0.031 mole) of 2,4-difluoronitrobenzene in 25 ml of tetrahydrofuran at -30° C. To this mixture was added dropwise 3.1 g (0.031 mole) of triethylamine. The temperature was allowed to rise to room temperature and stirring was continued for four hours. The tetrahydrofuran was evaporated under reduced pressure, and water and diethyl ether were added to the residue. The ether layer was separated and dried over anhydrous potassium carbonate. The ether was evaporated under reduced pressure, leaving a liquid residue. This residue was distilled at 105° C./1.2 mm of Hg, yielding 4.2 g of 2-allylthio-4-fluoronitrobenzene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: COC(=O)Cc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(OCCCl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a stirred solution of methyl 3-hydroxyphenylacetate (1.66 g, 10 mmol), 2-chloroethanol (1.34 mL, 2 eq.) and triphenylphosphine (5.24 g, 2 eq.) in THF (100 mL) at 0° C. was added dropwise diisopropylazodicarboxylate (3.96 mL, 2 eq.) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then quenched with NaHCO3 and the product was extracted with EtOAc. The EtOAc layers were washed with brinebrine, dried over sodium sulfate, and concentrated. Purification on a silica gel column with 10% EtOAc in hexane gave methyl 3-(2-chloroethyloxy)phenylacetate (1.6 g, 70% yield) which was converted to 3-(1-methylindol-3-yl)-4-[3-(2-aminoethyloxy)phenyl]-1H-pyrrole-2,5-dione by following the procedure described in Example 5, Steps 2-6 above.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[O:17]1[CH2:18][CH2:19][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:15][CH2:16]1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 90 °C
Yield: 85.2 %

Procedure:
To a solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (15 g, 79 mmol) in dimethylsulfoxide (160 mL) was added morpholine (13.8 mL, 159 mmol) and potassium carbonate (16.4 g, 119 mmol). The mixture was heated at about 90° C. for 18 hours. The mixture was cooled to ambient temperature and the solid was removed by filtration. The fitrate was partitioned between ethyl acetate (1.8 L) and water (1.5 L). The organic layer was washed with water (1.0 L) and brine (1.0 L) and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo to give 4-morpholino-3-(trifluoromethyl)benzonitrile (17.25 g, 85%). 1H NMR (DMSO-d6, 400 MHz) δ 8.18 (d, J=2.05 Hz, 1H), 8.09 (dd, J=8.51, 2.06 Hz, 1H), 7.60 (d, J=8.52 Hz, 1H), 3.69-3.75 (m, 4H), 2.97-3.04 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9]Br.[CH3:11][C:12]([O-:14])=[O:13].[Na+]>CN(C)C=O>[C:12]([O:14][CH2:9][C:3]1[C:4]([Br:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:13])[CH3:11]
Reactant: BrCc1c(Br)cccc1Br
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(Br)cccc1Br
Temperature: 100 °C
Reaction time: 1.75 h
Yield: 95 %

Procedure:
A mixture of 1,3-dibromo-2-(bromomethyl)benzene (27.6 g, 84 mmol), NaOAc (35.5 g, 5 eq.) and dimethylformamide (DMF) (150 mL) was stirred at 100° C. (hot oil bath temperature) for 1.75 h, allowed to cool, and then partitioned between heptane (500 mL) and water (200 mL). After removing the organic layer, the aqueous layer was extracted with heptane (200 mL). The combined organics were washed with H2O (2×300 mL), dried (Na2SO4), filtered, and evaporated to give 24.57 g (yield of 95%) of title product as a colorless oil. This oil contained 13% unreacted starting material but was successfully used without further purification. 1H NMR (300 MHz, CDCl3) δ 2.10 (s, 3H), 5.41 (s, 2H), 7.08 (t, 1H), 7.58 (d, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].[NH2:18][C:19]1[S:20][CH:21]=[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:23]=1>>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][C:22]1[N:23]=[C:19]([NH:18][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)[S:20][CH:21]=1)[CH3:29]
Reactant: CC(C)Oc1cc(OC(C)C)cc(C(=O)O)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2cc(OC(C)C)cc(OC(C)C)c2)n1

Procedure:
[2-(3,5-Diisopropoxy-benzoylamino)-thiazol-4-yl]acetic acid ethyl ester was prepared from 3,5-diisopropoxybenzoic acid (prepared as described in general synthetic descriptions B, using 2-bromopropane as alkylhalid) and ethyl 2-aminothiazol-4-ylacetate following synthetic description A.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[N:26]5[CH2:27][CH2:28][NH:29][CH2:30][C:25]5=[N:24][CH:23]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[N:26]5[CH2:27][CH2:28][N:29]([CH3:33])[CH2:30][C:25]5=[N:24][CH:23]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#CCC(C1CC1)n1cc(-c2nc(-c3cnc4n3CCNC4)cc3nccn23)cn1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCn2c(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CC5)c4)n3)cnc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To 3-cyclopropyl-3-(4-(7-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 56; 10 mg, 0.025 mmol) in DCM/MeOH (1 mL/1 mL) was added formaldehyde (50 mg, 0.50 mmol) and sodium triacetoxyborohydride (16 mg, 0.075 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to give the final product (5.0 mg, 48% yield). MS (apci) m/z=414.4 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.OC1C(=O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N2CCN(C(C)C)C(=O)C=12>>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12
Reactant: CC(C)N1CCn2c(Cc3ncccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CC(C)N1CCn2c(CC3(c4ccc(C(F)(F)F)cc4)CCCC3)nc(=O)c(O)c2C1=O
Product: CC(C)N1CCn2c(Cc3ncccc3-c3ccccc3)nc(=O)c(O)c2C1=O
Yield: 43.9 %

Procedure:
9-Hydroxy-2-isopropyl-6-(3-phenyl-pyridin-2-ylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (168) (12 mg, 40.98%) as a light yellow solid was synthesized from 9-benzyloxy-2-isopropyl-6-(3-phenyl-pyridin-2-ylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (167) (36 mg, 0.07 mmol) following the procedure as described for 9-hydroxy-2-isopropyl-6-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (168).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][NH2:21])[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH:33]([S:36](Cl)(=[O:38])=[O:37])([CH3:35])[CH3:34]>ClCCl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][NH:21][S:36]([CH:33]([CH3:35])[CH3:34])(=[O:38])=[O:37])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.7 %

Procedure:
0.08 g (0.239 mmol) of (3-((3-(trifluoromethyl)phenyl) ethynyl) imidazo[1,2-a]pyridin-2-yl) methanamine (prepared according to steps 1 to 4 of Example 11) were solubilised in 2 ml of dichloromethane with magnetic stirring, 0.208 ml (1.193 mmol) of diisopropylethylamine and 0.083 ml (0.716 mmol) of isopropylsulfonyl chloride were added. The mixture was stirred at r.t. for 16 h. A supplement of 0.083 ml (0.716 mmol) of isopropylsulfonyl chloride was added and the mixture was stirred at r.t. for 1 h before being concentrated in vacuo. The crude residue was directly purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol 95/5, v/v). 0.048 g (yield=22%) of N-((3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methyl)propane-2-sulfonamide were obtained as a white solid. LC-MS: m/z=422 (MH+); UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) δ 8.75 (d, J=6.8 Hz, 1H), 8.13 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.85-7.61 (m, 4H), 7.53-7.38 (m, 1H), 7.15 (t, J=6.8 Hz, 1H), 4.44 (d, J=5.9 Hz, 2H), 3.25 (dd, J=13.6, 6.8 Hz, 1H), 1.21 (d, J=6.8 Hz, 6H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH2:10][C:11]1[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]=[C:14]([CH3:16])[CH:15]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH2:17]([N:12]1[C:11]([CH2:10][CH2:9][OH:8])=[CH:15][C:14]([CH3:16])=[N:13]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1cc(C)nn1Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CCO)n(Cc2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
LAH (250 mg, 6.6 mmol) was suspended in THF (18 ml) in an inert atmosphere and cooled to 0° C. followed by the dropwise addition of a solution of (2-benzyl-5-methyl-2H-pyrazol-3-yl)-acetic acid methyl ester (1.07 g, 4.4 mmol) in THF (4 ml). Stirring was continued for 2 h at rt. At 0° C., water (0.25 ml), 15% aqueous NaOH-solution (0.25 ml) and again water (0.75 ml) were subsequently added. Stirring was continued for several hours followed by the addition of sodium sulfate and filtration. The filtrate was concentrated under reduced pressure to give 850 mg (89%) of 2-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-ethanol directly used in the next step without further purification. LC-MS: tR=0.66 min; [M+H]+=217.15.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=1)#[N:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=NC#N)c1ccccn1
Solvent: CO
Product: N#CNC(=NCc1ccc(Cl)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.1 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), 4-chlorobenzylamine (0.48 g, 3.4 mmol) was added, and the resulting mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether to give the title compound (0.13 g, 0.5 mmol, yield: 16%) as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[C:18](=[O:19])([O:7][C:6]1[C:5](=[O:8])[CH:4]([CH3:9])[O:3][C:2]=1[CH3:1])[O:20][CH2:21][CH3:22]
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)OC1=C(C)OC(C)C1=O
Yield: 72.5 %

Procedure:
A solution of 2,5-dimethyl-4-hydroxy-3(2H)-furanone (pineapple ketone, 133.0 g, 1.0 mole) and triethylamine (152.0 g, 1.5 moles) in methylene chloride (665 g) is cooled to 5° C. under nitrogen atmosphere. To the cooled solution is added over a period of 2.5 hours, a solution of ethyl chloroformate (127.7 g, 1.18 moles) in methylene chloride (600 g) stirred at 5°-8° C. for two additional hours. The reaction mixture is filtered through a Buchner funnel to remove the triethylamine hydrochloride. The salt is washed with methylene chloride (200 ml). The combined organic layers are washed twice with 100 ml portions of water and dried over sodium sulfate. The solvent is removed in vacuo and the crude product distilled (<0.1 torr) through a Goodloe column to yield 72.5% of ethyl 2,5-dimethyl-3-oxo-4(2H)-furyl carbonate product b.p. 87° C. (0.08 torr), IR (neat film) 2980(M), 1770(S), 1715(S), 1640(S), 1250(S) cm-1, 'H NMR δ1.58 (t, J=8 Hz, 3), 1.65 (d, J=7 Hz, 3), 2.32 (s, 3), 4.45 (q, J=7 Hz, 2), 4.75 (q, J=7 Hz, 1), and 3.3% of the diadduct, diethyl 2,5-dimethyl-3,4-furyl dicarbonate, b.p. 110° C. (0.08 torr), IR (neat film 2980(M), 1770(S), 1250(S), 'H NMR δ=1.50 (t, J=6 Hz, 6) 2.3 (S, 6) 4.45 (q, J=8 Hz, 4).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28].O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[C:19]([C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[O:28])[CH:20]=2)=[CH:3][C:4]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=1
Reactant: O=C(c1cc(B(O)O)ccc1F)N1CCOCC1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1cc(-c2cc(-c3ccc(F)c(C(=O)N4CCOCC4)c3)cnc2N)nn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and (4-fluoro-3-(morpholine-4-carbonyl)phenyl)boronic acid (197 mg, 0.77 mmol) in 1,4-dioxane (10.0 mL)/water (5.0 mL) was added Cs2CO3 (690 mg, 2.12 mmol) at room temperature. The reaction mixture was degassed with argon for 30 min. Then Pd(PPh3)4 (40 mg, 0.035 mmol) was added and allowed to stir at 110° C. for 30 min in CEM micro wave. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 5% MeOH in DCM to afford 210 mg (yield: 72.41%) of title compound as pale yellow solid.
Reaction SMILES: [CH3:1][S:2]([CH2:5]P(=O)(OCC)OCC)(=[O:4])=[O:3].[Li+].[Cl-].C1CCN2C(=NCCC2)CC1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:41]2[C:49]3[C:44](=[C:45]([CH:50]=O)[CH:46]=[CH:47][CH:48]=3)[CH:43]=[CH:42]2)([CH2:39][CH3:40])[C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=1>CC#N.C(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:41]2[C:49]3[C:44](=[C:45](/[CH:50]=[CH:5]/[S:2]([CH3:1])(=[O:3])=[O:4])[CH:46]=[CH:47][CH:48]=3)[CH:43]=[CH:42]2)([CH2:39][CH3:40])[C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=1
Reactant: CCOP(=O)(CS(C)(=O)=O)OCC
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(C=O)cccc21
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(/C=C/S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl methylsulfonylmethylphosphonate (1.05 g, 4.56 mmol) in CH3CN (30 mL) at RT was added LiCl (0.16 g, 3.80 mmol) and DBU (2.40 g, 9.56 mmol). After 5 min, a solution of methyl 2-(4-chlorophenyl)-2-(4-formyl-1H-indol-1-yl)butanoate (1.35 g, 3.80 mmol) in CH3CN (10 mL) was added dropwise. The resulting mixture was stirred for 4 hours at RT. Then it was diluted with DCM (50 mL) and the organic layer was washed with water (30 mL), dried over Na2SO4, filtered. After removal of the solvent, the residue was purified via column chromatography (0-30% EtOAc/hexanes) to provide the title compound. LC/MS m/z=432.0[M+H]+.
Reaction SMILES: C[O-].[Na+].[CH:4]([NH2:6])=[NH:5].O=[C:8]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10][CH:9]1[C:22](OC)=[O:23].C(O)(=O)C>CO>[OH:23][C:22]1[C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[N:6]=[CH:4][N:5]=1
Reactant: N=CN
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ncnc(O)c2CC1
Reaction time: 0.25 h

Procedure:
A solution of NaOMe in MeOH (13.6 mL, 25% in MeOH, 59.5 mmol) is added to a stirred solution of formamidine (2.2 g, 21 mmol) in MeOH (50 ml) at rt. The mixture is stirred for 15 min. 1-tert-Butyl 4-methyl 5-oxoazepane-1,4-dicarboxylate (5 g, 7.5 mmol) is added and the mixture is stirred at rt overnight. Acetic acid (2.33 g, 38.5 mmol) is added and the solvent is removed in vacuo. Water (30 ml) is added to the residue and the solution is extracted with DCM (3×30 ml). The combined extracts are washed with brine (40 ml), dried (Na2SO4) and evaporated, to provide a yellow solid that is used in the next step without further purification.