Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].O1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.O.[CH3:14][CH2:15][CH2:16][CH2:17][CH2:18]CC>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>[CH3:8][CH:9]1[C:18]2[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:11][O:10]1
Reactant: C1COCCO1
Reactant: CCCCCCC
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: O
Product: CC1OCc2ccccc21
Temperature: 135 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
The mixture of sodium 1-(2-bromo-phenyl)-ethoxymethyl trifluoroborate (30 mg, 0.092 mmol) synthesized in Example 20, tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.018 mmol), cesium carbonate (90 mg, 0.28 mmol), 1,4-dioxane (1.0 ml), and water (0.10 ml) was stirred at 135° C. for 90 minutes under microwave irradiation. The reaction mixture was cooled to room temperature, and then water and heptane were added thereto, followed by filtration with Celite. The organic layer of the filtrate was separated and washed with saturated saline. The solvents were evaporated under reduced pressure from the organic layer, and then the obtained residue was purified with silica gel column chromatography (hexane alone→hexane:diethyl ether=30:1), thereby obtaining the entitled compound (35.7 mg, 41%).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[C:13]([NH:18][NH:19][C:20](Cl)=[O:21])([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([NH:8][C:20](=[O:21])[NH:19][NH:18][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: Nc1c(F)c(F)c(F)c(F)c1F
Reactant: CCOC(=O)NNC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)NNC(=O)Nc1c(F)c(F)c(F)c(F)c1F

Procedure:
Pentafluoroaniline (17 g, 0.106 mol) is dissolved in 300 ml of toluene with heating. The 2-carbethoxyhydrazinecarbonyl chloride, 19.4 g (0.122 M) is added to the hot solution. The mixture is refluxed until a white solid precipitates. The solid is filtered to give 24.8 g. The product is crystallized by dissolving in ethyl acetate/toluene (1/2 by vol) and evaporating until crystals appear, mp 180°-182°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([O:1][CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(Cl)n1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)COc1cccc(Cl)n1
Reaction time: 1.5 h
Yield: 87 %

Procedure:
To a stirred mixture of 400 g (3.09 moles) of 2-hydroxy-6-chloropyridine and 450 g (3.26 moles) potassium carbonate in 3000 ml acetonitrile was added 551 g (3.08 moles) 1-bromo-3,3-dimethyl-2-butanone. The reaction mixture was stirred at 45°-50° C. for 1.5 hours and then filtered. The solids were washed several times with acetonitrile, the filtrate dried (MgSO4) and the solvent evaporated. Crystallization of the residue from pentane gave 610 g (87% yield) of 1-(6-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone. A second recrystallization from pentane gave product melting at 43°-44.5° C.
Reaction SMILES: Br([O-])(=O)=[O:2].[Na+].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C.O>[C:6]([OH:2])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [O-][Br+2]([O-])[O-]
Reactant: OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccccc1
Yield: 86.5 %

Procedure:
The separated catalyst was added to a fresh batch of sodium bromate (0.3 g) and benzyl alcohol (0.216 g, 2 mmol) in acetonitrile:water (5:7, 12 ml). The above procedure was repeated to give benzoic acid as a white solid (0.21 g, 87%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:34]([C:35](Cl)=[O:36])=[C:33]([CH3:38])[O:32][N:31]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:34]([C:35]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:36])=[C:33]([CH3:38])[O:32][N:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 523.1 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[NH:21][C:22]([C@@H:24]([NH2:29])[CH2:25][CH2:26][S:27][CH3:28])=[N:23][C:19]=2[CH:18]=1.C(O)(C(F)(F)F)=O>CS(C)=O>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[NH:21][C:22]([C@@H:24]([NH:29][C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:15][CH:14]=3)[CH2:25][CH2:26][S:27][CH3:28])=[N:23][C:19]=2[CH:18]=1
Reactant: CSCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CSCC[C@H](NC(=O)c1ccc(N2CCCC2=O)cc1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 27 from 4-(pyrrolidin-2-on-1-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propylamine, PfTU and TEA in DMSO at ambient temperature and subsequent Boc cleaving with TFA analogously to Example 1g.
Reaction SMILES: Cl[C:2]1[C:3]2[N:26]=[CH:25][CH:24]=[CH:23][C:4]=2[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][C@H:9]2[CH3:22])=[N:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=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>[CH3:22][C@H:9]1[N:8]([C:5]2[C:4]3[CH:23]=[CH:24][CH:25]=[N:26][C:3]=3[C:2]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=3)=[N:7][N:6]=2)[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10]1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2ncccc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [Na+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(C(F)(F)F)cc2)c2ncccc12

Procedure:
Using methods described in Example 6, and starting with (R)-(4-(8-chloropyrido[3,2-d]pyridazin-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone (180 mg, 489 μmol), 2 M sodium carbonate (489 μl, 979 μmol), tetrakis(triphenylphosphine)palladium (28 mg, 24 μmol), and 4-trifluoromethylphenylboronic acid (139 mg, 734 μmol) afforded (R)-(3-methyl-4-(8-(4-(trifluoromethyl)phenyl)pyrido[3,2-d]pyridazin-5-yl)piperazin-1-yl)(phenyl)methanone 86 after chromatographic purification. MS 477.2 (calc'd) 478.1 (M+H, found).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.O=[C:13]([CH2:19][CH3:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C1(C)C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:13]([CH2:19][CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(=CC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Reaction time: 15 h
Yield: 75.8 %

Procedure:
In a 2L-flask were placed 4-trifluoromethylaniline (161 g, 1.00 mol), methyl 3-oxopentanoate (143 g, 1.10 mol) and toluene (640 ml). To this solution was added p-toluenesulfonic acid monohydrate (3.2 g, 0.017 mol), and the resulting mixture was heated in a bath kept at 100° C. under a reduced pressure of 27 kPa, while the water generated was taken out of the reaction system by using a Dean-Stark trap under reflux. After 15 hours, the heating was discontinued, nitrogen leaked in, and the reaction mixture cooled. The solvent was evaporated by means of a rotary-evaporator, and the residue was distilled under reduced pressure to give 207 g of the title compound. The yield was 75.8%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:27][C:25]1[NH:24][N:23]=[C:22]([NH:21][C:13]2[N:12]=[C:11]([O:1][C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[C:5]#[N:6])[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: N#Cc1cccc(O)c1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3cccc(C#N)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-hydroxy-benzonitrile and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give 3-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 342(MH+).
Reaction SMILES: B.C1COCC1.[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12]2[CH:13]3[CH:17]([CH2:18][CH2:19][C:11]=2[CH:10]=1)[C:16](=O)[NH:15][C:14]3=O.[ClH:24]>>[ClH:24].[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12]2[CH:13]3[CH:17]([CH2:18][CH2:19][C:11]=2[CH:10]=1)[CH2:16][NH:15][CH2:14]3
Reactant: COc1ccc2c(c1)CCC1C(=O)NC(=O)C21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC1CNCC21

Procedure:
BH3.THF (1M solution, 52 mL) was added to the compound of example 20 (1.5 g, 6.5 mmole). The reaction mixture was stirred at reflux for 2 hrs., cooled to 0°, and 10 mL 6N HCl added. After 2 hours reflux, solvents were evaporated. CH3CN was added and evaporated several times. The residue was crystallized from MeOH/Et2O to obtain 1.0 g white solid; M+ 203.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:22][CH2:23][C:24]#[N:25]>CN(C)C=O.C(OCC)(=O)C>[CH3:12][C:11]1([CH3:13])[C:8]([CH3:9])([CH3:10])[O:7][B:6]([C:4]2[CH:3]=[N:2][N:1]([CH2:22][CH2:23][C:24]#[N:25])[CH:5]=2)[O:14]1
Reactant: N#CCCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C
Temperature: 90 °C

Procedure:
Pyrazole-4-boronic acid pinacol ester (1 g, 1 equiv, 5.15 mmol) was dissolved in dimethylformamide (15 mL) followed by the addition of Cs2CO3 (0.86 g, 1.5 equiv, 7.73 mmol) and 3-chloropropionitrile (1.1 equiv, 5.67 mmol, 0.44 mL). The mixture was heated at 90° C. overnight. The reaction was diluted with ethyl acetate and washed with water (3×) and brine (3×). The organic phases was concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to return the title compound (0.11 g, 9%). 1H NMR (500 MHz, DMSO): δ 1.26 (12H, s), 3.07 (2H, t), 4.40 (2H, t), 7.65 (1H, s), 8.04 (1H, s). MS m/z 248 (M+H+)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH2:35]O)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>CN(C)C=O.C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:7]=[C:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:14]([O:16][CH2:35][C:27]2[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=[C:25]([C:24]([F:23])([F:37])[F:38])[CH:26]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(C(=O)O)(c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1CCC(C(=O)OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
Oxalyl chloride (4.8 mL, 55 mmol) was added to a solution of 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 2, 6 g, 27 mmol) and dimethylformamide (1 drop) in toluene (150 mL) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and toluene was added. The solvent was evaporated under reduced pressure and the residue was dissolved in toluene (100 mL). 3,5-Bis(trifluoromethyl)benzenemethanol (6.25 g, 26 mmol) and 4-dimethylaminopyridine (3.62 g, 30 mmol) were added and the mixture was heated under reflux for 24 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and hydrochloric acid (2M, 100 mL). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/CH2Cl2 (60:40 increasing to 50:50) to give the title compound (4.5 g, 40%). 1H NMR (360 MHz, CDCl3) δ 2.33-2.53 (6H, m), 2.72-2.77 (2H, m), 5.23 (2H, s), 7.28-7.41 (5H, m), 7.51 (2H, s), and 7.77 (1H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:9]([Cl:10])=[C:8](Cl)[S:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2].C(N(CC)CC)C.[H][H]>[Pd].CO>[C:1]([NH:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)c1sc(Cl)c(Cl)c1NC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1scc(Cl)c1NC(C)=O

Procedure:
A mixture of 25 g of methyl 3-acetylamino-4,5-dichlorothiophene-2-carboxylate, about 10 g of triethylamine, 300 ml of methanol and 1 g of palladium on carbon is, at room temperature and under atmospheric pressure, hydrogenated until the uptake of hydrogen has stopped. The catalyst is filtered off and the mixture is then concentrated by distillation under reduced pressure until crystallization begins, water is then added and the solid is filtered off. Colorless crystals from isopropanol. M.p. 142-147° C.
Reaction SMILES: [I:1]I.[C:3]([O:7][C:8](=[O:20])[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[O:18][CH3:19])([CH3:6])([CH3:5])[CH3:4]>C(Cl)Cl>[C:3]([O:7][C:8](=[O:20])[NH:9][CH2:10][C:11]1[CH:16]=[C:15]([I:1])[C:14]([NH2:17])=[CH:13][C:12]=1[O:18][CH3:19])([CH3:6])([CH3:5])[CH3:4]
Reactant: II
Reactant: COc1cc(N)ccc1CNC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COc1cc(N)c(I)cc1CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a suspension of iodine and AgNO2 in methylene chloride was added a solution of (4-amino-2-methoxy-benzyl)-carbamic acid tert-butyl ester (1.3 g, 5.15 mmol) in methylene chloride at 0° C., and the mixture was stirred for 30 min at 0° C. and more stirred for 30 min at ambient temperature. The reaction was quenched with Na2S2O3. The reaction solution was extracted with methylenechloride, washed with water and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (hexane/ethylacetate=2/1) to yield (4-amino-5-iodo-2-methoxy-benzyl)-carbamic acid tert-butyl ester (925 mg, 47%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7](I)=[N:6]1.[Cu][C:20]#[N:21]>CS(C)=O>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:20]#[N:21])=[N:6]1
Reactant: N#C[Cu]
Reactant: Fc1ccccc1Cn1nc(I)c2cncnc21
Solvent: CS(C)=O
Product: N#Cc1nn(Cc2ccccc2F)c2ncncc12
Temperature: 150 °C

Procedure:
950 mg (purity 85%, approx. 2.281 mmol) of 1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 225 mg (2.509 mmol) of copper(I) cyanide were initially charged in 6 ml of absolute DMSO and the mixture was heated at 150° C. for 2 h. After cooling, the mixture was filtered through Celite and washed through with ethyl acetate and THF. The organic phase was washed with 25% aqueous ammonia solution, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. 685 mg (purity 84%, 99% of theory) of the target compound were obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[CH:15]=[C:14]3[C:19]([CH2:20][CH2:21][C:12]([C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][N:29]5[CH2:34][CH2:33][S:32][CH2:31][CH2:30]5)=[CH:8][CH:7]=4)=[O:11])=[CH:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: C1CSCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCSCC4)cc2)CC3)cc1
Temperature: 25 °C

Procedure:
In THF (10 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (300 mg), and to the mixture was added thiomorpholine (233 μl). The mixture was refluxed for 20 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 7—(4-methylphenyl)-N-[4—(thiomorpholinomethyl)phenyl]-3,4-dihydro-naphthalene-2-carboxamide (Compound 50) (309 mg) as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[N:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:19].O1CCOCC1>C(Cl)Cl>[ClH:19].[ClH:19].[Br:17][C:14]1[CH:15]=[N:16][C:11]([C:8]2([NH2:7])[CH2:9][CH2:10]2)=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ncc(Br)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(c2ncc(Br)cn2)CC1
Reaction time: 2 h

Procedure:
[1-(5-Bromo-pyrimidin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (1.18 g, 3.76 mmol) was dissolved in CH2Cl2 (5 mL) at room temperature. 4M HCl in dioxane (9.4 mL, 37.6 mmol) was added. After 2 h, the solvents were removed by a stream of N2 to give the title compound as a solid, m/z=216.3. The crude material was used without purification in subsequent steps.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH:13]=[C:12]([OH:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([O:17][C:12]1[CH2:11][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:15][C:14](=[O:16])[CH:13]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)=CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1=CC(=O)OC(CO[Si](C)(C)C(C)(C)C)C1

Procedure:
To 6-t-butyldimethylsilyloxymethyl-5,6-dihydro-4-hydroxy-pyran-2-one (0.26 parts) in dichloromethane (3 cm3) at ambient temperature was added pyridine (0.1 parts) and then acetyl chloride (0.1 parts). After approximately 30 minutes at ambient temperature the reaction mixture was washed with water, dried over MgSO4 and evaporated to yield 4-acetoxy-6-t-butyldimethylsilyloxymethyl-5,6-dihydropyran-2-one (0.2 parts).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([O:12]C)=[O:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: O=C1CCCC1Cl
Reactant: COC(=O)C(C)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(OC2CCCC2=O)cc1F
Yield: 32 %

Procedure:
To a solution of compound (8) obtained above (0.87 g, 4.4 mmol) in dry DMF (8.7 mL), potassium carbonate and chlorocyclopentanone (0.53 mL, 5.3 mmol) were added, and the obtained mixture was heated to reflux for 3 hours. After the reaction, the mixture was filtered and the obtained filtrate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (7:1) solution followed by conventional hydrolysis to give 0.28 g (32%) of compound (12) of interest as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:17](=[O:19])[CH3:18])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(=O)Cl
Reactant: Nc1cnc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5,6-dichloropyridin-3-amine (commercially available) and triethyl amine (3 eq) in CH2Cl2 (0.2 M) at 0° C. was added acetyl chloride (2 eq). After stirring at room temperature overnight the reaction mixture was concentrated under vacuum and the resulting crude residue was purified by chromatography (silica gel, 20-50% EtOAc in hexanes) to afford N-(5,6-dichloropyridin-3-yl)acetamide.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:23])[CH:21]=[CH2:22].O[C:25]1[NH:29][N:28]=[C:27]([N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[CH:26]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C>[CH2:20]([O:23][C:25]1[NH:29][N:28]=[C:27]([N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[CH:26]=1)[CH:21]=[CH2:22]
Reactant: O=C1c2ccccc2C(=O)N1c1cc(O)[nH]n1
Reactant: C=CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCOc1cc(N2C(=O)c3ccccc3C2=O)n[nH]1

Procedure:
To a mixture of triphenylphosphine (2.75 g, 10.5 mmol), allyl alcohol (0.714 ml, 10.5 mmol), and 2-(5-hydroxy-1H-pyrazol-3-yl)isoindoline-1,3-dione (2.000 g, 8.73 mmol) in DMF (25 mL) at RT was slowly added DIAD (2.04 ml, 10.5 mmol). After 18 hrs the solution was concentrated in vacuo, diluted with EtOAc, and washed with water and brine. The organic fraction was dried with sodium sulfate, concentrated in vacuo, and purified by silica gel chromatography using 40-70% Hexanes:EtOAc to afford 2-(5-(allyloxy)-1H-pyrazol-3-yl)isoindoline-1,3-dione as a light yellow solid. MH+=270.1. Step 2B: To a mixture of 2-(5-(allyloxy)-1H-pyrazol-3-yl)isoindoline-1,3-dione (0.684 g, 2.54 mmol) in EtOH (10 mL) at RT was added anhydrous hydrazine (0.319 ml, 10.2 mmol). The solution was heated at 50° C. for 18 hrs before cooling to 0° C. The resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo to afford crude 5-(allyloxy)-1H-pyrazol-3-amine that was advanced without further purification. MS: Found M+H+=147.2.