Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)Cl.[C:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2(O)[C:27]3[C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[S:24][C:23]=3[C:22]([C:33]#[C:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)(O)[C:21]3[C:20]4[CH:45]=[CH:46][CH:47]=[CH:48][C:19]=4[S:18][C:17]2=3)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]>C(O)(=O)C.CC(C)=O>[C:41]([C:38]1[CH:39]=[CH:40][C:35]([C:34]#[C:33][C:22]2[C:21]3[C:20]4[CH:45]=[CH:46][CH:47]=[CH:48][C:19]=4[S:18][C:17]=3[C:16]([C:15]#[C:14][C:11]3[CH:12]=[CH:13][C:8]([C:4]([CH3:6])([CH3:5])[CH3:7])=[CH:9][CH:10]=3)=[C:27]3[C:23]=2[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=23)=[CH:36][CH:37]=1)([CH3:42])([CH3:43])[CH3:44]
Reactant: CC(C)(C)c1ccc(C#CC2(O)c3sc4ccccc4c3C(O)(C#Cc3ccc(C(C)(C)C)cc3)c3sc4ccccc4c32)cc1
Agent: Cl[Sn]Cl
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C#Cc2c3sc4ccccc4c3c(C#Cc3ccc(C(C)(C)C)cc3)c3sc4ccccc4c23)cc1
Temperature: 8 °C

Procedure:
A solution of tin(II)chloride dehydrate (1.82 g, 8.05 mmol) in glacial acetic acid (30 ml) is added within ten minutes to a solution of 6,12-bis-(4-tert-butyl-phenylethynyl)-6,12-dihydro-dibenzo[d,d′]benzo[1,2-b;4,5-b′]dithiophene-6,12-diol (educt 2) in acetone (30 ml). There is a slight temperature increase (8° C.), and formation of a yellow suspension takes place. This suspension is stirred over night at ambient temperature, and then the solid is filtered off. The solid is then washed with water/glacial acetic acid (twice, 30 ml 1:1 v:v), water (twice with 30 ml), and twice with acetone (30 ml). The residue is then dried to give crude product which is recrystallised from anisol (65 ml). The product is filtered off, washed with anisol (8 ml), toluene (2 times 8 ml) and hexane (twice ca. 10 ml) and dried to give the title product as yellow crystals. Mp. (DSC) 349-350° C., MS (m/z 602 (100%), correct isotopic pattern), elementary analysis: C, 84.61%; (calcd. 83.68%); H, 5.89%; (calcd. 5.68%). 1H-NMR (CDCl3, 300 MHz) δ 1.33 (s, 9H, C(CH3)3); 7.41-7.47 (m, 4H, 2 Ph H, 2 benzothiophene H); 7.66 (AA′BB′, 2H, 2 Ph H); 7.84 (m, 1H), 9.15 (m, 1H) (2 benzothiophene H).
Reaction SMILES: C([O:7][C:8](=[O:24])[CH2:9][C:10]1[S:11][C:12]([CH:15]=[CH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)CCCCC.[OH-].[K+]>C(O)C.O>[O:23]=[C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:16]=[CH:15][C:12]1[S:11][C:10]([CH2:9][C:8]([OH:24])=[O:7])=[CH:14][CH:13]=1
Reactant: CCCCCCOC(=O)Cc1ccc(C=CC(=O)CCCCC)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(=O)C=Cc1ccc(CC(=O)O)s1
Yield: 45 %

Procedure:
3.5 G of 2-[5-(3-oxooct-1-enyl)thien-2-yl]acetic acid hexyl ester was dissolved in 20 ml of ethanol; then, a solution of 0.6 g of potassium hydroxide in 10 ml ethanol was added portionwise over aperiod of 4 hours. The resultant solution was stirred for an additional 4 hours, then was diluted with water. The water solution was extracted several times with ether, and the ether phases were discarded. The water solution was adjusted to pH 5.5 to 6 with dilute hydrochloric acid and extracted with ether, and the ether phase was washed with water, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, using benzene and ethyl acetate as eluants). There were thus obtained 1.2 g (45% yield) of the desired product, melting at 51° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(O)(=O)C.[C:24](=O)([O:28]CC)[O:25][CH2:26][CH3:27]>>[CH2:26]([O:25][C:24](=[O:28])[CH2:16][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:17])[CH3:27]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
1-(3-Benzyloxyphenyl)ethanone (218 g, 966.10 mmol) was dissolved in diethyl carbonate and sodium hydride (60% oil) (46.37 g, 1.15 mmol) was slowly added thereto at 0° C., and then stirred for 3 hours at 60° C. After the reaction was completed, ice water and acetic acid were added to the reaction mixture, extracted with ethyl acetate/saturated sodium chloride, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure and the resulting residue was purified by column chromatography (ethyl acetate:hexane=1:10) to obtain 3-(3-benzyloxyphenyl)-3-oxopropionate ethyl ester (184.68 g, yield 84%) in an oil state.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[O:17][C:18]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=2[N:20]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:16]2[O:17][C:18]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc2nc(Cl)oc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNc2nc3ccc(Cl)cc3o2)C1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 220 mg (1.1 mmol) 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (commercially available), 188 mg (1 mmol) 2,6-dichloro-benzooxazole (commercially available) and 303 mg (3 mmol) NEt3 in 4 mL DCM was stirred at room temperature over night. After evaporation to dryness the residue was purified with flash column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were evaporated to yield 351 mg (99%) of the title compound. MS (m/e): 352.4 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=2)(=O)=O)=CC=1>>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:32][CH:33]=1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Br)cc2)cc1
Product: O=C(N[C@H]1CCN(CCc2ccc(Br)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide and 2-(4-bromophenyl)ethyl p-toluenesulfonate were reacted under the same conditions as in Example 6 to give (S)-N-(1-(2-(4-bromophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide.
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH3:4].CN(CCN(C)C)C.[CH2:27]([Li])[CH2:28][CH2:29][CH3:30]>C1COCC1>[CH2:1]([C:5]1([CH2:27][CH2:28][CH2:29][CH3:30])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c2ccccc2nc2ccccc12
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CCCCC1(CCCC)c2ccccc2Nc2ccccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To an ice-cooled solution of 9-butylacridine (27.0 g, 0.115 mol) and TMEDA (4.1 mL, 0.027 mol) in THF (135 mL), was added 2.5 M n-butyllithium in hexanes (140 mL, 0.350 mol) dropwise. The mixture was stirred at 0° C. overnight and quenched with water. After stirring for an additional 0.5 hours, the reaction mixture was poured into crushed ice and extracted with ethyl acetate. The organic solution was washed with water and dried over MgSO4. The solvent was evaporated and the resulting residue was chromatographed on silica gel (hexanes:ethyl acetate=10:1 as eluent) to give 14.5 g (43%) of yellow powder.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:15]1([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:5][C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:20][CH2:19]2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Reaction time: 3 h

Procedure:
Combined 1-boc-4-piperidone (10.0 g, 50.2 mmol), benzyl 1-piperazine-carboxylate (19.3 mL, 100.4 mmol), HOAc (4.3 mL, 75.3 mmol) and TEA (7.0 mL, 50.2 mmol) in DCE (150 mL) were stirred at rt. Sodium triacetoxyborohydride was added (16.0 g, 75.3 mmol). The reaction was stirred for 3 h at which point TLC shows starting material is consumed. The reaction was quenched with NaHCO3 and extracted with DCM (3×). Combined organics were dried over MgSO4, filtered and concentrated in vacuo. Diluted crude material with DCM and adsorbed onto a prepacked silica gel solid loading cartridge and purified by column chromatography to give title compound of step A (yield not obtained). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.04-7.52 (m, 5H), 5.02 (s, 2H), 3.74-4.05 (m, 2H), 3.06-3.49 (m, 4H), 2.63 (br. s., 2H), 2.22-2.50 (m, 5H), 1.64 (d, J=12.1 Hz, 2H), 1.07-1.27 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].F[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26]>C(Cl)Cl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([NH:1][C:2]2[S:3][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: COC(=O)c1cc(-c2ccccc2)sc1N
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccccc2)sc1Nc1ccc(F)cc1[N+](=O)[O-]

Procedure:
Methyl 2-amino-5-phenyl-thiophene-3-carboxylate and 2,5-difluoronitrobenzene, m.p. 150° C. (CH2Cl2).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][O:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][CH3:18])[CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([N:17]([CH3:18])[C@H:14]2[CH2:13][CH2:12][C@H:11]([O:10][CH2:9][CH2:8][C:7]([N:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH3:20])=[O:19])[CH2:16][CH2:15]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: CN[C@H]1CC[C@H](OCCC(=O)N(C)CCCO)CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCCO)C(=O)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 158 mg (0.5 mmol) of trans-N-(3-hydroxy-propyl)-N-methyl-3-(4-methylamino-cyclohexyloxy)-propionamide-hydrochloride in 3 mL of CH2Cl2 were added 0.44 mL (2.6 mmol, 5 eq) of N,N-diisopropylethylamine followed by 0.14 mg (0.56 mmol, 1.1 eq) of 4-bromo-benzenesulfonyl chloride. The mixture was stirred at RT for 1 h and the organic phase was extracted with 1M KHSO4. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Column chromatography on silica gel with a gradient of CH2Cl2:MeOH 98:2 to 95:5 yielded 101 mg (40%) of trans-3-{4-[(4-bromo-benzenesulfonyl)-methyl-amino]-cyclohexyloxy}-N-(3-hydroxy-propyl)-N-methyl-propionamide as colorless oil, MS: 491 (MH+,1Br).
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH2:15][C:6]2[S:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:8][CH:7]=2)[CH:17]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: CCCc1cccs1
Product: CCCc1ccc(Cc2cc(Br)ccc2OC)s1

Procedure:
2-n-Propylthiophene and 5-bromo-2-methoxybenzaldehyde were used and treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 325/327 (M+H)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([F:16])[CH:5]=1)(=O)[CH3:2].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>C1COCC1.[Cl-].[Na+].O>[F:10][C:8]1[CH:9]=[C:4]([C:1](=[N:23][S:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:2])[CH:5]=[C:6]([F:16])[C:7]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CC(=O)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=NS(=O)C(C)(C)C)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of N-(4-acetyl-2,6-difluoro-phenyl)-methanesulfonamide (1.84 g, 7.38 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (1.07 g, 8.86 mL) in THF (15 mL) was added dropwise Ti(OEt)4 (2.61 mL, 12.6 mmol) at room temperature. The mixture was stirred overnight at 90° C. The mixture cooled to room temperature and then was added brine. After the mixture was extracted three times with EtOAc, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography to yield N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylimino)-ethyl]-phenyl}-methanesulfonamide (2.2 g, 85%). To a solution of N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylimino)-ethyl]-phenyl}-methanesulfonamide (2.2 g, 6.24 mmol) in THF (20 mL) was added portionwise NaBH4 (944 mg, 24.9 mmol) dissolved in THF (2 mL) at −48° C. The mixture was stirred for 10 hours at −48° C. room temperature, and then CH3OH was added dropwise until gas was no longer evolved. The mixture was concentrated under reduced pressure, and then was purified by chromatography to afford N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylamino)-ethyl]-phenyl}-methanesulfonamide (1.89 g, 50%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH:20]([SnH3])=[CH2:21].C(Cl)Cl>C1(C)C=CC=CC=1>[C:14]1([S:11]([N:6]2[C:7]3[C:3](=[C:2]([CH:20]=[CH2:21])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=C[SnH3]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 110 °C
Yield: 61.4 %

Procedure:
4-Bromo-1-(phenylsulfonyl)-1H-indole (8.52 g, 25.3 mmol, Intermediate 44) was dissolved in dry toluene (20 mL) under an N2(g) atmosphere before vinylstannane (16.07 g, 50.7 mmol) and bis[triphenylphosphine)palladium(II) acetate (0.95 g, 1.3 mmol) was added. The reaction was heated to 110° C. for 16 h cooled the reaction mixture to RT and filtered the reaction mixture through a celite pad, and evaporated the solvent. Dissolved the obtained oil in acetonitrile and hexanes, separated the phases. Evaporated the acetonitrile phase and purified the obtained crude product by flash chromatography using 30% DCM in hexanes. Isolated 4.4 g of the desired product as a white solid, yield 62%. MS (ESI+) for C16H13NO2S m/z 284 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1>CN(C)C=O>[C:13]1([N:3]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:6]3[CH:5]=[CH:4]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: Clc1nccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(-n3ccc4cccnc43)nccc2c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
0.894 g of 60% sodium hydride (37.25 mmol) was added with stirring to 20 cm3 of dimethylformamide under an argon atmosphere at a temperature in the region of 20° C. and then a solution of 4 g (33.86 mmol) of 1H-pyrrolo[2,3-b]pyridine in 20 cm3 of dimethylformamide was gradually added. After stirring at a temperature in the region of 20° C. for 30 minutes, a solution of 5.816 g (35.55 mmol) of 1-chloroisoquinoline in 20 cm3 of dimethylformamide was added and then the reaction mixture was heated at a temperature in the region of 100° C. for 15 h. After concentrating to dryness under reduced pressure (2.7 kPa), the residue was taken up in 2 times 50 cm3 of water. The residual oil was taken up in 30 cm3 of diethyl ether. The white crystals that formed were filtered off and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 20° C. 4.36 g of 1-(isoquinolin-1-yl)-1H-pyrrolo[2,3-b]pyridine were thus obtained in the form of an off-white solid melting at 87° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:11])[NH:9][NH:10][C:4]=2[CH:3]=1.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>N1C=CC=CC=1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:11])[NH:9][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: O=c1[nH][nH]c2cc(Cl)ncc12
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)n1[nH]c(=O)c2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (2.64 g, 15.57 mmol) in pyridine (10 mL) and water (14 mL) was added ethyl chloroformate (3.38 g, 31.1 mmol) drop-wise at 0° C. The reaction was removed from the ice bath and was stirred at room temperature overnight. The reaction mixture was filtered and the solid rinsed with water to afford ethyl 6-chloro-3-oxo-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate, which was carried onto the next step without further purification. MS ESI calc'd. for C9H8ClN3O3 [M+1]+242. found 242.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]([CH3:40])(=[N:13][C:14]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([C:33]4[N:37]([CH3:38])[N:36]=[C:35]([CH3:39])[CH:34]=4)=[O:32])[CH:25]=3)[CH:21]=2)=[O:15])=[O:12])[CH:6]=1.[OH-].[Na+].C(O)(=O)C>C1COCC1>[CH3:38][N:37]1[C:33]([C:31]([NH:30][C:26]2[CH:25]=[C:24]([C:23]#[C:22][C:20]3[CH:21]=[C:16]([C:14]([N:13]=[S:11]([C:7]4[CH:6]=[C:5]([CH2:4][C:3]([OH:41])=[O:2])[CH:10]=[CH:9][CH:8]=4)([CH3:40])=[O:12])=[O:15])[CH:17]=[N:18][CH:19]=3)[CH:29]=[CH:28][CH:27]=2)=[O:32])=[CH:34][C:35]([CH3:39])=[N:36]1
Reactant: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4cccc(CC(=O)O)c4)c3)c2)n(C)n1
Yield: 68.2 %

Procedure:
A 50 ml THF solution of methyl{3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}acetate (216 mg, 0.38 mmol) and 0.5M NaOH (6.1 ml, 3.04 mmol) was stirred at room temperature for 2 hours. The reaction was quenched with acetic acid (0.174 ml, 3.04 mmol) and rotary evaporated to remove the THF solvent. Additional impure lots of product (22 mg) were combined and the aqueous mixture partitioned between EtOAc and NaHCO3 solution. The EtOAc layer was extracted with another portion of NaHCO3 solution. The combined basic aqueous layers were adjusted to pH 4 using 10% HCl and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried with anhydrous Na2SO4 and rotary evaporated. The off-white solid foam was chromatographed eluting with CHCl3/MeOH and then recrystallized from a mixture of CHCl3/EtOAc/MeCN to give white solid (144 mg, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:11]12(O)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.CS(O)(=O)=O>>[C:11]12([C:6]3[C:5]4[O:8][CH2:9][O:10][C:4]=4[CH:3]=[C:2]([Br:1])[CH:7]=3)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2
Reactant: Brc1ccc2c(c1)OCO2
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)O
Product: Brc1cc2c(c(C34CC5CC(CC(C5)C3)C4)c1)OCO2
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A mixture of 4-bromo-1,2-methylenedioxybenzene (2.00 g, 9.95 mmol), 1-adamantanol (1.52 g, 9.95 mmol), and MeSO3H (5 mL) was stirred for 1 h. The resulting solution was quenched with H2O (40 mL) and extracted with EtOAc (110 mL). The extract was washed with 0.5 N NaOH, sat. NaHCO3, and brine and dried. The residue obtained on concentration was purified on silica gel (hexane) to give 2.86 g (86%) of 4-(1-adamantyl)-6-bromobenzo[1,3]dioxole as a white solid, mp 135-136° C. IR 2901, 2843, 1435, 1189 cm−1; 1H NMR δ (CDCl3) 1.76 (bs, 6H, AdCH2), 1.98 (bs, 6H, AdCH2), 2.06 (bs, 3H, AdCH), 5.93 (s, 2H, CH2), 6.84 (s, 1H, 7-ArH), 6.86 ppm (s, 1H, 5-ArH).
Reaction SMILES: [C:1]([O:8]C)(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].B1C2CCCC1CCC2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:28]1[CH:33]=[C:32]([N:34](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:31]2[N:51]=[CH:52][C:53]([C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[C:30]2[N:29]=1>C1COCC1.CN(C=O)C>[NH2:34][C:32]1[N:31]2[N:51]=[CH:52][C:53]([C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[C:30]2[N:29]=[C:28]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7])[CH:33]=1
Reactant: C=CCCCC(=O)OC
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1cc(CCCCCC(=O)O)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
To a solution of methyl hex-5-enoate (12 mg, 0.1 mmol) in THF (0.5 ml) under argon at 0° C. was added 9-BBN (0.2 mmol, 0.4 ml of 0.5 M solution in THF). The mixture was warmed to room temperature and stirred for 16 h. Potassium phosphate (3 M in H2O, 0.2 mmol) was added followed by the addition of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (50 mg, 0.09 mmol) in DMF (0.5 ml) and Pd(dppf) Cl2—CH2Cl2 (5 mg, 0.005 mmol). The reaction mixture was heated at 90° C. for 16 h under argon. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 2:1 THF:MeOH (3 mL) and was treated with 2N NaOH(aq) (0.25 mL). The resulting solution was stirred at room temperature for 4 hours followed by the addition of 2N hydrochloride solution (1.0 ml). The solution was heated at 65° C. for 2 h, cooled to room temperature, concentrated and purified by prep-LC to afford the title compound (8.2 mg): LC/MS RT=2.74 min. Mass calculated for, M+H 376.17, observed 376.17.