Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:8]=1[S:9]([NH2:12])(=[O:11])=[O:10])([OH:3])=O.CS(O)(=O)=O.[CH2:24](O)[CH:25]=[CH2:26]>>[CH2:26]([C:1]([C:4]1[CH:5]=[N:6][N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:8]=1[S:9]([NH2:12])(=[O:11])=[O:10])=[O:3])[CH:25]=[CH2:24]
Reactant: C=CCO
Reactant: NS(=O)(=O)c1c(C(=O)O)cnn1-c1ccccn1
Agent: CS(=O)(=O)O
Product: C=CCC(=O)c1cnn(-c2ccccn2)c1S(N)(=O)=O
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To a mixture of 2.2 of 4-carboxy-1-(2-pyridyl)pyrazole-5-sulfonamide and 20 ml of allyl alcohol, 1 ml of methanesulfonic acid was added, followed by stirring at 110° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, and purified by silica gel chromatography to obtain 0.7 g of the title compound. m.p.: 140° to 142° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:14]1([CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:13].C(N(CC)CC)C>C(Cl)Cl.O>[C:12]([C:14]1([CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=[O:11])[CH3:13]
Reactant: CC(O)C1(CCO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)C1(CCO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
To a solution of oxalyl chloride (3.0 mL, 34 mmol) in methylene chloride (400 mL) at −70° C. was added DMSO (4.8 mL, 68 mmol) over 5 min. After 15 min, a solution of tert-butyl 4-(1-hydroxyeth-1-yl)-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (6.6 g, 17 mmol) in methylene chloride (125 mL) was slowly added over 15 min. After 1 h, triethylamine (19 mL, 136 mmol) was added and the reaction was allowed to warm to room temperature for 1 h. The mixture was poured into water and extracted three times with methylene chloride. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate in hexanes) to afford the title product (4.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11](OC)=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1
Reactant: COC(=O)c1oc2ccc(OC)cc2c1C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2oc(C=O)c(C)c2c1
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a solution (100 mL) of methyl 5-methoxy-3-methyl-1-benzofuran-2-carboxylate (5.00 g) in tetrahydrofuran was added lithium aluminum hydride (862 mg) at 0° C., and the mixture was stirred for 1.5 hr. Water (860 μL) was added to quench the reaction, 1N aqueous sodium hydroxide solution (860 μL) was added, and the mixture was stirred at room temperature for 1 hr. The resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a pale-yellow solid. To a solution of the obtained solid in tetrahydrofuran (80 mL) was added active manganese dioxide (21.2 g), and the mixture was stirred at 50° C. overnight. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure to give the title object compound (3.41 g, 79%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:12]([O-])(=[O:15])[CH2:13][CH3:14].CC(C)([O-])C.[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:14]=[CH:13][C:12]([OH:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCC(=O)[O-]
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Oc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
N′-(3,4-Dichlorophenyl)hydrazine was liberated from its hydrochloride (8.7 g, 40.6 mmol) by partitioning the solid between dilutes Na2CO3 solution and ethyl acetate. The aqueous layer was extracted 2 more times with AcOEt, dried over Na2SO4 and the solvent removed in vacuo. The residue is taken up in t-butyl alcohol (60 ml) and, in a dry nitrogen atmosphere, the ethyle propionate (4.6 ml, 44.66 mmol) was dropwise added. The mixture was ice-cooled and potassium t-butoxide (10.5 g, 81.2 mmol) was slowly added over the time of 1 hr. The resulting mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo and ice-water was added. The resulting aqueous solution is extracted with dichloromethane and acidified to pH 6 with acetic acid. The solid precipitated was filtered off, dried and crystallized from ethyl acetate yielding 2.4 g of brown solid. The mother liquors were evaporated to dryness and the crude residue was column chromatographied on silica gel (petroleum ether/AcOEt 9:1) another fraction of 1 g was obtained (total yield 37%)
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[F:20])[NH:5][CH:4]=1)[CH3:2].N1C=CC=NC=1N.Cl.Cl[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[N:33]=[C:32]([NH2:40])[N:31]=1.[OH-].[Na+]>O>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:19]=[CH:18][C:16]([NH:17][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:37])[F:38])[N:33]=[C:32]([NH2:40])[N:31]=3)=[CH:15][C:14]=2[F:20])[NH:5][CH:4]=1)[CH3:2]
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: CCc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Agent: Cl
Agent: Nc1ncccn1
Agent: [Na+]
Solvent: O
Product: CCc1c[nH]c2nccc(Oc3ccc(Nc4cc(C(F)(F)F)nc(N)n4)cc3F)c12

Procedure:
45 mg (0.17 mmol) of 4-[(3-ethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3-fluoroaniline and 34 mg (0.17 mmol) of 4-chloro-6-trifluoromethyl)pyrimidine-2-amine are suspended in 5 ml of water. 24 μl of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Another 70 mg (0.35 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine and 40 μl of 37% strength hydrochloric acid are then added, and the mixture is heated at reflux for another night. Using 1N aqueous sodium hydroxide solution, the pH is then adjusted to 10. The mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol 100:1 to 10:1). The product obtained is purified further by preparative HPLC.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:27][S:28]([O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:10][CH:11]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of 2-(4-((tert-butyl(dimethyl)silyl]oxy}phenyl)ethanol (653 mg) and diisopropylethylamine (1.8 ml) in DCM (15 ml) at 0° under nitrogen was treated with methanesulfonyl chloride (0.44 ml) and the mixture was stirred at 0° C. for 6 h. Saturated NaHCO3 solution was added and the mixture stirred for 15 min. Water (20 ml) was added and the mixture was extracted with DCM. The extract was dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound (904 mg). LCMS RT=3.85 min.
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.OC[C:12]1(N)[CH2:16][CH2:15][CH2:14]C1.OCCN.C1(=O)CCC1>>[CH2:14]1[C:15]2([O:9][CH2:7][C:2]3([CH2:3][CH2:4][CH2:5][CH2:6]3)[NH:1]2)[CH2:16][CH2:12]1
Reactant: NC1(C(=O)O)CCCC1
Reactant: NC1(CO)CCCC1
Agent: O=C1CCC1
Solvent: NCCO
Product: C1CCC2(C1)COC1(CCC1)N2

Procedure:
1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B1c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. The 2-hydroxyethylamine was reacted with cyclobutanone according to Method B4a, Step 1 to give 5-aza-12-oxadispiro[3.1.4.2]dodecane. The oxazolidine was reduced according to Method B4a, Step 2 to give 1-(cyclobutylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to 1-(cyclobutylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1-cyclobutyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[O:9])[N:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[N:3]=1
Reactant: O=Cc1nccc(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1nccc(Cl)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Chloropyrimidine-2-carbaldehyde (4.53 g, 31.8 mmol) was taken up in MeOH (65 mL) and cooled to 0° C. NaBH4 (1.262 g, 33.4 mmol) was added and the mixture stirred at 0° C. for 90 minutes. Water was added and the reaction mixture was extracted with CHCl3 (3×).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.[N:13]1([CH2:18][C:19]2([CH2:22][NH2:23])[CH2:21][CH2:20]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:23][CH2:22][C:19]2([CH2:18][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:20][CH2:21]2)=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Reactant: NCC1(CN2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1cc(F)c(C(=O)NCC2(CN3CCCC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-amino-2,5-difluoro-benzoic acid (Rare Chemicals GmbH; 700 mg, 4.04 mmol), [1-(pyrrolidin-1-ylmethyl)cyclopropyl]methanamine (Intermediate 33; 655 mg, 4.25 mmol), HATU (1.69 g, 4.44 mmol) and DIPEA (2.1 mL, 12.12 mmol) were combined in DMF (10 mL) and stirred at room temperature for 2 hours. The reaction mixture divided into two portions and each loaded on to an SCX-2 column (20 g) pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were evaporated and the residue taken up in DCM and purified on a silica column eluting with a 0-5% gradient of 2M ammonia in MeOH/DCM then 5% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to yield the title compound as an orange gum which solidified on standing to an orange solid (472 mg, 38%)
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH3:11][C:5]1[CH:6]=[CH:7][C:8]([S:1]([OH:4])(=[O:3])=[O:2])=[CH:9][CH:10]=1
Reactant: Cc1ccccc1
Reactant: O=S(=O)=O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 50 °C
Reaction time: 22 h
Yield: 28 %

Procedure:
Sulfur trioxide (0.6 g, 7.5 mmol, stabilized, 99% from Aldrich, Milwaukee, Wis.) was weighed into a 100-ml round-bottom flask in the dry box. Toluene (50 g) was added to the sulfur trioxide via syringe under an inert atmosphere. The solution was stirred at 50° C. for 22 hours under a nitrogen atmosphere before it was cooled to room temperature. A dark colored oil formed at the bottom of the solution. The toluene and oil layer was extracted with three 10-cc portions of distilled water. The analysis by HPLC showed 28% yield of p-TSA and 5.5% o-TSA (ratio p/o=5.1) for a total yield of 33.5%.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[CH3:16])/[C:11]([O:13]CC)=[O:12])=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:17][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[C:10](\[CH3:16])/[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(N(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C(=C\c1ccc(N(C)C)cc1)C(=O)O

Procedure:
1 b) The ester from 1 a) was hydrolyzed in accordance with a standard method (sodium hydroxide in methanol). E-3-(4-Dimethylamino-phenyl)-2-methyl-acrylic acid was isolated.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:37]=[CH:36][C:23]2[N:24]([CH2:34][CH3:35])[C:25](=[O:33])[C:26]([CH3:32])([CH3:31])[C:27](=[O:30])[N:28]([CH3:29])[C:22]=2[CH:21]=1.[BH4-].[Na+]>CO>[CH2:34]([N:24]1[C:25](=[O:33])[C:26]([CH3:32])([CH3:31])[C:27](=[O:30])[N:28]([CH3:29])[C:22]2[CH:21]=[C:20]([CH2:19][CH2:18][NH:17][CH2:14][C:11]3[CH:10]=[CH:9][N:8]=[CH:13][CH:12]=3)[CH:37]=[CH:36][C:23]1=2)[CH3:35]
Reactant: O=Cc1ccncc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCN)ccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCNCc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine(0.1 ml) and 4-pyridine carbaldehyde(0.094 ml) were added to a methanol solution (10 ml) of 7-(2-aminoethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione hydrochloride(0.26 g). The mixture was stirred at room temperature for 1 hour. Sodium borohydride(0.11 g) was added, and the mixture was further stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol=9:1→3:2). The purified product was condensed under reduced pressure to give the title compound(0.21 g) as a colorless oily matter.
Reaction SMILES: FC(F)(F)S(OC1CCCC2C=C(OC)C=CC=2C=1)(=O)=O.C([Sn](CCCC)(CCCC)C1C=CC=CC=1[N+]([O-])=O)CCC.[CH3:44][O:45][C:46]1[CH:65]=[CH:64][C:49]2[CH:50]=[C:51]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[N+:61]([O-])=O)[CH2:52][CH2:53][CH2:54][C:48]=2[CH:47]=1>>[CH3:44][O:45][C:46]1[CH:65]=[CH:64][C:49]2[CH2:50][CH:51]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[NH2:61])[CH2:52][CH2:53][CH2:54][C:48]=2[CH:47]=1
Reactant: COc1ccc2c(c1)CCCC(c1ccccc1[N+](=O)[O-])=C2
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccc1[N+](=O)[O-]
Agent: COc1ccc2c(c1)CCCC(OS(=O)(=O)C(F)(F)F)=C2
Product: COc1ccc2c(c1)CCCC(c1ccccc1N)C2
Yield: 65 %

Procedure:
Synthesized from 2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl trifluoromethanesulfonate and tributyl(2-nitrophenyl)tin according to an analogous synthetic method to Preparation Example 77, 3-methoxy-8-(2-nitrophenyl)-6,7-dihydro-5H-benzocycloheptene (850 mg) was used according to an analogous synthetic method to Example 30 to provide the title compound (500 mg).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:9]([O:20][CH2:21][CH3:22])(=[O:19])[C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1.N1C=CN=C1>O1CCCC1>[Si:1]([O:16][C:15]1[CH:17]=[CH:18][C:10]([C:9]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][C:12]=1[O:13][CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.7 %

Procedure:
Tert-butyldimethylsilyl chloride (14 g) was added to a mixture of ethyl vanillate (15 g), imidazole (13 g) and tetrahydrofuran (100 ml) and the mixture was stirred at ambient temperature for 48 hours. The mixture was filtered and evaporated to give ethyl 4-(tert-butyldimethylsilyloxy)-3-methoxybenzoate (25.1 g). A solution of the product so obtained in tetrahydrofuran (50 ml) was cooled to -70° C. and to this was added a cooled (-70° C.) solution of thiazol-2-yl-lithium [prepared by adding 2-bromothiazole (14.1 g) to a mixture of n-butyl-lithium (1.5M in hexane, 57.3 ml) and diethyl ether (30 ml) which had been cooled to -70° C⟧ The mixture was stirred for 16 hours are allowed to warm to ambient temperature. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water and with a saturated aqueous sodium chloride solution, dried (MgSO4 ) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 4-hydroxy-3-methoxyphenyl 2-thiazolyl ketone (4.5 g) in 24% yield, m.p. 103° C.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][CH3:18])=[CH:13][CH:14]=1)[CH3:3].C(O)(=O)/C=C/C=C/C>CC(C)=O>[CH3:3][CH:2]([NH:4][CH2:5][C@H:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][CH3:18])=[CH:13][CH:14]=1)[CH3:1]
Reactant: COCCc1ccc(OCC(O)CNC(C)C)cc1
Agent: C/C=C/C=C/C(=O)O
Solvent: CC(C)=O
Product: COCCc1ccc(OC[C@@H](O)CNC(C)C)cc1
Temperature: 0 °C
Yield: 115.3 %

Procedure:
To the stirred acetone solution of metoprolol base (19.3 mol), acetone (30 l) and sorbic acid (2.12 kg, 18.9 mol) were added at room temperature. The mixture was heated to reflux and the hot solution was filtered. The filtrate was allowed to cool slowly to 0° C. The crystals were centrifugated off, washed with cold acetone (10 l) and dried for three days in vacuo at room temperature to yield 5.95 kg of crystalline (S)-metoprolol. (81% from (4)).
Reaction SMILES: [C:1]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+].[I-].[Na+]>CN(C)C=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:13][C:11]3[N:12]=[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[S:9][CH:10]=3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CC(C)(C)C(=O)Nc1nc(CCl)cs1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Yield: 41.6 %

Procedure:
A mixture of 2-pivaloylamino-4-chloromethylthiazole (0.42 g), 3-(4-piperidyl)indole (0.34 g), sodium hydrogen carbonate (0.23 g), N,N-dimethylformamide (4.2 ml) and a trace amount of sodium iodide was stirred at 50° C. for 2 hours. The insoluble material was filtered off and the filtrate was washed with a mixture of chloroform and methanol (10:1 V/V). The washings and the filtrate were combined and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and recrystallized from ethanol to give 4-[4-(3-indolyl)piperidinomethyl]-2-pivaloylaminothiazole (280 mg).
Reaction SMILES: C([O:4][CH:5]1[C:10]2=[N:11][C:12]([CH3:20])=[C:13]([C:15]([O:17][CH2:18]C)=[O:16])[CH:14]=[C:9]2[CH2:8][CH2:7][CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:4][CH:5]1[C:10]2=[N:11][C:12]([CH3:20])=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:14]=[C:9]2[CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)c1cc2c(nc1C)C(OC(C)=O)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)c1cc2c(nc1C)C(O)CCC2
Reaction time: 14 h
Yield: 93.9 %

Procedure:
Ethyl 8-acetoxy-2-methyl-5,6,7,8-tetrahydrocyclohexa[b]pyridine-3-carboxylate (6.12 g, 22.1 mmol) was dissolved in ethanol (30.0 ml), and the solution was mixed with potassium carbonate (3.68 g) and stirred at from 0° C. to room temperature for 14 hours. The solvent was evaporated under reduced pressure, and the thus obtained residue was mixed with water and ethyl acetate and extracted with ethyl acetate. The thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:1) to obtain the title compound (4.59 g, 93.9%) as white amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[CH:33][C:32]([F:49])=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[CH:33][C:32]([F:49])=[CH:31][C:30]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
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: COCCOC
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one (130c) (240 mg, 0.636 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (336 mg, 0.763 mmol), Pd(PPh3)4 (37 mg, 0.0318 mmol), Na2CO3 aqueous solution (1.0 N, 2.1 mL, 2.1 mmol), 1,2-dimethoxyethane (4.2 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (3×30 mL), brine (30 mL), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 242a.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[O:15])=[CH:11][C:10]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][C:38](Cl)=[O:39].CCN(CC)CC>C1COCC1>[C:30]([C:10]1[CH:11]=[C:12]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)=[O:15])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:38](=[O:39])[CH2:37][CH2:36][O:35][CH3:34])=[CH:3][CH:4]=2)[N:9]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COCCC(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(N)cc2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCC(=O)Nc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 21.4 %

Procedure:
To a solution of 1-[2-(4-aminophenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea (200 mg, 0.45 mmol) and 3-methoxypropionyl chloride (55 mg, 0.45 mmol) in anhydrous THF (5 mL) was added Et3N (69 mg, 0.68 mmol). The reaction was stirred at room temperature for 7 h, and then partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (1:1 hexanes/EtOAc) to give 51 mg (21%) of the desired product. 1H-NMR (DMSO-d6) δ 10.16 (s, 1H), 9.14 (s, 1H), 8.42 (d, J=4.8 Hz, 2H), 8.34 (s, 1H), 7.74 (d, J=6.9 Hz, 2H), 7.48 (d, J=6.9 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 7.08 (d, J=6.6 Hz, 2H), 6.88 (d, J=5.4 Hz, 2H), 6.35 (s, 1H), 3.63 (t, J=6.0 Hz, 2H), 3.33 (s, 3H), 2.57 (t, J=6.0 Hz, 2H), 1.27 (s, 9H); MS LC-MS [M+H]+=529, RT=2.20 min.