Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([OH:12])[C:9]([C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[CH:8][C:5]=1[CH:6]=[O:7].I[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C=O)C>[CH2:24]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:10][CH2:11][CH2:4][CH2:5][CH2:8][CH3:9])[C:9]([C:13]23[CH2:14][CH:15]4[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]4)[CH2:22]2)[CH2:20]3)=[CH:8][C:5]=1[CH:6]=[O:7])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=Cc1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Reactant: CCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(OCCCCCC)c(C23CC4CC(CC(C4)C2)C3)cc1C=O
Reaction time: 4 h

Procedure:
1.3 g (35.2 mmol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 4.8 g (17.6 mmol) of 2,4-dihydroxy-5-(1-adamantyl)-benzaldehyde dissolved in 70 ml of DMF was added dropwise and stirring was carried out at room temperature until gas evolution has ceased. 6.5 ml (35.2 mmol) of 1-iodohexane were then added dropwise and stirring was carried out at room temperature for four hours.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[CH2:5]1[O:14][C:8]([CH2:10][CH2:11][CH2:12]Cl)([CH3:9])[O:7][CH2:6]1>CO>[CH2:5]1[O:14][C:8]([CH2:10][CH2:11][CH2:12][O:2][CH3:1])([CH3:9])[O:7][CH2:6]1
Reactant: CC1(CCCCl)OCCO1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COCCCC1(C)OCCO1

Procedure:
To a solution of sodium methoxide prepared by the addition of 0.8 g of sodium to 35 mL of methanol was added 5-chloro-2-pentanone ethylene ketal (3 g, 180 mmol). The mixture was heated in a steel bomb at 100° C. for 18 hours. The methanol was removed by evaporation under reduced pressure and the residue was extracted into 20 mL of ether. The ether extract was washed with water, saturated saline solution and dried over magnesium sulfate. Evaporation of the ether yielded 1.6 grams of 5-methoxy-2-pentanone ethylene ketal. This was stirred in 10 mL of 75% formic acid for 24 h at room temperature. The mixture was neutralized with sodium bicarbonate and extracted with 50 mL of ether. The ether extract was washed with water, saturated saline solution and dried over magnesium sulfate. Evaporation yielded 1.2 g of the desired ketone as an oil. Step B: Preparation of 1-(R)-(3,4-dihydroxyphenyl)-2-(1-methyl-4-methoxybutylamino)ethanol oxalate salt
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH2:20])=[N:16][NH:17]2)=[CH:13][CH:12]=1.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](Cl)=[O:29]>N1C=CC=CC=1>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH:20][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[O:29])=[N:16][NH:17]2)=[CH:13][CH:12]=1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1n[nH]c2cc(Cl)ccc12)c1ccccn1
Temperature: 8 °C
Reaction time: 18 h

Procedure:
4.2 cm3 of diisopropylethylamine are added to 1 g of 6-chloro-1H-indazole-3-amine in 15 cm3 of pyridine. The reaction medium is cooled to about 8° C. to add 1.08 g of picolinoyl chloride hydrochloride, and the temperature is allowed to return to room temperature over 18 hours. The reaction medium is concentrated to dryness under reduced pressure (2 kPa; 40° C.) and the residue is then taken up in 25 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed with 25 cm3 of water and then with 25 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulphate, filtration and concentration under reduced pressure (2 kPa; 40° C.), the residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a dichloromethane/methanol mixture (99/1 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 2×15 cm of diisopropyl ether. After filtration on a sinter funnel and drying under reduced pressure (90 Pa; 50° C.), 572 mg of N-[6-chloro-1H-indazol-3-yl]-2-pyridinecarboxamide are obtained in the form of a white solid melting at 177° C.
Reaction SMILES: C([O:3][C:4]([CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Na+]>CO>[C:4]([CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C=CCCCc1cccc2cncn12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=CCCCc1cccc2cncn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 300 mg of 5-(5-ethoxycarbonylpent-4-enyl)-imidazo[1,5-a]pyridine in 20 ml methanol is added 5 ml of 1 N sodium hydroxide. The reaction mixture is stirred at room temperature for 18 hours. The methanol is evaporated under reduced pressure and an additional 5 ml of water is added to the aqueous residue, which is then extracted with 3×5 ml aliquots of ethyl acetate. The basic aqueous layer is then adjusted to pH 5 and extracted with 3×5 ml portions of ethyl acetate. These extracts are dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield 5-(5-carboxypent-4-enyl)-imidazo[1,5-a]pyridine melting at 142°-144°.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][NH:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([ClH][C:21](=[O:30])[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:23])(=O)C.C(N(CC)CC)C.[OH-].[Li+]>C(Cl)(Cl)Cl.O1CCCC1.CO>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][N:9]([CH3:10])[C:21](=[O:30])[CH:22]([OH:23])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CNCC(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(O)c1ccccc1
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a stirred solution of (2,2-diphenylethyl)methylamine (4.97 g, 23.5 mmol) in chloroform (50 mL) was added O-acetylmandelic chloride (5.3 mL, 24 mmol) followed by triethylamine (4.0 mL, 29 mmol). The reaction was stirred for 1 hour and then concentrated. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a colorless gum. The crude amide was taken up in 1:1 tetrahydrofuran/methanol (80 mL) and treated with 1 N aqueous lithium hydroxide (30 mL, 30 mmol). The mixture was stirred for 2 hours and concentrated to remove the organic solvents. The remaining aqueous solution was diluted with water and extracted twice with ethyl acetate and once with methylene chloride. The combined organic extracts were dried sodium sulfate) and concentrated to afford an off-white solid. This material was triturated with diethyl ether to afford 7.59 g (93%) of product as a white solid: 1H NMR (CDCl3) δ 7.43-6.98 (m, 15H), 5.07 (s, 1H), 4.57-4.44 (m, 1H), 4.36-4.28 (m, 1H), 3.76-3.64 (m, 1H), 2.46 (s, 3H) ppm.
Reaction SMILES: [CH:1](/[C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:2]\[CH3:3].C(OCC)(=O)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[CH:1](/[C:4]1[C:14]2[O:13][CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:2]\[CH3:3]
Reactant: C/C=C/c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: C/C=C/c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A mixture of tert-butyl 9-[(1E)-propa-1-ene-1-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (178 mg, 0.615 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (121 mg, 87.7%) as a solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Fc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Yield: 133.9 %

Procedure:
The procedure described in Example 4.1. is repeated. Starting from 2.5 g (11.6 mmol) of 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidine-carboxylate and 8.13 g (46.4 mmol) of 1-bromo-4-fluorobenzene gives 5.75 g of crude product in oil form.
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][N:16]([CH3:18])[N:17]=2)=[CH:9][C:8]=1[N+:19]([O-])=O)[C:4]([NH2:6])=[O:5])#[N:2]>CN(C=O)C.O.CO.[Zn]>[NH2:2][C:1]1[NH:19][C:8]2[C:7]([C:3]=1[C:4]([NH2:6])=[O:5])=[CH:12][CH:11]=[C:10]([C:13]1[N:14]=[N:15][N:16]([CH3:18])[N:17]=1)[CH:9]=2
Reactant: Cn1nnc(-c2ccc(C(C#N)C(N)=O)c([N+](=O)[O-])c2)n1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Cn1nnc(-c2ccc3c(C(N)=O)c(N)[nH]c3c2)n1
Temperature: 100 °C
Yield: 39.8 %

Procedure:
Ferric chloride hexahydrate (2.82 g, 10.44 mmol) and zinc (2.276 g, 34.8 mmol) were added portionwise to a mixture of 2-cyano-2-(4-(2-methyl-2H-tetrazol-5-yl)-2-nitrophenyl)acetamide (1 g, 3.48 mmol) in DMF (8.71 mL) and water (8.71 mL) to give a yellow suspension which was heated to 100° C. for 1.25 hour. The mixture was then cooled to 20° C., diluted with MeOH (50.0 mL), filtered over Celite and concentrated under reduced pressure to ca. 20 mL (to remove most of the MeOH). Then the mixture was diluted with water (50 mL) and EtOAc (100 mL), stirred vigorously and filtered. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic layers were washed with sat. NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried over anh. MgSO4, filtered and concentrated to give 489 mg as a purple solid which was purified by flash chromatography to give 2-amino-6-(2-methyl-2H-tetrazol-5-yl)-1H-indole-3-carboxamide (356 mg, 39.7% yield) as a purple solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 4.38 (s, 3H) 6.57 (s, 2H) 7.01 (s, 2H) 7.61-7.69 (m, 2H) 7.81 (s, 1H) 10.77 (s, 1H); MS m/z 258.2 (M+H)+; HPLC ca. 78%, RT=1.34 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][C:10]=1[O:13][CH3:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(OC)c(C)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OC)c(CBr)c1Cl
Reaction time: 4 h

Procedure:
To 50 ml carbon tetrachloride, was dissolved methyl 2-chloro-4-methoxy-3-methylbenzoate in an amount of 5.0 g (0.025 mole), and the resulting solution was then stirred for 4 hours under reflux and heating after the addition of N-bromosuccinimide in an amount of 4.9 g (0.028 mole) and benzoyl peroxide in an amount of 0.1 g into the solution. After cooling the mixture, insoluble material therein were separated by filtration, and the filtrate was washed with aqueous solution of sodium hydrogenbisulfite and then dried with anhydrous magnesium sulfate. The solvent remained in the filtrate was condensed under reduced pressure to obtain methyl 3-bromomethyl-2-chloro-4-methoxybenzoate in an amount of 7.5 g in crude crystalline form.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N(CC)CC)C.[Br:27][C:28]1[S:32][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:29]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:27][C:28]1[S:32][C:31]([S:33]([NH:3][C@@H:4]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])(=[O:35])=[O:34])=[CH:30][CH:29]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Br)s1
Yield: 44 %

Procedure:
To a solution of (R)-benzyl 3-amino-4-(dimethylamino)butanoate dihydrochloride (1 g, 3.2 mmol), triethylamine (1.3 mL, 9.6 mmol) and DMAP (20 mg, 0.16 mmol) in anhydrous CH2Cl2 (25 mL) was added 5-bromothiophene-2-sulfonyl chloride (2.5 g, 9.6 mmol). Methylene chloride (200 mL) was added and the solution was washed with dilute NaOH (10 mL), water (10 mL), dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to give the title compound as a yellow solid (650 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 1H, J=3.8 Hz), 7.41-7.27 (m, 5H), 7.04 (d, 1H, J=3.8 Hz), 5.14-5.07 (m, 2H), 3.87-8.83 (m, 1H), 2.92-2.89 (m, 1H), 2.83-2.78 (m, 1H), 2.69-2.64 (m, 1H), 2.60-2.54 (m, 1H), 2.43 (s, 6H); MS ESI 461.3 [M+H]+, calcd for [C17H21BrN2O4S2]+ 461.00.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[CH:41]=[N:40][C:39]2[NH:38][CH2:37][CH2:36][O:35][C:34]=2[CH:33]=1>>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:32]3[CH:41]=[N:40][C:39]4[NH:38][CH2:37][CH2:36][O:35][C:34]=4[CH:33]=3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1cnc2c(c1)OCCN2
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide and 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. MS (ESI): mass calcd. for C23H24FN3O3S, 441.15; m/z found, 442.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.15-8.12 (m, 1H), 7.80 (d, J=0.9, 1H), 7.72-7.69 (m, 1H), 7.68-7.62 (m, 1H), 7.60-7.54 (m, 2H), 7.39-7.33 (m, 3H), 4.42-4.33 (m, 2H), 3.75-3.69 (m, 2H), 1.09 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:22]1>>[CH3:19][O:20][CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][C:29]([NH:32][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:28][CH:27]=2)[CH2:22]1
Reactant: COC1CCN(c2ccc(N)cn2)C1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COC1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine. LCMS calcd for C21H19F3N4O3 (m/e) 432, obsd 433 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CC#N>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.O>[CH3:9][NH:8][C:6]1[N:7]=[C:2]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH3:30])[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])=[O:17])[CH2:12][CH2:11]2)[N:5]=1
Reactant: CNc1nc(Cl)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Reactant: Cc1ccccc1B(O)O
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+]
Solvent: CC#N
Solvent: O
Product: CNc1nc(-c2ccccc2C)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Temperature: 90 °C
Yield: 30.4 %

Procedure:
To a suspension of 1-[4-chloro-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[2-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide (Intermediate 7d, 75 mg, 0.17 mmol, 1.0 equiv), (2-methylphenyl)boronic acid (29 mg, 0.21 mmol, 1.2 equiv), and Na2CO3 (37 mg, 0.35 mmol, 2.0 equiv) in 3:1 CH3CN:H2O was added Pd(PPh3)4 (10 mg, 0.0088 mmol, 0.05 equiv). The reaction mixture was heated at 90° C. for 1 h. The resulting suspension was filtered through an SCX resin (55 □m, 70 A, 2 g/12 mL giga tubes) using MeOH, and the product was recovered by eluting with 2.0 M NH3 in MeOH. The filtrate was concentrated, and the resulting residue was purified using reverse-phase HPLC (XBridge, 10-80% CH3CN/H2O, 0.1% TFA, 12 min) to afford 25 mg (30%) of the title compound. MS (ES+): m/e 485.2 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:37]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:39]5[CH:38]=[N:37][C:36]([N:33]6[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]6)=[CH:41][CH:40]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:11]=2)=[CH:14][CH:15]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(N5CCN(C)CC5)nc4)cc2-3)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.75 g, 1.5 mmol), 1-Methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (0.5 g, 17 mmol), Na2CO3 (2 M, 3.6 mL), and Pd(PPh3)2Cl2 (110 mg, 0.15 mmol) in toluene/ethanol (1:1, 12 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 6-(4-Methoxy-phenyl)-2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 60% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])OC2C=CC=CC=2)=[CH:11][N:10]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH2:31][CH2:30]2>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:32]2[C:33]3[C:29](=[CH:28][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:35][CH:34]=3)[CH2:30][CH2:31]2)=[O:24])=[CH:11][N:10]=1
Reactant: O=C(Nc1ccc(OCc2ccccn2)nc1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc2c(c1)CCN2
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OCc2ccccn2)nc1)N1CCc2cc(C(F)(F)F)ccc21
Temperature: 100 °C
Yield: 31.1 %

Procedure:
Phenyl N-[2-(pyridin-2-ylmethyloxy)pyridin-5-yl] carbamate (D3, 0.20 g, 0.62 mmol) in dry dimethylformamide (10 ml) was treated with 5-trifluoromethylindoline (D6, 0.12 g, 0.62 mmol) and heated at 100° C. for 1 hour. After cooling to ambient temperature, the solvent was removed in vacuo. The residue was dissolved in dichloromethane, washed with 10% aqueous sodium hydroxide solution, dried (Na2SO4) and evaporated in vacuo. The resulting oil was chromatographed on silica gel eluting with 2% methanol/dichloromethane and triturated with diethyl ether to afford the title compound (0.08 g, 31%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)[N:13]=2)=[CH:4][CH:3]=1.OOS([O-])=O.[K+].CC(O)C.[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:41][C:40]4[CH:42]=[CH:43][C:37]([O:36][CH3:35])=[CH:38][CH:39]=4)[N:18]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1
Reactant: CSc1nccc(-c2cnn3nc(-c4ccc(F)cc4)ccc23)n1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: COc1ccc(Nc2nccc(-c3cnn4nc(-c5ccc(F)cc5)ccc34)n2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
To a solution of 6-(4-fluorophenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-b]pyridazine (42 mg, 0.124 mmol) in MeOH (2 mL) was added Oxone (77 mg, 0.124 mmol) in water (1 mL). The reaction mixture was stirred for about 2 hours then water (10 mL) was added. The aqueous layer was washed with EtOAc (3×40 mL) and aqueous NaHCO3 (1×20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give a brown solid. This solid was-added to iPrOH (1.0 mL) and 4-methoxyaniline (20 mg, 0.162 mmol) in a sealed tube. The reaction mixture was heated at an oil bath temperature of 130° C. for about 16 hours. The mixture was cooled to RT and the solid collected by filtration to give the title compound as a brown solid (17 mg, 339% b). 1H-NMR (300 MHz, d6-DMSO) δ 9.41 (s, 1H), 9.14 (d, 1H, J=9.1 Hz), 8.88 (s, 1H), 8.41 (d, 1H, J=5.1 Hz), 8.22 (dd, 2H, J=8.5, 5.6 Hz), 8.02 (d, 1H, J=9.3 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.42 (t, 2H, J=8.8 Hz), 7.30 (d, 1H, J=5.2 Hz), 6.94 (d, 2H, J=8.8 Hz), 3.75 (s, 3H); MS (ESI) (M+H)+ 413.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24]([SH:26])=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24]([S:26][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc3[nH]c(S)nc3c2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CSc1nc2cc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
A mixture of 5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1H-benzimidazole-2-thiol obtained in Example 27 (750 mg), tert-butyl bromoacetate (429 mg), potassium carbonate (415 mg), and N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 90:10-50:50 hexane/ethyl acetate) to provide the title compound (785 mg, 81%) as an amorphous.