Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][NH2:33].[BH4-].[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:33][CH3:32])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC)c4)cc23)CC1
Yield: 83.1 %

Procedure:
Following the general procedure of example 24, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.045 mmol), methylamine (130 uL, 0.27 mmol) and NaBH4 (10 mg, 0.27 mmol) were reacted to give title compound (17.0 mg, 83%).
Reaction SMILES: C(=O)([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:12]([N:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH3:15])=[O:13])[CH:5]=1)C.[OH-].[K+].C([N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:39]1[CH2:53]Br)(=O)C.Cl>C(O)C>[C:28]([O:27][C:25]([NH:24][C@H:11]([C:12]([N:14]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:15])=[O:13])[CH2:10][C:6]1[CH:5]=[C:4]([S:3][CH2:53][C:39]2[NH:38][C:46]3[C:41]([C:40]=2[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:9]=[CH:8][CH:7]=1)=[O:26])([CH3:30])([CH3:31])[CH3:29]
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(SC(C)=O)c2)NC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)Cc1c(CBr)n(C(C)=O)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Cc1c(CSc2cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c3ccc(OC)cc3)c2)[nH]c2ccccc12
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
To a solution of (S)—S-3-(2-(tert-butoxycarbonylamino)-3-((4-methoxyphenyl)(methyl)amino)-3-oxopropyl)phenyl ethanethioate (335 mg, 0.73 mmol) in ethanol (2 ml) was added potassium hydroxide (82 mg, 1.46 mmol). After 10 minutes, ethyl 2-(1-acetyl-2-(bromomethyl)-1H-indol-3-yl)acetate (I-4A, 272 mg, 0.8 mmol) was added. The reaction was stirred for 2 hours and then neutralized with 1N (aq) HCl then extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (1-5% MeOH/DCM) to provide the desired product (347 mg, 0.55 mmol), 75.3%. MS (m/z) 632 [M+H]+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:6]([C:7]1[N:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cnc2cccnn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnc2cccnn12
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
To a solution of 3-((trimethylsilyl)ethynyl) imidazo[1,2-b]pyridazine (28.46 g, 0.132 mol) in 200 mL of THF was added 145 mL (0.145 mol) of tetrabutylammonium fluoride (1.0M in THF) at ambient temperature. The solution was stirred for 15 min, concentrated, and the crude product purified by silica gel flash chromatography (eluted with 0-5% MeOH/DCM) to provide 17.84 g of product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[N:16]1([CH2:21][C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCCC2)cc1
Yield: 42.9 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.00 mmol) was reacted with 4-(pyrrolidin-1-ylmethyl)aniline (374 mg, 1.50 mmol) to afford the desired product (182 mg, 43%) as a light orange solid. ESI MS m/z 424 [C22H22BrN3O+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[C:12]=2[C:21](OCC)=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[C:12]=2[C:21]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: CCOC(=O)C1=C(c2ccc(OC)c(OC)c2)c2ccccc2C1=O
Agent: Cl
Product: COc1ccc(C2=C(C(=O)N3CCOCC3)C(=O)c3ccccc32)cc1OC
Yield: 98 %

Procedure:
The indenone obtained in Example 108 (0.9 g) is heated with morpholine (10 ml) for 1 hour. The reaction mixture is poured into a solution of dilute hydrochloric acid and extracted with ethyl acetate, washed with water and concentrated. The produce is obtained with a yield of 98% (m.p.=71.5°; compound no. 109).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=3)[O:11][C:10]=2[CH3:21])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:24][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[O:11][C:10]=1[CH3:21]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccc(F)cn2)cc1C(O)C1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccc(F)cn2)cc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl[5-(5-fluoropyridin-2-yl)-2-methylfuran-3-yl]methanol (0.7 g) in toluene (10 mL) was added thionyl chloride (0.3 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (0.7 g, 100%) as a yellow crystal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH2:10][C:11]([O:13]CC)=O)=[O:7])C.COC(=O)CC(N(CC1C=CC=CC=1)CCC(OCC)=O)=O.C[O-].[Na+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:1][O:3][C:4]([CH:5]1[C:11](=[O:13])[CH2:10][CH2:9][N:8]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:6]1=[O:7])=[O:23]
Reactant: CCOC(=O)CCN(Cc1ccccc1)C(=O)CC(=O)OCC
Agent: CCOC(=O)CCN(Cc1ccccc1)C(=O)CC(=O)OC
Agent: C[O-]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: COC(=O)C1C(=O)CCN(Cc2ccccc2)C1=O
Yield: 68 %

Procedure:
The generated mixture of N-benzyl-N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester and N-benzyl-N-(2-ethoxycarbonyl-ethyl)-malonamic acid methyl ester was treated with sodium methoxide (2.97 mL, 13.0 mmol, 25% solution) in toluene at reflux for 18 hours. The cooled reaction mixture was acidified with 10% sulfuric acid and concentrated under vacuum. The resulting residue was dissolved in DCM and washed with water and brine, then dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel (gradient: 0 to 2% methanol in DCM) to afford 2.09 g (68%) of 1-benzyl-2,4-dioxo-piperidine-3-carboxylic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ: 7.29 (m, 5H), 4.70 (s, 1H), 4.64 (s, 2H), 3.93 (s, 3H), 3.34 (t, 2H), 2.59 (t, 2H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[N:6]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:7]2[C:12]([N:13]=1)=[C:11]([NH2:14])[N:10]=[C:9]([NH:15][C@@H:16]([CH3:20])[CH2:17][CH2:18][CH3:19])[N:8]=2>CO>[CH3:20][C@H:16]([NH:15][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:5]([O:2][CH3:1])[N:6]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:11]([NH2:14])[N:10]=1)[CH2:17][CH2:18][CH3:19]
Reactant: C[O-]
Reactant: CCC[C@H](C)Nc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](C)Nc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Reaction time: 18 h

Procedure:
A solution of sodium methoxide in methanol (0.5M, 13 ml, 6.5 mmol) was added to a solution of 8-bromo-N2-[(1S)-1-methylbutyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (1.26 g, 3.29 mmol) in methanol (10 ml) and the resulting solution heated under reflux for 4 hours. More sodium methoxide in methanol (0.5M, 12 ml, 6 mmol) was then added and refluxing continued for a further 18 hours. The mixture was cooled and evaporated and the residue partitioned between ethyl acetate (75 ml) and water (75 ml). The aqueous phase was re-extracted with ethyl acetate (75 ml) and the combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in dichloromethane and purified on a 100 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate in cyclohexane gradient followed by a 0-20% methanol (+1% triethylamine) gradient over 15 mins. The product-containing fractions were combined and evaporated in vacuo to give the title compound as a white foam (0.848 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:26])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C#N)cc(C(=O)O)cc1C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)Cl)cc1C(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-cyano-5-isopropyl-4-methoxybenzoic acid (658 mg), toluene (7 mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.33 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (710 mg) as a brown oily substance.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1.N1C=CN=C1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].Cl>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH2:7][O:8][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20])[S:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1nc(Br)cs1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1nc(Br)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-bromothiazol-2-yl)methanol (1.30 g) and imidazole (600 mg) in THF (10 mL) was added dropwise tert-butyldimethylchlorosilane (1.60 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.90 g) as a colorless oil.
Reaction SMILES: I[CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1.Cl.[CH3:21][N:22]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:21][N:22]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2([CH3:19])[O:18][C:6]3=[C:7]([CH3:17])[C:8]4[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=4[C:13]([CH3:14])=[C:5]3[CH2:4]2)[CH2:34][CH2:33]1)[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1
Reactant: CN(c1nc2ccccc2s1)C1CCNCC1
Reactant: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CI)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CN1CCC(N(C)c3nc4ccccc4s3)CC1)C2
Temperature: 180 °C
Reaction time: 4.5 h
Yield: 47.1 %

Procedure:
A suspension of 3,5,6,7-tetrahydro-2-(iodomethyl)-2,4,6,6,8-pentamethyl-2H-furo[2,3-f]indole (372 mg, 1.00 mmol), N-methyl-N-(4-piperidinyl)-1,3-benzothiazole-2-amine hydrochloride (427 mg, 1.50 mmol) and potassium carbonate (485 mg, 3.51 mmol) in N,N-dimethylacetamide (2 ml) was stirred for 4.5 hours at 180° C. under nitrogen atmosphere. Water was added to the reaction mixture and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane:ethyl acetate=5:1) and crystallized from ethyl acetate-hexane to obtain 231 mg of the title compound.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([O:29]CC)=O)=[O:24])[CH:19]=[CH:20][CH:21]=1)(=O)C.[H-].[Na+]>C(O)C>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]([N:22]2[C:27](=[O:29])[CH2:26][NH:25][C:23]2=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CNC(=O)Nc1cccc(CCCCOCCCCCCOC(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CNC(=O)N1c1cccc(CCCCOCCCCCCO)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 112.7 %

Procedure:
A solution of ethyl N-({[3-(4-{[6-(acetyloxy)hexyl]oxy}butyl)phenyl]amino}-carbonyl)glycinate (2.967 g) in ethanol (30 ml) was treated under nitrogen with sodium hydride (60% oil dispersion; 280 mg) and the mixture was stirred for 18 h. The solvent was removed under reduced pressure, the residue was dissolved in acetic acid (10 ml) and conc. HBr (1 ml) and the mixture was heated to 75° C. for 1 h. The solvent was removed under reduced pressure, the residue was partitioned between EtOAc and brine. The organic solution was washed with brine, dried and evaporated to dryness. The residue was dissolved in MeOH (30 ml), SOCl2 (0.5 ml) was added, and the solution was stirred for 2 h. The solvent was removed under reduced pressure to give the title compound (2.67 g) ES+ve 349 (MH)+.
Reaction SMILES: [C:1]([CH:6]1[CH:10]2[O:11][C:12](=[O:22])[CH:13]3[CH:14]([C:15]([O:17]C(C)(C)C)=[O:16])[CH:7]1[CH2:8][CH:9]23)(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C)C=CC=CC=1.C(OC(C)(C)C)=O>C(O)=O>[C:1]([CH:6]1[CH:10]2[O:11][C:12](=[O:22])[CH:13]3[CH:14]([C:15]([OH:17])=[O:16])[CH:7]1[CH2:8][CH:9]23)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)C1C2CC3C1OC(=O)C3C2C(=O)OC(C)(C)C
Agent: CC(C)(C)OC=O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)C1C2CC3C1OC(=O)C3C2C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
In 80 g of formic acid was dissolved 20.0 g of the methacrylate obtained in Example 1-1-1. The solution was stirred at room temperature overnight. Toluene was added to the reaction solution, from which formic acid and tert-butyl formate were azeotroped off. Recrystallization from hexane yielded 14.7 g of the target compound (yield 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH:11]([OH:18])[CH2:12]OS(C)(=O)=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>C(O)(C)C>[CH:19]([NH:22][CH2:12][CH:11]([OH:18])[CH2:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)([CH3:21])[CH3:20]
Reactant: COc1ncccc1OCC(O)COS(C)(=O)=O
Reactant: CC(C)N
Solvent: CC(C)O
Product: COc1ncccc1OCC(O)CNC(C)C

Procedure:
22 g of crude 2-methoxy-3-(3'-methanesulphonyloxy-2'-hydroxy-propoxy)-pyridine, 50 ml of isopropylamine and 150 ml of isopropanol are heated for 16 hours under reflux. After working up analogously to Example 14, 3-(3'-isopropylamino-2'-hydroxypropoxy)-2-methoxy-pyridine is obtained, which melts at 50°-65° C. after recrystallisation from ether-pentane. After reaction with half the equivalent amount of fumaric acid, the neutral fumarate of melting point 146°-147° C. (recrystallised from acetone) is obtained.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]4[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=O)=O)C=CC=CC=1.C(O)C.[OH-].[Na+].Cl>C(OCC)(=O)C>[CH:28]1([CH:27]=[C:26]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([CH:19]4[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[O:20]4)[CH:18]=[C:13]3[CH:12]=2)[C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC1(C)OCC(c2cnc3c(c2)cc(C(=CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n3S(=O)(=O)c2ccccc2)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)OCC(c2cnc3[nH]c(C(=CC4CCCC4)c4ccc(S(C)(=O)=O)cc4)cc3c2)O1
Yield: 95.6 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridine (950 mg, 1.57 mmol), ethanol (3 mL), and a 10% aqueous sodium hydroxide solution (1.5 mL) was heated at 100° C. for 1 h. The mixture was acidified to pH 4-5 with a 2N aqueous hydrochloric acid solution, diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridine (700 mg, 96%) as a light yellow solid: LC/MS m/e calcd for C26H30N2O4S [M+H]+ 467.6, observed 467.1.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([O:10]O)([CH3:9])([CH3:8])[CH3:7].S(=O)(=O)(O)O>O>[C:1]([O:5][O:10][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)OOC(C)(C)C

Procedure:
In Unit 3, the dehydration stage, the mixture of tertiary butanol and tertiary butyl hydroperoxide is dehydrated with concentrated sulphuric acid to form di-tertiary butyl peroxide and water. The products of Unit 3, di-tertiary butyl peroxide and water, present as an aqueous solution of sulphuric acid, are immiscible and can conventiently be separated by decantation, the di-tertiary butyl peroxide layer being fed to Unit 4 for carbonylation and the aqueous layer containing sulphuric acid being fed to a concentrator Unit 6 prior to recycling to Unit 3. The dehydration step is typically carried out in the temperature range 20°-80° C. preferably 30°-60° C. and at a pressure of up to 150 psig. A typical dehydration process using sulphuric acid is described in U.S. Pat. No. 2,862,973.
Reaction SMILES: [Cl-].[O:2]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1>>[O:2]([C:9]([CH3:14])([CH3:13])[C:10]([N:25]1[CH2:24][CH2:23][N:22]([CH2:21][C:20]2[CH:28]=[CH:29][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH2:27][CH2:26]1)=[O:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(Oc1ccccc1)C(=O)O
Agent: [Cl-]
Product: COc1ccc(CN2CCN(C(=O)C(C)(C)Oc3ccccc3)CC2)cc1

Procedure:
By carrying out the preparation as in Example 12, but using the chloride of 2-phenoxy-2-methylpropionic acid and 1-(4-methoxybenzyl)piperazine, the title product is obtained.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[CH2:24][CH3:25]>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[CH2:24][CH3:25]
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reactant: CCCI
Product: CCCN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using propyl iodide as the alkyl halide and following the procedure of Step B-D of Example 255, as an amorphous tan solid. 1H NMR (CDCl3, 300 MHz) δ 0.94 (t, 2H), 1.40–2.01 (m, 6H), 2.65–2.70 (t, J=9.6 Hz, 2H), 2.70–2.95 (m, 2H), 2.95–3.45 (m, 7H)), 3.3.60–3.95 (m, 1H), 6.37 (d, J=7.7 Hz, 1H), 6.46 (d, J=7.0 Hz, 1H), 6.64 (t, J=7.6 Hz) ppm. MS (CI): 258 (M+H+).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][O:42][CH:43]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:39]4[CH:40]=[N:41][O:42][CH:43]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2c(-c3cnoc3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Yield: 22.5 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (100 mg, 0.191 mmol) in 1,4-dioxane (2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (55.8 mg, 0.286 mmol), potassium carbonate (79 mg, 0.573 mmol) and bis(triphenylphosphine)palladium(II) chloride (13.40 mg, 0.019 mmol). Water (0.5 mL) was then added and the mixture heated at 100° C. in a microwave for 15 min. The solvent was then removed in vacuo and the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase was re-extracted with ethyl acetate (2×20 mL). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-40% ethyl acetate in cyclohexane, to give the title compound (22 mg). LCMS (A) m/z: 512 [M+1]+, Rt 1.36 min (acidic).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:12][CH:13]1[C:20](OC)([O:21]C)[CH2:19][CH2:18][C:15]2([O:17][CH2:16]2)[C:14]1([OH:29])[C:25]([CH3:28])=[CH:26][CH3:27]>CC(C)=O.O>[Br:12][CH:13]1[C:20](=[O:21])[CH2:19][CH2:18][C:15]2([O:17][CH2:16]2)[C:14]1([OH:29])[C:25]([CH3:28])=[CH:26][CH3:27]
Reactant: CC=C(C)C1(O)C(Br)C(OC)(OC)CCC12CO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC=C(C)C1(O)C(Br)C(=O)CCC12CO2
Yield: 81.3 %

Procedure:
1.9 g (9.96 mmol) of para-toluenesulphonic acid are added at room temperature to a solution of 3.2 g (9.96 mmol) of the compound obtained in Step B in 120 ml of an acetone/water mixture (3:2). When the reaction, followed by thin-layer chromatrography, is complete, the acetone is evaporated off. The aqueous phase remaining is then extracted with ethyl acetate (200 ml). After conventional treatment of the organic phase, 2.23 g (8.1 mmol) of the expected product are obtained.