Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][C@@H:8]1[C@@H:11]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C:9]1=O)([CH3:4])[CH3:3].Cl.[O:25]([NH2:27])[CH3:26].CC(C)=O.CCOC(C)=O>N1C=CC=CC=1.CCCCCC>[CH3:26][O:25][N:27]=[C:9]1[CH2:10][C@H:11]([CH2:12][O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[C@H:8]1[CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:4])[CH3:1])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CC(=O)[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CON=C1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A solution of 415.3 g (1.16 mol) of [2S,3S]-2,3bis(((1,1-dimethylethyl)dimethylsilyl) oxymethyl)cyclobutanone, the product of Step 1D, in 540 mL of pyridine is added to 117 g (1.2 equivalents) of methoxylamine hydrochloride. The reaction mixture was stirred mechanically for 1 hour at ambient temperature and checked by TLC on silica gel eluting with 4% acetone in hexane. The reaction mixture was stirred until the starting material was consumed according to TLC analysis, and then it was concentrated in vacuo. The residue was then diluted with ethyl acetate (1 L) and water (0.5 L). The resultant layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solution was washed twice with water (250 mL) and once with brine (150 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on 1 kg silica gel column eluted with 10% diethyl ether in hexane to give 425 g (94% yield) of the title compound, [α]D @ 25° C.=-25.8° (c 3.36; EtOAc).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O.CC(C)=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 20 h
Yield: 88.8 %

Procedure:
To a solution of D-valine (6.40 g, 54.6 mmol) in H2O (62 mL) and acetone (25 mL) was added triethylamine (16.2 mL, 117 mmol). The solution was cooled to zero degrees C. in an ice/H2O bath and a solution of 4-fluorobenzenesulfonyl chloride (10.0 g, 51.4 mmol) in acetone (25 mL) was added dropwise. After stirring at room temperature for 20 hours, the resulting yellow solution was concentrated in vacuo to remove the acetone. The aqueous residue was extracted with toluene (2×50 mL) and acidified to pH=1 with 12 M HCl. The solution was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed successively with 1M KHSO4 (50 mL), H2O (50 mL), and sat'd NaCl (50 mL), then dried over MgSO4. Concentration in vacuo and trituration with hexane afforded N-[(4-fluorophenyl)-sulfonyl]-D-valine as a white solid (12.56 g, 89%): MS MH+ calcd. for Anal. Calc'd for C11H14NO4SF: C, H, N. Found: C, H, N. HR mass calculated for C11H14NO4S: 276.0706. Found: 276.0710.
Reaction SMILES: [O:1]([CH2:9][C:10]1([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[N+:24]([O-:26])=[O:25])[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12][CH2:11]1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].O>O1CCCC1>[CH3:16][C:13]1([CH3:17])[O:12][CH2:11][C:10]([CH2:9][OH:1])([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[N+:24]([O-:26])=[O:25])[CH2:15][O:14]1
Reactant: CC1(C)OCC(CO[Si](C)(C)C(C)(C)C)(Cn2ccnc2[N+](=O)[O-])CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OCC(CO)(Cn2ccnc2[N+](=O)[O-])CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
363 mg (0.942 mmol equivalents) of 5-(t-butyldimethylsiloxymethyl)-2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane was dissolved in 10.0 mL of tetrahydrofuran, 0.94 mL (1.0 mol/L solution, 0.94 mmol equivalents) of a tetrahydrofuran solution of tetrabutylammonium fluoride was added thereto, and the mixture was stirred at room temperature (25° C.) for 10 minutes. After completion of the reaction, a saturated aqueous solution of ammonium chloride and water were added thereto, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate and subsequently concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=1/3) to give 221 mg (0.815 mmol equivalents) of 2,2-dimethyl-5-hydroxymethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:33])=[C:17]([C@:19]23[CH2:27][O:26][C@H:25]([C:28]([F:31])([F:30])[F:29])[C@H:24]2[CH2:23][S:22][C:21]([NH2:32])=[N:20]3)[CH:18]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[NH4+]>CCOC(C)=O.O>[NH2:32][C:21]1[S:22][CH2:23][C@@H:24]2[C@@H:25]([C:28]([F:31])([F:29])[F:30])[O:26][CH2:27][C@:19]2([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[N:4][C:3]([CH2:2][F:1])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:33])[N:20]=1
Reactant: O=C(O)c1cnc(CF)cn1
Reactant: NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(CF)cn4)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 70.8 %

Procedure:
5-(Fluoromethyl)pyrazine-2-carboxylic acid (32.6 g, 1.05 equiv) and (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (70.0 g, 1.0 equiv) were charged to a reactor and EtOAc (630 mL) was added to the mixture to give a suspension. A solution of ®T3P (146 g, 1.10 equiv, 50 wt % in EtOAc) (Archimica, Germany) was added at ambient temperature while controlling the internal temperature below 30° C. The reaction mixture was stirred at 40-45° C.>3 hours and monitored by HPLC. The reaction mixture was cooled to 15-20° C. and water (140 mL) was charged. After 10-15 minutes charged 28% ammonium hydroxide (175 mL) while controlling the temperature below 30° C. EtOAc (245 mL0 was added and the reaction mixture was stirred for 30 minutes at ambient temperature. The aqueous phase was separated and back-extracted with EtOAc (490 mL). The organic phases were combined and washed with 15% aq. NaCl (140 mL) and water (140 mL). The organic layer was filtered over Celite (1.0 Wt) and rinsed with EtOAc (140 mL). The solution was concentrated under vacuum to obtain a beige solid (quantitative crude yield) which was recrystallized from 1-propanol to afford N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide as a white solid (70.0 g).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>C(Cl)Cl>[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([O:14][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: ON=C1CCCCC1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: O=NC1(OC(=O)c2ccc(Cl)cc2Cl)CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-Nitrosocyclohexyl 2,4-dichlorobenzoate was prepared according to General Method 3. A solution of cyclohexanone oxime (2.66 g, 23.5 mmol) in DCM (50 ml) was added dropwise to a solution of lead tetra acetate (10.42 g, 23.5 mmol) and 2,4 dichlorobenzoic acid (45.0 g, 235 mmol) in DCM (300 ml) at 0° C. A blue color gradually appears on addition of the oxime solution. Upon complete addition (1 hour) the reaction was allowed to warm to ambient temperature and stirring was continued for a further 2-3 hours. The reaction was quenched by the addition of water, the phases separated and the organics dried over Na2SO4 and concentrated in vacuo to afford 1-nitrosocyclohexyl 2,4-dichlorobenzoate which was purified by column chromatography on silica gel with hexane:EtOAc as the eluent to afford the title compound as a blue oil in 9% yield. δH (400 MHz, DMSO-d6) δ 8.02 (1H, d, 8.4 Hz), 7.85 (1H, d, 2.0 Hz), 7.64 (1H, dd, 8.4, 2.0 Hz), 2.03-2.12 (2H, m), 1.38-1.93 (8H, m).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[S:9]([CH2:12][C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:23][CH3:24])[C:16]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[H][H]>[Pd].C1COCC1.C(O)C>[CH:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH2:3][CH:2]2[S:9]([CH2:12][C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:23][CH3:24])[C:16]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1c(CS(=O)(=O)C2CC3C=CC2CC3)ccc(-c2ccoc2)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1c(CS(=O)(=O)C2CC3CCC2CC3)ccc(-c2ccoc2)c1OC
Yield: 11.1 %

Procedure:
A mixture of methyl 6-(bicyclo[2.2.2]oct-5-ene-2-ylsulphonylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 170, 0.26 g) and palladium on carbon (10%, 0.01 g) in THF (15 ml) and ethanol (10 ml) was stirred in an atmosphere of hydrogen (balloon) for 1 hour. The mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate in cyclohexane with a gradient of 10-50% to give methyl 6-(bicyclo[2.2.2]octane-2-ylsulphonylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (0.029 g).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[ClH:15].Cl.[CH3:17][O:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][CH2:24][NH:25][C:26]([NH:28][C:29]([NH2:31])=[NH:30])=[NH:27])=[CH:21][CH:20]=1>C(O)C>[ClH:15].[NH2:31][C:29]1[NH:28][C:26]([NH:25][CH2:24][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:33][CH:32]=2)=[N:27][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:30]=1
Reactant: CCCCCCCCCCCCC=O
Reactant: COc1ccc(CCNC(=N)NC(=N)N)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCC1N=C(N)NC(NCCc2ccc(OC)cc2)=N1

Procedure:
100 ml of ethanol, 8.8 ml (37.1 mmol) of 1-tridecanal and 0.8 ml of concentrated hydrochloric acid were added to 5.0 g (18.4 mmol) of N1-(4-methoxyphenethyl)-biguanide hydrochloride, and the mixture was refluxed for 22 hours. The solvent was distilled of f under reduced pressure, and the residue was purified by silica gel column chromatography. The first main fraction eluted with a mixture of chloroform and methanol (9:1.5) was recrystallized from 70% aqueous acetonitrile to obtain 0.92 g of colorless crystals (1) having a melting point of 100 to 102° C., and the second main eluate was recrystallized from 70% aqueous acetonitrile to obtain 1.1 g of colorless crystals (2) having a melting point of 165 to 170° C.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C=C>[O:1]=[C:2]([CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])[CH2:3][C:4]([O:6][CH2:7][CH:8]=[CH2:23])=[O:5]
Reactant: CCOC(=O)CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C=CCO
Product: C=CCOC(=O)CC(=O)CCN1C(=O)c2ccccc2C1=O

Procedure:
A solution of 2.89 g (10.0 mmol) of ethyl 3-oxo-5-phthalimidopentanoate in 14 ml of allyl alcohol was heated at 80° C. in the presence of catalytic amounts of p-toluenesulphonic acid hydrate for 3 days. The solvent was then evaporated in vacuo and the residue was purified by chromatography on 170 g of silica gel (toluene:ethyl acetate 4:1). The title compound was obtained as colorless crystals, melting point: 53°-55° C., Rf: 0.40 (toluene:ethyl acetate 4:1).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:36])[C:34]3[CH:41]=[CH:42][CH:43]=[C:44]([CH3:45])[C:33]=3[Cl:32])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1cccc(C)c1Cl
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cccc(C)c1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (984 mg, 2.0 mmol) in THF (10 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 2.5 mL, 5.0 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of 2-chloro-N-methoxy-3,N-dimethyl-benzamide (852 mg, 4.0 mmol) at 0° C. The mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NH4Cl solution (5 mL), and extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. The residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (586 mg) in 52% yield. ESMS m/z (relative intensity): 534.9 [(M−32+H)]+ (70), 588.9 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)Cl>[Br:27][C:10]1[N:11]=[C:12]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[O:13][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Clc1ccc(Sc2cnc(C3CCOCC3)o2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Clc1ccc(Sc2oc(C3CCOCC3)nc2Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole (5.21 g, 17.61 mmol) in DCM (176 ml) was added NBS (3.45 g, 19.38 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica 330 g, 5 to 30% EtOAc in hexane), to give 4-bromo-5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole (6.16 g). MS: M+H=376. H1NMR (400 MHz, CDCl3) δ: 7.28 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 4.01 (dt, J=11.7 Hz, 3.6 Hz, 2H), 3.50 (td, J=11.7 Hz, 2.7 Hz, 2H), 3.09-2.98 (m, 1H), 2.02-1.86 (m, 4H).
Reaction SMILES: NCC1CCCC(CN)C1.NC1C=CC=C(N)N=1.NC1C=NC=CC=1N.NC1N=C(N)C=CN=1.[NH2:35][C:36]1[CH:37]=[CH:38][C:39]2[C:48]([CH:49]=1)=N[C:46]1[C:41](=[CH:42][CH:43]=[C:44]([NH2:50])[CH:45]=1)[CH:40]=2.NC1C=CC2NC3C(C=2C=1)=CC(N)=CC=3>>[CH2:40]([CH:39]1[CH2:38][CH2:37][CH:36]([NH2:35])[CH2:49][CH2:48]1)[CH:41]1[CH2:42][CH2:43][CH:44]([NH2:50])[CH2:45][CH2:46]1
Reactant: Nc1ccc2cc3ccc(N)cc3nc2c1
Agent: NCC1CCCC(CN)C1
Agent: Nc1ccc2[nH]c3ccc(N)cc3c2c1
Agent: Nc1cccc(N)n1
Product: NC1CCC(CC2CCC(N)CC2)CC1

Procedure:
1,3-bis(aminomethyl)cyclohexane; compounds represented by the formulae (35) to (69); 2,6-diaminopyridine; 3,4-diaminopyridine; 2,4-diaminopyrimidine; 3,6-diaminoacridine; 3,6-diaminocarbazole;
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])#[CH:2].Br[C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH:14]=[O:15].C(N(CC)CC)C>CN(C)C=O>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: C#Cc1ccccc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2OC)c(C=O)c1
Yield: 67.3 %

Procedure:
The resulting 2-ethynylanisole (0.79 g) and 2-bromo-5-methoxybenzaldehyde (1.14 g) were reacted in dimethylformamide (50 ml) in the presence of dichloro-bis-triphenylphosphine palladium (1.0 g), cuprous iodide (0.5 g) and triethylamine (15 ml), in nitrogen atmosphere at 50° C. for 6 hr. The resulting reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give 0.95 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[N:21][OH:22])[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C[Si]([N:27]=[C:28]=[O:29])(C)C.N1C=CC=CC=1>C1COCC1>[C:28]([O:22][N:21]=[C:17]([C:16]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12)[CH:18]([CH3:19])[CH3:20])(=[O:29])[NH2:27]
Reactant: CC(C)C(=NO)c1c(-c2ccc(Cl)cc2)nn2ccccc12
Reactant: C[Si](C)(C)N=C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)C(=NOC(N)=O)c1c(-c2ccc(Cl)cc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.6 %

Procedure:
To a solution of 783 mg (2.5 mmol) of 1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature over 48 hrs, followed by addition of 500 μl pyridine. After stirring for another 4 hours, the solvent was removed and the residue was extracted by ethyl acetate three times. The combined organic layers were washed with 1N HCl twice, brine and dried over MgSO4. After evaporation of the solvent under vacuum, 935 mg of crude product was obtained. Purification on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant furnished 621 mg (69.6%) of 1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime. Compound 1026.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH2:10](N)[CH2:11][NH2:12].[Cl-].[Na+]>C(Cl)(Cl)Cl.O>[NH:9]1[CH2:10][CH2:11][N:12]=[C:8]1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: N#Cc1cnc(N)cn1
Reactant: NCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1cnc(C2=NCCN2)cn1
Temperature: 120 °C
Yield: 48.1 %

Procedure:
A mixture of 2-amino-5-cyanopyrazine (500.0 mg, 4.163 mmol), ethylenediamine (3.0 mL, 44.88 mmol), and phosphorous pentasulfide (185.1 mg, 0.416 mmol) was placed in a sealed tube and heated at 120° C. for 3 h. At this time, the reaction was poured onto ice. The resulting reaction mixture was diluted with chloroform (50 mL), water (10 mL), and a saturated aqueous sodium chloride solution (20 mL). The layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 5-(4,5-dihydro-1H-imidazol-2-yl)-pyrazin-2-ylamine (327.0 mg, 48.1%) as a white solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[NH:30]([C:14]1[N:13]=[C:12]2[N:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10](=[O:29])[N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[CH2:18][C:17]2=[CH:16][N:15]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: Nc1ccccc1
Product: O=C1N(c2c(Cl)cccc2Cl)Cc2cnc(Nc3ccccc3)nc2N1c1ccccc1
Temperature: 180 °C
Yield: 11.3 %

Procedure:
A mixture of 40 mg (0.096 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one and 1 ml (11 mmol) of aniline was heated at 180° C. for 45 minutes, cooled and partitioned between 30 ml of ethyl acetate and 30 ml of 2M hydrochloric acid. The separated organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel using ethyl acetate/hexane (1:2) for the elution. Product-containing fractions were combined and evaporated to give a tan solid which was purified further by HPLC. The mobile phase was water/0.1% trifluoroacetic acid (A) and acetonitrile/0.07% trifluoroacetic acid (B); the gradient was 5%-95% B over 20 minutes; and the product was detected with an ultraviolet detector at a wavelength of 215 nm. The product-containing fraction was lyophilized to give 5 mg (4%) of 7-anilino-3-(2,6-dichlorophenyl)-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 138° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[NH:32]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[C:35]=2[CH:34]=[N:33]1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:36]3[CH:37]=[CH:38][CH:39]=[C:40]4[C:35]=3[CH:34]=[N:33][NH:32]4)[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cccc3[nH]ncc23)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 8.7 %

Procedure:
To a solution of Example 57c (0.350 g, 1.00 mmoles) in DMF (8 ml), ethanol (4 ml) and water (4 ml), 4-Indazoleboronic acid pinacol ester (0.322 g, 1.32 mmoles) and sodium carbonate (0.349 g, 3.3 mmoles) were added and the system is degassed for 30 min. Tetrakis triphenylphosphine Palladium (0.150 g, 0.130 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.045 g, 13% yield). MP: 231-233° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.25(s,1H), 8.10(s,1H), 8.06(m, 2H), 7.86(m,1H), 7.66(t, J=9.0 Hz, 2H), 7.54(m, 2H), 7.33(t, J=6.7 Hz, 2H), 7.11-7.06(m,3H), 6.07(q, J=7.1 Hz, 1H),1.94(d, J=7.0 Hz, 3H). Mass: 517.96(M+).