Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(N(CC)CC)C>[C:10]1([C:16]#[C:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C#Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 62.5 %

Procedure:
4-Bromobenzaldehyde (370 mg, 2 mmol), phenylacetylene (306 mg, 3 mmol) and tetrakistriphenylphosphine palladium (45 mg) were dissolved in triethylamine (4 ml), and the obtained solution was stirred at 80° C. in argon atmosphere for 24 hours. The solvent was evaporated, and the product was purified by the silica gel column chromatography to obtain 4-(2-phenylethynyl)benzaldehyde (yield: 258 mg, 63%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:12])[CH3:11].O1CCOCC1.[OH-].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:12][CH2:10][CH3:11])[N:3]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCNc1nc(N)nc(N)n1
Yield: 74.6 %

Procedure:
A mixed solution of 14.5 g (0.1 mol) of 2,4-diamino-6-chloro-1,3,5-triazine prepared in Reference Example 1, 12.8 g (0.2 mol) of aqueous ethylamine solution (70%), 20 mL of water, and 50 mL of 1,4-dioxane was warmed with stirring and allowed to react at a reflux temperature for 4 hours. Thereafter, a solution of 4.0 g (0.1 mol) of sodium hydroxide in 15 mL of water was dropwise added thereto over 1 hour while maintaining the reflux state. After cooling the reaction mixture, the solvent and excess ethylamine were distilled off under reduced pressure, 30 mL each of methanol and acetonitrile were added, and the unnecessary salts were filtered. To the residue obtained by distilling off the solvent from the filtered solution were added 5 mL of methanol and 40 mL of acetone to precipitate crystals, which were collected by filtration, washed with 10 mL of acetone, and dried to obtain 11.5 g (yield 75%) of the titled compound. Melting point: 171° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH2:14][Cl:15])=[O:24])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SCCCCl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)CCCCl)cc1
Reaction time: 8 h

Procedure:
A solution of 1.22 g. (0.005 mole) of 3-(p-acetamidophenylthio)propyl chloride in 25 ml. of methylene chloride is cooled in an ice bath while 0.88 g. (0.005 mole) of m-chloro-perbenzoic acid is added in portions. After keeping at room temperature overnight the reaction mixture is washed with excess 0.5 N sodium hydroxide, dried, and concentrated to a light brown oil. By triturating with ether, 1.06 g. of 3-(p-acetamidophenylsulfinyl)propyl chloride is obtained. Anal. Calcd for C11H14ClNO2S: C, 50.86; H, 5.43; N, 5.39; Cl, 13.65. Found: C, 50.53; H, 5.59; N, 5.23; Cl, 13.67.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[NH:8][C:9](=O)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:2]1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([NH:6][C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(Nc2cc[nH]n2)cc2ccccc12
Product: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Temperature: 130 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
3-(1H-Pyrazol-3-ylamino)-2H-isoquinolin-1-one (7.4 g, 0.03 mol) and POCl3 (80 ml) were sealed in 4 different bottles (20 ml). The mixture was heated at 130° C. for 15 minutes under microwave irradiation. The mixture was concentrated, the residue was treated with 15 ml MeOH and stirred for 2 hours at room temperature. The solid was collected and dried to give product (4.7 g, 61% yield). LC-MS: 245(MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1B(O)O.Br[C:16]1[N:17]=[CH:18][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>[Pd].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:16]1[N:17]=[CH:18][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:20][CH:21]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(Nc1cnc(Br)cn1)c1c(F)cccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cnc(-c2cc(C(F)(F)F)ccc2Cl)cn1)c1c(F)cccc1F
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-5-trifluoromethyl-benzeneboronic acid (a, 5 mmol), N-(5-bromo-pyrazin-2-yl)-2,6-difluoro-benzamide (b, 5 mmol), palladium catalyst (0.30 mmol), potassium carbonate (1 g) in dry 1,4-dioxane (20 mL) was heated at 100° C. for 24 h. The mixture was taken up with ethyl acetate (EtOAc) (100 mL), washed with water (2×100 mL) and dried over Na2SO4. The oil obtained on concentration was purified by flash chromatography followed by recrystallization to give Compound 1 as a yellowish solid (0.19 g).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH:8]=C)=[O:5].[C:11]1([CH2:17][C:18]([NH2:20])=[S:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>N1C=CC=CC=1>[CH2:17]([C:18]1[S:19][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=S)Cc1ccccc1
Reactant: C=CCOC(=O)C(=O)CBr
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1csc(Cc2ccccc2)n1

Procedure:
40 g of allyl bromopyruvate were progressively added to a mixture of 30.2 gof phenylthioacetamide, 120 ml of ethanol and 20 ml of pyridine and the mixture was refluxed for 16 hours. The mixture was evaporated to dryness under reduced pressure and the residue was added to a water-ether mixture.The mixture was stirred and the decanted aqueous phase was extracte with ether. The combined organic phases were evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 7-3 hexane-ethyl acetate mixture yielded 22.5 g of ethyl 2-benzyl-thiazole-4-carboxylate melting at 78°-79° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][CH:8]=[C:9]3[C:18]([N:17]=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[C:15]4[C:19](O)=[O:20])=[N:10]3)=[C:5]2[CH:4]=[CH:3]1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:15]1[C:16]2[C:11](=[N:10][C:9]3[C:18]([N:17]=2)=[C:5]2[CH:4]=[CH:3][N:2]([CH3:1])[C:6]2=[CH:7][CH:8]=3)[CH:12]=[CH:13][CH:14]=1)=[O:20]
Reactant: Cn1ccc2c3nc4c(C(=O)O)cccc4nc3ccc21
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(ccn4C)c3nc12

Procedure:
3-Methyl-3H-pyrrolo[3,2-α]phenazine-10-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 3-methyl-3H-pyrrolo[3,2-α]phenazine-10-carboxylic acid and N,N-dimethylethylenediamine
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+]([O-])=O)[C:4]=1[C:12]#[N:13])#[N:2].[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+].O>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:12]#[N:13])#[N:2]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(Oc2ccccc2)c1C#N
Yield: 60 %

Procedure:
A solution of 1,2-dicyano-3-nitrobenzene (2.77 parts) and sodium phenoxide (2.79 parts) in dimethylformamide (50 parts) was stirred at 120° C. for 2 hours. The reaction mixture was poured into water and extracted with diethyl ether (100 parts). The diethyl ether extract was washed with 5% aqueous potassium hydroxide solution (2×200 parts) and water (2×200 parts) and the diethyl ether was removed under reduced pressure to leave a solid. Recrystallisation of the solid from a 1:1 diethyl ether:petroleum spirit (b.pt.60°-80° C.) gave 1,2-dicyano-3-phenoxybenzene (2.1 parts, 60%) as a pale green solid, m.pt.110°-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.[F:25][C:26]([F:39])([O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:27]([Cl:30])([Cl:29])[Cl:28].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([O:31][C:26]([F:25])([F:39])[C:27]([Cl:28])([Cl:29])[Cl:30])=[CH:38][CH:37]=3)=[O:20])=[CH:23][CH:24]=1)[CH:6]=[N:5]2
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Reactant: Nc1ccc(OC(F)(F)C(Cl)(Cl)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)C(Cl)(Cl)Cl)cc1

Procedure:
A solution of 4.35 mmol of 2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)propanoyl chloride (previously prepared from 1.5 g of the corresponding acid) in 15 ml of acetonitrile was added to a mixture prepared from 1.20 g (4.35 mmol) of 4-(1,1-difluoro-2,2,2-trichloroethoxy)aniline, 0.66 g (6.5 mmol) of triethylamine and 10 ml of acetonitrile. The mixture was warmed at reflux for a period of 2.5 hours and then poured over ice and aqueous NaOH added. The resulting precipitate was filtered and dried and then recrystallized from methylcyclohexane. This left 2.2 g (84 percent of theoretical) of the above-named product as a brown solid, m.p. 139°-141° C. (Compound 36)
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[C:26]2[CH2:32]Br>CN(C)C=O>[F:20][C:21]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[C:26]2[CH2:32][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)[CH3:1]
Reactant: Fc1cc(F)c2cccc(CBr)c2c1
Reactant: CNCc1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc2c(F)cc(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.3 g of N-methyl-4-tert.butylbenzylamine, 0.25 g of potassium carbonate and 5 ml of abs. dimethylformamide (DMF) are added dropwise 0.4 g of 5,7-difluoro-1-bromomethylnaphthalene and the mixture stirred overnight at RT. The solvent is removed under vacuum and the residue partitioned between ether and water. The organic phase is dried and evaporated. The pure product is obtained as an oil following chromatography on silica gel (eluant:hexane/ethylacetate=95/5).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11](O)=[O:12])=[CH:8][C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)=[CH:16][CH:15]=3)=[N:6][C:5]=2[N:4]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[N:3]=1.[CH2:33]([N:40]1[CH2:45][C:44]([CH3:47])([CH3:46])[NH:43][CH2:42][C:41]1([CH3:49])[CH3:48])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([N:40]1[C:41]([CH3:49])([CH3:48])[CH2:42][N:43]([C:11]([C:9]2[CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)=[CH:16][CH:15]=3)[N:6]=[C:5]3[N:4]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)[N:3]=[C:2]([CH3:1])[C:10]=23)=[O:12])[C:44]([CH3:47])([CH3:46])[CH2:45]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC1(C)CN(Cc2ccccc2)C(C)(C)CN1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)O)c12
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)N3CC(C)(C)N(Cc4ccccc4)CC3(C)C)c12
Yield: 75.7 %

Procedure:
In a similar manner as in Exampe 40 step (b) 400 mg of 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid was reacted with 212 mg 1-benzyl-2,2,5,5-tetramethyl-piperazine to obtain 450 mg (76%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1(B(O)O)[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][NH:15]1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:19]3[C:14]([O:13][CH3:12])=[N:15][CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: COC1(B(O)O)C=CC(C(F)(F)F)=CN1
Reactant: Clc1nc2c(Br)cccn2n1
Product: COc1ncc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-methoxy-5-trifluoromethyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-methoxy-5-trifluoromethylpyridineboronic acid in a manner analogous to Example 2c (0.46 g, 65%). MP=183-185° C. MS=329 (MH)+.
Reaction SMILES: [O:1]=[C:2]([C:4]1[CH:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:6][N:5]=1)[CH3:3].[BH4-].[Na+].O>CO>[OH:1][CH:2]([C:4]1[CH:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:6][N:5]=1)[CH3:3]
Reactant: CC(=O)c1cc(-c2ncccn2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1cc(-c2ncccn2)on1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(3-(1-oxo-ethyl)-isoxazol-5-yl)-pyrimidine (1.2 gm) in methanol (20 ml) was added sodium borohydride (0.485 gm) in lots at 0° C. It was stirred at 30° C. over a period of 2 h. The reaction mixture was evaporated under vacuum to provide a residue. The residue was stirred with water and extracted with ethyl acetate (25 ml X3). Combined organic layers was washed with aqueous sodium bicarbonate solution followed by water and concentrated under vacuum to provide title compound in 1.1 gm quantity (91%). It as used as without purification for the next reaction.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:35])[CH:11]=2)[CH:6]=1.[OH-].[Li+]>C1COCC1.O>[F:35][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:36])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([S:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])(=[O:23])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3ccccc3[N+](=O)[O-])CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)Cc2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
To a light yellow solution of {6-fluoro-3-methyl-4-[1-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (100 mg, 0.194 mmol) in THF (4 mL) was added a solution of lithium hydroxide (93.1 mg, 3.89 mmol) in water (1 mL) at room temperature. The resulting light brown solution was stirred for 15 hours at room temperature. The THF was evaporated off under vacuum and the basic aqueous layer was neutralized with 1.0 N HCl. The resulting solids were filtered using filter paper and washed with water and hexanes. The white solid (82 mg) was dissolved in ethyl acetate (˜5 mL) with heating and the mixture was diluted with hexanes. During the dilution some precipitate was formed. Cooling in the refrigerator precipitated additional solids. {6-Fluoro-3-methyl-4-[1-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (88 mg, 90%) was isolated as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (br. s, 1H), 8.08 (d, J=8.03 Hz, 1H), 7.90 (dd, J=8.91, 6.65 Hz, 1H), 7.74-7.86 (m, 3H), 7.64-7.73 (m, 2H), 7.36 (t, J=8.03 Hz, 1H), 4.97 (s, 2H), 3.52-3.90 (m, 7H), 2.42 (br. s, 3H), 1.60-184 (m, 4H). MS cald. for C25H25FN2O6S [(M+H)+] 500, obsd. 501.1.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.OS(O)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
201 g tert-Butyl 4-hydroxypiperidine-1-carboxylate, 160 ml triethylamine and 6.0 g 4-dimethylaminopyridine are dissolved in 750 ml DCM. 191 g 4-toluenesulfonylchloride is added and the mixture is refluxed for 7 h. The mixture is cooled in ice and acidified with 100 ml of 1M H2SO4; the organic layer is washed with 300 ml of water (twice), 250 ml of 1 M Na2CO3 solution (twice), dried over MgSO4, filtered and concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(c1ccc([N+](=O)[O-])cc1Br)N1CCCC1

Procedure:
Prepared analogously to Example 1a from 2-bromo-4-nitro-benzoic acid and pyrrolidine with TBTU and NMM in DMF.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH2:11][C:12]#[N:13])[CH:3]=1.[NH2:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6]([OH:7])=[N:13][C:12]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:11]2
Reactant: N#CCc1cc(Br)ccc1C(=O)O
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3cc(Br)ccc3c(O)n2)n[nH]1

Procedure:
Similar procedure as described in example 9B was used, starting from 4-Bromo-2-cyanomethyl-benzoic acid, 3-amino-5-methylpyrazole and acetic acid to give 6-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol. LC-MS: m/e 319 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:36]=[C:37]([C:45]([F:48])([F:46])[F:47])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=3)=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: FC(F)(F)c1cc(Sc2ccc(Br)cc2)cc(C(F)(F)F)c1
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: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)c1C
Yield: 37.8 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-3,5-bis-trifluoromethyl-benzene (0.29 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(3,5-bis-trifluoromethyl-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.115 g, 37%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][CH2:32][C@@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]1[NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][CH2:32][C@@H:33]4[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]4[NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1CN
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)n3)c3cc(Cl)cnc32)cc1
Reaction time: 1.3 h

Procedure:
A mixture of 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 15a, (0.42 g, 0.90 mmol) and tert-butyl trans-2-(aminomethyl)cyclohexylcarbamate (0.24 g, 1.06 mmol) were heated in THF (10 mL) to 70° C. After 1.3 hours, the mixture was concentrated in vacuo. Flash chromatography (SiO2, 0-60% EA/Hex, gradient elution) provided the desired intermediate, tert-butyl trans-2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexylcarbamate, 14e, as a racemic mixture of trans isomers, which was taken into the next reaction without further purification (0.52 g, 92% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:11]=[CH:12][N:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([O:20][CH3:21])=[CH:15]2.CN(C=O)C>CCOC(C)=O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[CH:11][CH:12]=[N:13]2)=[N:18][CH:17]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: Nc1ccc(S)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cnc2c(Sc3ccc(N)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A RBF was charged with 4-aminothiophenol (161 mg, 1.285 mmol), 8-chloro-3-methoxy-1,5-naphthyridine (250 mg, 1.285 mmol) and 5.2 mL of DMF, and the mixture was stirred at RT for 45 min. The orange, heterogeneous mixture was diluted with EtOAc and washed with 1N NaHCO3. The aqueous portion was extracted two additional times with EtOAc and the combined organics were dried with MgSO4, filtered and concentrated. The crude oil was concentrated twice from toluene to remove DMF and the resulting solids were dried under high vacuum to provide 4-(7-methoxy-1,5-naphthyridin-4-ylthio)benzenamine as a tan solid. MS m/z=284 [M+H]+. Calc'd for C15H13N3OS: 283.35.