Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)[CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([C:28]([O:30]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[NH:25][C:26]=1[CH3:27]>>[Br:21][C:22]1[CH:23]=[C:24]([C:28]([N:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]3[CH:5]=[C:4]([C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH:3]=[C:2]([Cl:1])[N:7]=3)[CH2:13][CH2:12]2)[CH3:15])=[O:30])[NH:25][C:26]=1[CH3:27]
Reactant: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Reactant: CNC1CCN(c2cc(-c3nnn[nH]3)cc(Cl)n2)CC1
Product: Cc1[nH]c(C(=O)N(C)C2CCN(c3cc(-c4nnn[nH]4)cc(Cl)n3)CC2)cc1Br

Procedure:
The title compound was synthesised by an analogous method to Example 18 starting from 1-[6-chloro-4-(1H-tetrazol-5-yl)pyridin-2-yl]-N-methylpiperidin-4-amine (Intermediate 64) and pentafluorophenyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 17).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.C[N:36](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:36])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Reactant: O=C(O)c1sc(-n2cnc3ccc(CCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(CCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a mixture of 0.050 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-morpholin-4-yl-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid (I.41 g), 1 mL of dimethylformamide and 0.0418 g (0.11 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) was added 0.016 g (0.3 mmole) of ammonium chloride and 0.052 mL (0.3 mmole) of ethyldiisopropylamine. The mixture was stirred at ambient temperature for 1 hour. The solid was removed by filtration and the filtrate was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 20:80-100:0) to give 0.032 g of 4-(3-chloro-phenyl)-2-[6-(4-morpholin-4-yl-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.41) as a white powder. MH+/Z=496
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:12]4[CH2:13][C:14]5[S:15][CH:16]=[CH:17][C:18]=5[C:11]=4[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=3)=[CH:4][CH:3]=2)=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Reactant: COc1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sccc3-4)cc2)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.45 g, 1.0 mmol), 4-Methoxy-phenylamine (0.31 g, 2.5 mmol), Cs2CO3 (2 M, 3.0 mL), Xantphos (58 mg, 0.1 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) in dioxane (5 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give (4-Methoxy-phenyl)-{4-[4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-amine as brown solid in 60% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic ethyl ester (4.7 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3 g (67%); white solid; mp 182° C.; MS: 446 (M+H)+
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[N:14]([C@H:15]([CH2:19][OH:20])[C@@H:16]([OH:18])[CH3:17])[CH:13]=[N:12][C:11]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[OH:18][C@@H:16]([CH3:17])[C@H:15]([N:14]1[CH:10]=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:12]=[CH:13]1)[CH2:19][OH:20]
Reactant: CCOC(=O)c1ncn([C@H](CO)[C@H](C)O)c1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn([C@H](CO)[C@H](C)O)cn1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
To a refluxing solution of isoamyl nitrite (1.5 mL) in tetrahydrofuran (4.6 mL) was added a solution of ethyl 5-amino-1-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)propyl]-1H-imidazole-4-carboxylate (0.92 g) in tetrahydrofuran (23 mL) dropwise over 45 minutes, and the mixture was refluxed for 75 minutes. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; 10:1 to 5:1 chloroform-1% ammonium hydroxide/methanol) to give ethyl 1-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)propyl]-1H-imidazole-4-carboxylate (0.50 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)(=O)=O.[CH3:39][NH:40][CH3:41].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][CH2:6][N:40]([CH3:41])[CH3:39])[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:36])[C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=3)[C:11]=12
Reactant: CNC
Reactant: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2nn(CCN(C)C)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 70 °C
Yield: 13.3 %

Procedure:
A mixture of 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate (Intermediate 4) (0.080 g, 0.15 mmol), dimethylamine (2.0 M in THF, 0.07 mL, 0.15 mmol), triethylamine (0.021 mL, 0.15 mmol), and sodium iodide (0.021 g, 0.15 mmol) in DMF (2.5 mL) was heated in a resealable tube at 70° C. for 15 h. Additional dimethylamine solution (0.10 mL) was added and the reaction mixture was heated at 70° C. for 20 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Water (5 mL) was added and the resulting precipitate was collected by filtration and purified by silica gel column chromatography (elution with 20% MeOH:CH2Cl2 to 10:30:60 Et3N:MeOH:CH2Cl2); the appropriate fractions were combined and concentrated to afford N2-(4-{4-amino-1-[2-(dimethylamino)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide as a white solid (0.009 g, 0.02 mmol). RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.52. MS: M+485.2.
Reaction SMILES: [S-:1][C:2]#N.[K+].[CH2:5]([O:12][C:13]1[C:22]2[CH2:21][CH:20]3OC3[CH2:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([O:12][C:13]1[C:22]2[CH2:21][CH:20]3[S:1][CH:2]3[CH2:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(COc2cccc3c2CC2OC2C3)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(COc2cccc3c2CC2SC2C3)cc1
Reaction time: 48 h

Procedure:
To 0.125 mole of potassium thiocyanate in 20 ml. of 50% ethanol is added 0.10 mole of 6,7-epoxy-5,6,7,8-tetrahydro-1-naphthyl benzyl ether and the mixture stirred vigorously for 48 hours. The product is extracted into ether, washed with salt solution, dried and freed of solvent. Ref: O.S. IV 232.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:16][CH:14]([CH2:15]2)[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]3=[O:23])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:15][CH:14]([CH2:16]2)[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]3=[O:23])=[CH:8][CH:9]=1
Reactant: CCCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1, 2.58 g of 1-(4-nitrophenyl)-3-n-pentyl-3-azabicyclo[3.1.1]heptane-2,4-dione in 75 ml of ethanol are hydrogenated in the presence of 0.15 g of palladium-on-carbon and worked up. Melting point 92°-94° (from ethyl acetate/petroleum ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
To a stirred suspension of 4-chlorophenylacetic acid (85.3 g) in 500 ml of toluene, 45 ml of thionyl chloride (74.4 g) are added. The resulting mixture is stirred at RT, heated slowly to boiling, and stirred overnight under reflux. After cooling the reaction mixture to RT, the solvent is evaporated in vacuo. Distillation of the residue affords 38.15 g of a red liquid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[O:24][CH3:25].C(N(CC)CC)C.[C:33](Cl)(Cl)=[S:34].O>C(Cl)Cl>[CH3:25][O:24][C:15]1[CH:16]=[CH:17][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]=1[N:13]1[C:4]2[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=2[NH:2][C:33]1=[S:34]
Reactant: COc1ccc(C(F)(F)F)cc1Nc1ccc(C(F)(F)F)cc1N
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1-n1c(=S)[nH]c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled suspension of N-(2-amino-4-trifluoromethylphenyl)-2-methoxy-5-trifluoromethylaniline, hydrochloride (3 mmol, 1.2 g) in dry methylenechloride (20 ml) is added triethylamine (9 mmol, 0.73 ml) and thiophosgene (3 mmol, 0.23 ml). The reaction mixture is stirred at room temperature overnight and poured into water. The mixture is extracted with methylenechloride and the organic phases are dried and concentrated in vacuo. The crude product is subjected to column chromatography using petroleum ether+ethylacetate (4+1) as eluent. The fractions containing the product are concentrated in vacuo yielding a yellow oil which solidifies upon treatment with petroleum ether, yielding the title compound as off white crystals, which were used without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=2)[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CN(C=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:27]=[N:26][NH:25][CH:24]=4)=[C:2]([C:45]4[CH:44]=[CH:43][CH:42]=[C:41]([N:38]5[CH2:37][CH2:36][O:35][CH2:40][CH2:39]5)[CH:46]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cnn(C(=O)OC(C)(C)C)c3)sc2n1
Reactant: OB(O)c1cccc(N2CCOCC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N4CCOCC4)c3)c(-c3cn[nH]c3)sc2n1
Temperature: 120 °C

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Description 75) (100 mg, 0.171 mmol), 3-(morpholino)phenylboronic acid, pinacol ester (99 mg, 0.343 mmol), tetrakis(triphenylphosphine)palladium(0) (19.79 mg, 0.017 mmol), bis(triphenylphosphine)palladium(II) chloride (12.02 mg, 0.017 mmol) and potassium carbonate (71.0 mg, 0.514 mmol) were weighed into a microwave vial. 1,4-Dioxane (1.5 mL), DMF (0.75 mL) and water (0.38 mL) were added and the mixture heated in a microwave at 120° C. for 15 min. At this point, the five reaction mixtures were combined and concentrated. The residue was passed through an SCX cartridge, eluting with MeOH (150 mL) and then 2M NH3 in MeOH (200 mL). The basic methanolic solution was concentrated and the residue was purified by MDAP (acidic conditions), to give the title compound (115 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([C:17](Cl)=[O:18])[CH:12]=1.[CH3:20][NH:21][O:22][CH3:23]>C(Cl)Cl>[CH3:23][O:22][N:21]([CH3:20])[C:17]([C:13]1[CH:12]=[C:11]([Cl:10])[N:16]=[CH:15][N:14]=1)=[O:18]
Reactant: CNOC
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20.7 mL (0.120 mol) DIPEA were added at 0° C. to 10.7 g (54.4 mmol) 6-chloropyrimidine-4-carboxylic acid chloride and 5.50 g (56.4 mmol) N,O-dimethylhydroxylamine in 150 mL DCM and stirred for 1 h at 0° C. and 1 h at RT. The mixture was diluted with DCM and washed with water. The organic phase was dried on sodium sulphate, filtered and evaporated down.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH2:12](OC1C(=CC=CC=1)C=O)[CH:13]1[O:15][CH2:14]1.C(=O)C1C(=CC=CC=1)O>>[CH2:12]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH:13]1[O:15][CH2:14]1
Reactant: O=Cc1ccccc1OCC1CO1
Reactant: COc1cc(C=O)ccc1O
Solvent: O=Cc1ccccc1O
Product: COc1cc(C=O)ccc1OCC1CO1
Yield: 96 %

Procedure:
Vanillin glycidyl ether (3-methoxy-4-glycidyloxybenzaldehyde) was prepared in a similar manner to Method A, but starting from vanillin in place of p-hydroxybenzaldehyde. The yield was 96% of theory, the product having an epoxide content of 4.41 equivalents/kg (theoretical value 4.8 equivalents/kg). A sample was recrystallised from ethanol, giving 95% recovery of product having an epoxide content of 4.76 equivalents/kg, melting point 101° C. Salicylaldehyde glycidyl ether (o-glycidyloxybenzaldehyde) may be prepared in a like manner from salicylaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH:5]=[N:6][CH:7]=1
Reactant: OCc1cncc(Br)c1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)COCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of (5-Bromo-pyridin-3-yl)-methanol (600 mg, 3.2 mmol) in THF (50 mL) is added 60% NaH (160 mg, 3.9 mmol) at 0° C. under N2 atmosphere. The mixture is stirred at room temperature for 1 hour. Then 2-chloro-N,N-dimethyl-acetamide (420 mg, 3.5 mmol) is added into the mixture at 0° C. After addition, the mixture is stirred at room temperature for 16 hrs. After quenching with saturated NH4Cl aqueous solution, the mixture is extracted with EtOAc for three times. The organic layers are combined, dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative TLC to give 700 mg of 2-(5-bromo-pyridin-3-ylmethoxy)-N,N-dimethyl-acetamide.
Reaction SMILES: [CH:1]([N:4]([CH:27]([CH3:29])[CH3:28])[C:5](=O)[CH2:6][CH:7]([C:14]1[CH:19]=[C:18]([C:20](OC)=[O:21])[CH:17]=[CH:16][C:15]=1[O:24]C)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[Cl-].[Al+3].[Cl-].[Cl-]>O1CCCC1>[CH:27]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[CH:16][C:15]=1[OH:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc(OC)c(C(CC(=O)N(C(C)C)C(C)C)c2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)N(CCC(c1ccccc1)c1cc(CO)ccc1O)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (±)-N,N-diisopropyl-3-(2-methoxy-5-methoxycarbonylphenyl)-3-phenylpropionamide (0.79 g, 2.0 mmol) in 20 ml of tetrahydrofuran was cooled to 5° C. and then treated with 2.5 ml of 1M LiAlH4/THF. After stirring at room temperature for 18 hrs. finely powdered aluminium chloride (0.3 g) was added and stirring was continued for additional 4 hrs. The reaction was quenched at 5° C. by the dropwise addition of water followed by aqueous sodium hydroxide solution. The mixture was diluted with diethyl ether (150 ml) and the organic phase was washed with half saturated brine, dried (sodium sulphate), and evaporated to dryness to give the title compound as a solid off-white foam. Tlc (2) 0.16, m.p. 48-51° C. A portion of the material was converted into the hydrochloride (ethereal hydrochloric acid), m.p. 186-189° C. (dec.).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10](=[O:13])[O:11][CH:12]=1)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:6]([C:7]1[CH:8]=[CH:9][C:10](=[O:13])[O:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(=O)oc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#Cc1ccc(=O)oc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of 5-[(trimethylsilyl)ethynyl]-2H-pyran-2-one (0.5 g, 2.6 mmol) and acetic acid (0.6 g, 10 mmol) in THF (50 mL) at 0° C. was added dropwise over 10 min tetrabutylammonium fluoride. The mixture was stirred for 1 h at 0° C. then was partitioned between sat. NaHCO3 and ether. The organic phase was washed with brine then dried (MgSO4). The solvent was passed through a plug of silica gel and then evaporated to give the title compound (0.30 g, 96%) as an off white solid; mp 99-100° C. 1H NMR (CDCl3 , 300 MHz): δ 7.73 (dd, 1H), 7.33 (dd, 1H), 6.32 (dd, 1H), 3.11 (s, 1H). 13C NMR (CDCl3 , 300 MHz) 159.4; 155.7; 144.6; 116.1; 103.3; 80.7; 75.7. Anal. Calc'd for C7H4O2: C, 70.00; H 3.36. Found: C, 70.09; H, 3.47.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[NH:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[O:15][CH3:16])[CH3:2].O=P(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[Cl:19][C:8]1[C:7]2[C:12](=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[C:5]([O:15][CH3:16])[CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc2nc[nH]c(=O)c2cc1OC
Solvent: Cc1ccccc1
Product: CCOc1cc2ncnc(Cl)c2cc1OC
Yield: 96 %

Procedure:
A mixture of 7-ethoxy-6-methoxyquinazolin-4(3H)-one (1.20 g, 5.45 mmol) and POCl3 (3 mL), in toluene (10 mL) was heated at 125° C. for 5 hours. It was concentrated under reduced pressure to dryness. To it was added CH2Cl2 and it was washed with saturated NaHCO3. The organic layer was dried over MgSO4 and concentrated to give 4-chloro-7-ethoxy-6-methoxyquinazoline as solid (1.254 g, 96%). 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 4.34 (q, 2H), 4.08 (s, 3H), 1.59 (t, 3H).
Reaction SMILES: [CH3:1][N:2](C=O)C.[OH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1I.CCN(C(C)C)C(C)C.CN.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:7]=1[OH:6])[C:11]([O:13][CH3:14])=[O:12])#[N:2]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(O)c(C#N)c1
Reaction time: 14 h
Yield: 144.6 %

Procedure:
To a solution of 1 in DMF (158 mg, 0.41 mmol) were added amino acid 2 (100 mg, 0.52 mmol) and DIEA (272 μL, 0.16 mmol). The reaction was stirred for 14 h. Methylamine (2 M in THF, 0.4 mL) and HBTU (295 mg, 0.78 mmol) were then added. The reaction mixture was stirred for 5 h. The product was purified by RP-HPLC using a mixture of acetonitrile and H2O to give 3 (105 mg, 63%). LRMS (M+H+) m/z 401.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2=[CH:6]OC=[C:4]2[C:3]=1I.C([Sn](CCCC)(CCCC)CCCC)C=C.[Li+].[Cl-].[CH3:30][CH2:31][O:32][C:33]([CH3:35])=[O:34]>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[CH:3]=[CH:4][C:35]2[C:33](=[O:34])[O:32][CH2:31][C:30]=2[C:10]=1[CH2:9][CH:5]=[CH2:6]
Reactant: CCOC(C)=O
Reactant: Brc1ccc2cocc2c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C=CCc1c(Br)ccc2c1COC2=O
Temperature: 95 °C

Procedure:
A mixture of 5-bromo-4-iodo-2-benzofuran-[(3H]-one (2.42 g, 7.13 mmol), allyltributyltin (2.36 g, 7.13 mmol), LiCl (1.50 g, 35.7 mmol) and Pd (PPh3)4 (200 g, 0.173 mmol) in toluene (50 mL) was heated at 90-100° C. under N2 overnight; LC indicated that reaction had gone to completion, to the solution was poured EtOAc (100 mL) and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated to dryness, absorbed into silica gel and was then separated over silica gel column to give the title compound.