Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]=O.Cl.[C:13]([NH:16][C:17]([CH2:38][CH2:39][CH2:40][NH2:41])([CH2:25][CH2:26][CH2:27][CH2:28][B:29]1[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]1)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=[O:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:13]([NH:16][C:17]([CH2:38][CH2:39][CH2:40][NH:41][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([CH2:25][CH2:26][CH2:27][CH2:28][B:29]1[O:30][C:31]([CH3:37])([CH3:36])[C:32]([CH3:35])([CH3:34])[O:33]1)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=[O:15])[CH3:14]
Reactant: O=CCc1ccc(Cl)cc1Cl
Reactant: CC(=O)NC(CCCN)(CCCCB1OC(C)(C)C(C)(C)O1)C(=O)NC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(CCCNCCc1ccc(Cl)cc1Cl)C(=O)NC(C)(C)C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
A solution of (2,4-dichlorophenyl)acetaldehyde (0.8 mmol) and 2-acetamido-2-(3-aminopropyl)-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide hydrochloride (260 mg, 0.58 mmol) in dichloromethane (5 mL) was stirred at room temperature. After 30 min, sodium triacetoxyborohydride (310 mg, 1.45 mmol) was added in one portion and stirring was continued overnight. Once complete, the solution was diluted with dichloromethane (10 mL), quenched with aq 5% NaHCO3 (W/V, 5 mL) and stirred vigorously for 30 min. The layers were separated and the organic phase was washed with water and sat'd aq sodium chloride, dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (1-20% methanol in dichloromethane) gave 2-acetamido-N-tert-butyl-2-(3-(2,4-dichlorophenethylamino)propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (140 mg, 47%). ESI MS found for C29H48BCl2N3O4 m/z [584.6/586.6 (M+1)].
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH2:9][CH2:10][CH3:11])[CH:8]=1)[CH2:2][CH3:3].[CH2:17]=O>>[CH2:1]([C:4]1[NH:5][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH2:9][CH2:10][CH3:11])[C:8]=1[CH3:17])[CH2:2][CH3:3]
Reactant: CCCc1cc(CCC)c(C(=O)OCC)[nH]1
Reactant: C=O
Product: CCCc1[nH]c(C(=O)OCC)c(CCC)c1C

Procedure:
The crude product, obtained as in Example 74 but using 2,4-di-n-propyl-5-carbethoxypyrrole and paraformaldehyde, was extracted with ether then sublimed (65° C. 1 × 10-4 mm), m.p. 78°-80° C. (17%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:16][CH3:17])[C:5]2[N:6]([CH:8]=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH:7]=1.[NH3:18]>>[Br:1][C:2]1[N:3]=[C:4]([NH:16][CH3:17])[C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH2:18])=[O:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cn2cc(Br)nc(NC)c2n1
Reactant: N
Product: CNc1nc(Br)cn2cc(C(N)=O)nc12
Yield: 40 %

Procedure:
A suspension of 0.470 g (1.57 mmol) of ethyl 6-bromo-8-methylaminoimidazo[1,2-a]pyrazine-2-carboxylate, obtained according to the process described in Example 3, in 50 ml of concentrated aqueous ammonia solution, is brought to reflux for 4 hours. After the mixture is cooled, the precipitate is drained, washed and dried. 0.160 g (Yld=40%) of 6-bromo-8-methylaminoimidazo[1,2-a]pyrazine-2-carboxamide (m.p. 312° C.) is obtained.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:49][C:50]([C:52]1[C:53]2[CH:54]=[CH:55][N:56]=[CH:57][C:58]=2[CH:59]=[CH:60][CH:61]=1)=[NH:51]>CN(C)C=O>[CH3:4][C:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]2[O:12][N:51]=[C:50]([C:52]3[CH:61]=[CH:60][CH:59]=[C:58]4[C:53]=3[CH:54]=[CH:55][N:56]=[CH:57]4)[N:49]=2)=[CH:13][CH:14]=1)([CH3:1])[CH3:3]
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
A mixture of 4-[(1,1-dimethylethyl)oxy]benzoic acid (Apin chemicals) (117 mg, 0.603 mmol), HATU (232 mg, 0.610 mmol), Hunig's base (0.263 mL, 1.506 mmol) in N,N-Dimethylformamide (DMF) (1 ml) was stirred for 1 hr before the addition of N-hydroxy-5-isoquinolinecarboximidamide (D1; 94 mg, 0.502 mmol) in N,N-dimethylformamide (DMF) (1 ml). The reaction was left to stir at room temperature for 2 hrs and then heated to 120° C. for 2 hr in the microwave. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Waters Sunfire C18 column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN+0.1% Formic acid)) to give the title compound (31.5 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([C:10]([CH3:12])=O)=[CH2:9]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:12][C:10]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[CH:9][CH:8]=1
Reactant: Nc1ccccc1
Reactant: C=CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1ccnc2ccccc12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
To a stirred solution of aniline (1 g. 10 mmol) in acetic acid (10 ml), activated silferc (1.72 g. ferric chloride 10 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.83 g, 11.8 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.46 g. 10 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 55%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([OH:25])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[C:19](=[O:26])[NH:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[Sn](CCCC)(CCCC)CCCC)[CH3:31].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([OH:25])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[C:19](=[O:26])[NH:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH3:31]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1[nH]c(=O)c1occc12
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c([nH]c(=O)c3occc32)c1C(=O)O
Temperature: 80 °C
Yield: 30.6 %

Procedure:
A mixture of 7-(2-bromo-4-fluorobenzenesulfonylamino)-4-oxo-4,5-dihydrofuro[2,3-c]quinoline-6-carboxylic acid (Intermediate 86, 0.190 g), N,N-diethyl-N-((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.476 g), tris-(dibenzylideneacetone)dipalladium (0.043 g) and tri-tert-butylphosphonium tetrafluoroborate (0.023 g) in dioxane (5 mL) was heated under argon to 80° C. in a sealed vessel for 1 hour. The hot reaction mixture was filtered through Celite and washed with dioxane, ethyl acetate and acetonitrile. The filtrate was concentrated in vacuo and the residue was triturated with water and acetonitrile and then acetone. The solid was collected by filtration, dissolved in DMSO and filtered. The filtrate was purified by HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 25-75% acetonitrile, to give 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4-oxo-4,5-dihydrofuro[2,3-c]quinoline-6-carboxylic acid (0.062 g).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Cl:11][C:12]1[CH:13]=[C:14]([F:19])[C:15](F)=[N:16][CH:17]=1.Cl>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([F:19])[C:15]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:16][CH:17]=1
Reactant: Oc1ccc(O)cc1
Reactant: Fc1cc(Cl)cnc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
A mixture of 27.5 g (0.25 mol) of hydroquinone, 11.2 g (0.2 mol) of potassium hydroxide in 600 ml of dimethylsulfoxide is stirred at room temperature under a nitrogen atmosphere until everything is dissolved. A solution of 30 g (0.2 mol) of 5-chloro-2,3-difluoropyridine in 200 ml of dimethylsulfoxide is added dropwise thereto. The reaction mixture is then heated to 70° and stirred at that temperature for 4 hours. Then it is poured into ice/water and the mixture is acidified with hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated to dryness. The residue is taken up in a hexane/ethyl acetate 2:1 solvent and passed over a silicagel column for purification. After concentrating the eluate, the residue crystallizes to yield 33 g of white crystals, melting at 97°-98°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[O:26]1[CH2:31][CH2:30][CH:29]([O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[CH:15]=[CH:16][C:17]([C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])=[CH:18][CH:19]=4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:28][CH2:27]1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccc(O)cc3)CC2)cc1
Reactant: OC1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccc(OC4CCOCC4)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
34 mg (0.10 mmol) (S)—N-{1-(4-[1-(4-Hydroxyphenyl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound 1.48), 15 mg (0.15 mmol) tetrahydro-4H-pyran-4-ol and 39 mg (0.15 mmol) triphenylphosphine on solid support are suspended in 2 mL anhydrous THF at 0° C. 35 mg (0.15 mmol) di-tert-Butyl azodicarboxylate are added and the mixture is allowed to warm to rt. Stirring is continued over night followed by addition of 0.5 equivalents of triphenylphosphine on solid support and 0.5 equivalents of di-tert-butyl azodicarboxylate. After stirring for 2 h at rt, the mixture is filtered over basic aluminum oxide and washed with DMF/MeOH (9:1). After evaporation the residue is purified using reversed phase HPLC (water/MeOH, 0.1% TFA) to yield the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.BrCC1CCCCO1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2([C:42]3[C:33](=[CH:34][C:35]4[O:40][CH2:39][CH2:38][O:37][C:36]=4[CH:41]=3)[O:32][CH2:31]2)[C:23]1=[O:43]>>[O:13]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]4([C:42]5[C:33](=[CH:34][C:35]6[O:40][CH2:39][CH2:38][O:37][C:36]=6[CH:41]=5)[O:32][CH2:31]4)[C:23]3=[O:43])=[CH:4][CH:5]=2)=[CH:10][CH:11]=[N:12]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: BrCc1ccc(-c2ccno2)cc1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(-c3ccno3)cc2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-(4-(bromomethyl)phenyl)isoxazole (0.20 g, 0.84 mmol) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(4-isoxazol-5-ylbenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (70%) as a colorless solid: mp 209-212° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ8.28-8.25 (m, 1H), 7.77 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.23-7.13 (m, 2H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.52-6.47 (m, 2H), 6.22 (s, 1H), 5.11 (d, J=15.8 Hz, 1H), 4.94 (d, J=8.9 Hz, 1H), 4.84 (d, J=15.8 Hz, 1H), 4.66 (d, J=8.9 Hz, 1H), 4.22-4.08 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.6, 168.8, 155.3, 150.9, 144.7, 141.9, 138.4, 138.0, 132.2, 128.9, 128.0, 126.9, 126.5, 126.2, 124.1, 123.6, 120.9, 111.5, 109.2, 99.5, 98.9, 80.2, 64.5, 64.0, 58.1, 43.9, 29.7; MS (ES+) m/z 453.0 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=1>[Pd]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]1
Reactant: COCOc1ccc(C2=CC(=O)CC2)c(OCOC)c1
Agent: [Pd]
Product: COCOc1ccc(C2CCC(=O)C2)c(OCOC)c1
Yield: 15.9 %

Procedure:
3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclopenten-1-one (50 mg) and palladium (10 mg, 10% on carbon) were stirred under an atmosphere of hydrogen for 15 hr. The mixture was then filtered through a plug of Celite, washing with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as a colourless oil (8 mg, 16%); m/z (ES+) 583 (2M+Na)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][C:31](Br)=[CH:30][CH:29]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38](C=O)C>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.[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][C:31]([C:37]#[N:38])=[CH:30][CH:29]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5cc(Br)ccc5cn4)c3)cn2)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5cc(C#N)ccc5cn4)c3)cn2)CC1

Procedure:
Following the General Procedure for Conversion of Bromo(het)aryl to Cyano(het)aryl, 4-{4-[6-amino-5-(6-bromoisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (220 mg, 0.240 mmol) was reacted with Pd(PPh3)4 (38.9 mg, 0.0336 mmol) and zinc cyanide (28.2 mg, 0.240 mmol) in DMF (6 ml). The crude product was purified by chromatography on silica gel (8 g) eluting with DCM (100 ml), 1% (100 ml), 2% (100 ml), 3% (100 ml) and 4% (50 ml) MeOH/DCM to give the title compound as a yellow solid. MS(ES+): m/z=496.22 (100) [MH+]. HPLC: tR=2.82 min (ZQ3, polar—5 min).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24]O>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: COc1cc(C)ccc1CO
Product: COc1cc(C)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-methoxy-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.37 (3H, s), 3.89 (3H, s), 5.23 (2H, s), 5.80 (1H, d, J=2.0 Hz), 6.76-6.79 (2H, m), 7.24-7.26 (1H, m), 7.37 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d, J=1.6 Hz), 8.08 (1H, s), 8.70 (1H, d, J=4.4 Hz). [M+H] Calc'd for C18H16N4O2, 321. Found, 321.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][CH2:18]1.[F:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[N:17]2[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:26])[CH3:27])[CH3:24])[CH2:19][CH2:18]2)=[CH:3][C:2]([C:33]2[CH:34]=[C:29]([F:28])[C:30]([OH:45])=[C:31]([F:44])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(F)c2)OC1(C)C
Reactant: CC(C1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1)N(C)C
Product: CC(C1CCN(c2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(F)c4)cc23)CC1)N(C)C
Yield: 45 %

Procedure:
Following general procedure F, (6-bromo-4-{4-[1-(dimethylamino)ethyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (60 mg, 0.139 mmol) was reacted with 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (39 mg, 0.153 mmol) to afford the desired product (30 mg, 44%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 8.82 (s, 1H), 8.26 (s, 1H), 8.03 (p, J=8.8 Hz, 2H), 7.35 (dd, J=8.0, 1.7 Hz, 2H), 3.56 (t, J=10.3 Hz, 2H), 3.26-3.17 (m, 3H), 2.80 (s, 6H), 2.66-2.53 (m, 1H), 1.96 (d, J=11.2 Hz, 3H), 1.87-1.68 (m, 2H), 1.37-1.22 (m, 8H); ESI MS m/z 480 [C28H31F2N3O2+H]+; HPLC 98.6% (AUC), tR=10.24 min.
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:13]2)C1)=O)(C)(C)C.[CH3:33][C@H:34]1CN[CH2:37][C@@H:36](C)[NH:35]1>>[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:24]2[N:25]=[C:17]([CH2:16][N:12]3[CH2:13][C@H:36]([CH3:37])[NH:35][C@H:34]([CH3:33])[CH2:11]3)[S:18][C:19]=2[N:20]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Product: C[C@@H]1CN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)C[C@H](C)N1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using cis-2,6-dimethyl-piperazine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a pale yellow solid (32 mg, 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C=O.[C:19]([BH3-])#N.[Na+]>>[CH3:19][NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Product: CNc1cccc(CNC(=O)OC(C)(C)C)c1

Procedure:
Tert-butyl 3-aminobenzylcarbamate was converted to the target molecule following standard reductive amination conditions using formaldehyde and sodium cyanoborohydride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13].C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH3:19][N:20]([CH3:22])[CH:21]=[C:9]1[CH2:10][CH2:11][CH2:12][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]1=[O:13]
Reactant: O=C1CCCCC1c1ccccn1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCC(c2ccccn2)C1=O

Procedure:
2-Pyridin-2-yl-cyclohexanone (175 mg, 1.0 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (226 mg) as a yellow solid which was used directly in the next step. MS ISP (m/e): 231.4 (100) [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[C:7]([CH2:12][C:13]#[CH:14])[CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[OH:16][C:17]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>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.[Cu](I)I.C(N(CC)CC)C>[OH:16][C:17]1[CH:26]=[C:25]([C:14]#[C:13][CH2:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[S:5][CH2:4][CH2:3][C:2]3([CH3:15])[CH3:1])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: C#CCc1cccc2c1SCCC2(C)C
Reactant: COC(=O)c1ccc(I)cc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCc2cccc3c2SCCC3(C)C)cc1O
Temperature: 25 °C

Procedure:
670 mg (3.1 mmol) of 3-(4,4-dimethylthiochroman-8-yl)prop-1-yne, 860 mg (3.1 mmol) of methyl 2-hydroxy-4-iodobenzoate and 33 ml of triethylamine are introduced into a three-necked flask under argon. The reaction mixture is degassed by sparging with nitrogen, 174 mg (0.25 mmol) of bis(triphenylphosphine)palladium(II) chloride and 71 mg of copper iodide are introduced and the reaction mixture is stirred at room temperature for eight. hours. The reaction mixture is evaporated to dryness, the residue is taken up in ethyl acetate and hydrochloric acid (1N) and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica column eluted with a mixture composed of 99% heptane and 1% ethyl acetate. After evaporating the solvents, 1.50 g (75%) of methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-yn-yl]benzoate are collected in the form of a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10].Cl>O>[C:8]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)Cl
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)C(=O)NCC(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
Glycine (75 g, 1 mol) is dissolved in 500 ml of 40 g (1 mol) of sodium hydroxide in the ice bath and the clear solution is reacted with 105 g (1 mol) of methacryloyl chloride and 40 g (1 mol) of sodium hydroxide in 150 ml of water simultaneously. The reaction temperature is kept below 5° C. throughout the addition. The reaction mixture is allowed to rise to room temperature and stirred at that temperature for three hours. The clear solution was titrated with 1N HCl to pH 3.0 and extracted with ethylacetate. The combined organic layer is dried over anhydrous magnesium sulfate and evaporated to leave 70 g (46%) of a crystalline material. Melting point 104° C. (literature 104°-105.5° C.). NMR (D2O), 5.7 gamma (s, 1H, =CH2), 5.4 gamma (s, 1H, =CH2), 4.0 gamma (s, 2H, CH2 ), 1.9 gamma (s, 3H, CH3). Purity by neutralization, 100.1%; purity by bromination, 100.8%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[NH:18]C(=O)C)[CH:3]=1.C(=O)(O)[O-].[Na+]>C(O)C.O1CCOCC1.Cl>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[C:12]([NH2:18])=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: CSc1nc(Cl)cc(Nc2ccc(C)cc2NC(C)=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CSc1nc(Cl)cc(Nc2ccc(C)cc2N)n1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
N-(2-{[6-Chloro-2-(methylsulfanyl)pyrimidin-4-yl]amino}-5-methylphenyl)acetamide (270 mg) was dissolved in a mixed solvent of ethanol (2.8 mL) and 1,4-dioxane (2.8 mL), and 6 M hydrochloric acid (9.6 mL) was added thereto, followed by heating and refluxing for 3 hours. After air-cooling to room temperature, the pH was adjusted to 6 to 7 using saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain N1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-4-methylbenzene-1,2-diamine (230 mg).