Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[PH:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13].CCN(CC)CC>C1(C)C=CC=CC=1.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>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[P:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)PC(C)C
Reactant: BrC1=Cc2ccccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)P(C1=Cc2ccccc2C1)C(C)C

Procedure:
Following the procedure described for the synthesis of 3 (method A), 15.81 g (0.081 mol) of 2-bromo-1H-indene, 9.54 g (0.081 mol) of iPr2PH, 13.9 ml (10.09 g, 0.100 mol) of Et3N, and 2.95 g (2.55 mmol) of Pd(PPh3)4 in 60 ml of toluene gave 1H-Inden-2-yl(diisopropyl)phosphine. The crude product was distilled in vacuum (104–106° C./2 mm). Yield 14.8 g (80%) of colorless oil of 1H-Inden-2-yl(diisopropyl)phosphine, 4.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][N:5]=[C:4]([C:7]2[CH2:8][N:9](/[N:14]=[CH:15]/[C:16]3[CH:17]=[N:18][CH:19]=[C:20]([F:22])[CH:21]=3)[C:10](=[O:13])[NH:11][N:12]=2)[CH2:3]1.[H-].[Na+].Br[CH2:27][C:28]#[N:29]>C1COCC1>[CH3:1][C:2]1([CH3:23])[O:6][N:5]=[C:4]([C:7]2[CH2:8][N:9](/[N:14]=[CH:15]/[C:16]3[CH:17]=[N:18][CH:19]=[C:20]([F:22])[CH:21]=3)[C:10](=[O:13])[N:11]([CH2:27][C:28]#[N:29])[N:12]=2)[CH2:3]1
Reactant: N#CCBr
Reactant: CC1(C)CC(C2=NNC(=O)N(/N=C/c3cncc(F)c3)C2)=NO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(C2=NN(CC#N)C(=O)N(/N=C/c3cncc(F)c3)C2)=NO1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(5,5-dimethyl-4H-isoxazol-3-yl)-4-[(E)-(5-fluoro-3-pyridyl)methyleneamino]-2,5-dihydro-1,2,4-triazin-3-one (150 mg, 0.471 mmol) in anhydrous THF (8.0 mL) was added NaH (28.2 mg, 0.707 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min followed by dropwise addition of 2-bromoacetonitrile (36.2 μL, 62.2 mg, 0.518 mmol). The reaction mixture was allowed to warm to room temp. and stirring was continued for 2 h. The reaction mixture was quenched by addition of methanol followed by ice. The organic layer was evaporated in rotavap and aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to furnish the crude product. Purification by flash chromatography (60-70% EtOAc/hexanes) provided the desired product as a white solid. M.p. 195-197° C.
Reaction SMILES: C([O:8][C:9]([C:11]1[NH:12][C:13]([CH3:23])=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15]=1[CH3:16])=[O:10])C1C=CC=CC=1>[Pd].CO>[C:9]([C:11]1[NH:12][C:13]([CH3:23])=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15]=1[CH3:16])([OH:10])=[O:8]
Reactant: COC(=O)CCc1c(C)[nH]c(C(=O)OCc2ccccc2)c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1c(C)[nH]c(C(=O)O)c1C
Yield: 91 %

Procedure:
2-Benzyloxycarbonyl-3,5-dimethyl-4-(2-methoxycarbonylethyl)pyrrole (Aldrich, 2.0 g) was hydrogenated over 0.2 g of 10% palladium on carbon in 40 mL of methanol for 2 hours at room temperature. The catalyst was removed by filtration and washed with 40 mL of methanol. The filtrate was evaporated to dryness and dried overnight in a vacuum oven to give 1.3 g (92% yield) of 2-carboxy-3,5-dimethyl-4-(2-methoxycarbonylethyl)pyrrole.
Reaction SMILES: [C:1](=[O:14])([O:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[O:2][CH2:3]Cl.[I-:15].[Na+]>C(#N)C>[C:1](=[O:14])([O:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[O:2][CH2:3][I:15]
Reactant: CC(C)(C)OC(=O)COC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COC(=O)OCI
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Chloromethyl tert-butoxycarbonylmethyl carbonate (6.45 g) was added to a solution of sodium iodide (16.5 g) in acetonitril (65 ml). After stirring at 40° C. for 4 hours the reaction mixture was cooled in ice, filtered and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous sodium bicarbonate and sodium thiosulfate, dried over magnesium sulfate, filtered and evaporated in vacuo. Purification on silica gel with hexane/ethyl acetate (3:1) as eluent gave the title compound as a colourless oil.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:11])[CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21](O)=[O:22])=[N:13]1.C(N(CC)CC)C>ClCCl>[CH3:3][N:4]([CH3:11])[CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][N:13]=2)=[O:22])[CH2:6]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CN(C)C1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C1CCCN(C(=O)c2n[nH]c3ccccc23)C1
Reaction time: 48 h
Yield: 12.1 %

Procedure:
Dicyclohexycarbodiimide (1.25 g) was added to a stirred solution of 3-dimethylaminopiperidine dihydrochloride (1 g, 5 mmol), indazole3-carboxylic acid (1.05 g, 6 mmol) and triethylamine (1.25 g) in dichloromethane (25 ml). The mixture was stirred for 48 h, filtered and the filtrate extracted with 1M hydrochloric acid. The acid extracts were combined, washed with a little dichloromethane then basified with ammonia solution and back-extracted into chloroform. The extract was dried and evaporated. The residue was chromotographed on silica using methanol-methyl acetate (1:9) as eluent to give the product which was crystallised from a low volume of ethyl acetate to give the product (0.165 g) mp 141-142° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[O:18])[CH3:17].CON(C)[C:22]([C:24]1[N:25]=[N:26][N:27]([CH2:35][C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[C:28]=1[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:23].Cl>C1COCC1>[F:45][C:42]([F:43])([F:44])[C:40]1[CH:41]=[C:36]([CH:37]=[C:38]([C:46]([F:47])([F:49])[F:48])[CH:39]=1)[CH2:35][N:27]1[C:28]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[C:24]([C:22](=[O:23])[CH2:17][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])=[O:18])[N:25]=[N:26]1
Reactant: CON(C)C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Reactant: CC(=O)c1ccccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1)c1ccccc1Cl
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
Add lithium diisopropylamide (6 mL, 1.0 M in THF) to a solution of 1-(2-chloro-phenyl)-ethanone (0.929 g, 6.01 mmol) in THF (10 mL) at −78° C. and stir for 30 min. To the above enolate solution at −78° C., add a solution of 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid methoxy-N-methyl-amide (1.29 g, 2.81 mmol) in THF (15 mL) via cannula. Warm solution to 70° C. and stir for 4 hours, than add 1N HCl (6 mL) and stir for an additional 30 min. Concentrate the mixture in vacuo to ¼ volume, dilute with EtOAc (60 mL) and wash with water (30 mL), saturated NaHCO3 (30 mL), and brine (30 mL). Dry, filter, and concentrate the organic phase and purify the crude material by flash chromatography using a linear gradient of 20% to 80% EtOAc/hexanes to give the title compound (1.07 g, 69%) as an orange foam. MS (IS) 553.2 (M+1), MS (ES−) 551.2 (M−1). 1H NMR (400 MHz, CDCl3): δ 15.5 (m, 1H), 7.78 (dd, 1H, J=1.3, 4.8), 8.54 (d, 1H, J=2.2), 7.81 (s, 1H), 7.64 (dd, 1H, J=2.0, 7.7), 7.57 (dt, 1H, J=2.0, 7.9), 7.44 (m, 4H), 7.38 (dt, 1H, J=1.8, 7.5), 7.33 (dt, 1H, J=1.5, 7.5), 7.19 (s, 1H), 5.59 (s, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.O([CH2:26][C:27]([F:30])([F:29])[F:28])S(C(F)(F)F)(=O)=O>O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 103.5 %

Procedure:
A mixture of 4-iodo-pyrazole (582 mg, 3.0 mmole) and cesium carbonate (1.96 g, 6.0 mmole) was stirred with DMF (6 mL) for 5 minutes. Trifluoroethyl triflate (0.52 mL, 870 mg, 3.75 mmole) was added and the reaction was stirred at room temperature for 4.5 hours. The reaction was added to water (60 mL) and extracted with ether (3×25 mL). The combined organic extracts were washed with water (3×20 mL) and with brine; then dried (MgSO4) and evaporated to afford the title compound (857 mg, 89%). 1H-NMR (CDCl3, 500 MHz): δ 4.72 (q, J=8.20, 2H), 7.58 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[OH:12][C:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]=2[O:16][S:15](=O)(=O)[CH:14]=1.Cl>CN(C=O)C>[OH:12][C:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]=2[O:16][S:15][C:14]=1[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: O=C=Nc1ccccc1
Reactant: O=S1(=O)C=C(O)c2cccc(-c3ccccc3)c2O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)C1=C(O)c2cccc(-c3ccccc3)c2OS1
Yield: 101.3 %

Procedure:
Phenylisocyanate (20.5 mmol) was added to a cooled DMF solution (25 ml) containing 20.5 mmol of NaH and 5.0 g (18.3 mmol) of 4-hydroxy-8-phenyl-1,2-benzoxathiin-2,2-dioxide. The resultant mixture was heated at 75° for 2.5 hours. The mixture was cooled, poured into ice-H2O (100 ml) and acidified with HCl. The resultant precipitate was collected by filtration and gave 6.70 g (93.3%) of the expected product, mp. 175°. The crude product was purified by recrystallization from 2-PrOH/hexane to give the analytical sample, mp. 181°-183°.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]([C:28]#[N:29])([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:15][CH:14]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[H-].[Na+]>COCCOC>[CH3:12][O:11][C:9]([CH:8]1[CH2:7][C:6]([C:28]#[N:29])([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:14]=2)[CH2:5][CH2:4][C:3]1=[O:2])=[O:10]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OCCCN2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1CC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CCC1=O
Temperature: 20 °C
Reaction time: 4.5 h
Yield: 81.4 %

Procedure:
To a solution of 4-cyano-4-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-heptanedioic acid dimethyl ester (8.8 g, 21.1 mmol) in 1,2-dimethoxyethane (176 mL) was charged portions of NaH (60% dispersion, 2.55 g, 63.4 mmol). The reaction mixture was heated to reflux. After 4.5 hr, the ¾ of solvent were evaporated and the mixture cooled to 20° C. with an ice bath and quenched with water (100 mL), HCl 1N (100 mL). The aqueous layer was extracted with ether (100 mL). After basification with NaOH the aqueous phases were extracted with dichloromethane. The combined organics were washed with water, dried over Na2SO4, filtrered and concentrated to provide 5-cyano-2-oxo-5-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexane-carboxylic acid methyl ester (6.6 g, 81%) as an oil. 1H NMR (400 MHz, CDCl3) δ12.2 (bs, 1H); 7.33 (d, 2H); 6.95 (d, 2H); 4.08-4.00 (m, 2H); 3.75 (s, 3H); 2.95 (d, 1H); 2.80-2.70 (m, 1H); 2.65-2.60 (m, 2H); 2.50-2.42 (m, 6H); 2.30-2.15 (m, 2H); 2.05-1.95 (m, 2H); 1.90-1.85 (m, 4H).
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:17](=[O:28])([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[NH2:18]>C(OCC)C>[CH3:3][C:2]([CH3:4])=[CH:1][NH:18][C:17](=[O:28])[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC(C)C=O
Reactant: CCCCCCCCOC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCCCCCCOC(=O)NC=C(C)C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
126 parts of isobutyraldehyde and 7 parts of p-toluenesulfonic acid are added in succession to a solution of 605.5 parts of n-octyl carbamate in 1,750 parts by volume of diethyl ether at 25° C., after which the temperature rises to 40° C. for one hour. After one day, the solid product which as crystallized out is filtered off with suction and fractionally distilled in the presence of 10 parts of p-toluenesulfonic acid and one part of hydroquinone. 298.3 parts of n-octyl N-(2-methyl-1-propenyl)-carbamate (75.1% yield, based on isobutyraldehyde employed) of boiling point 126° C./1 mbar are obtained, and 279.5 parts of n-octyl carbamate are recovered and can be re-used.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2c(cc1Br)N(C(C)=O)CC2
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A stirred solution of 1-acetyl-6-bromoindolin-5-ol (Tetrahedron 1973, 29(8), 1115; 40 g, 0.15 mole) in DMF (500 ml) was treated with K2CO3 (61 g, 0.45 mole) and iodomethane (11.7 ml, 0.19 mole) and maintained at room temperature for 20 h, then concentrated under vacuum to 200 ml. The residue was treated with water (200 ml) and the precipitate filtered off, dried and recrystallised from EtOAc to afford the title compound as a white solid (35.7 g, 85%). MH+ 270/272.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[C:10]=1[CH3:11])[C:5](Cl)=[O:6].[N+:16](=[CH2:18])=[N-:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH:18]=[N+:16]=[N-:17])[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[C:10]=1[CH3:11]
Reactant: Cc1c(Cl)cc(C(=O)Cl)cc1S(N)(=O)=O
Reactant: C=[N+]=[N-]
Product: Cc1c(Cl)cc(C(=O)C=[N+]=[N-])cc1S(N)(=O)=O

Procedure:
26.7 g of 3-chloro-4-methyl-5-sulfamoyl-benzoyl chloride were reacted in a manner analogous to that described in Example 1 b with diazomethane to yield the 3'-chloro-4'-methyl-5'-sulfamoyl-diazoacetophenone, M.p. 184° C.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[NH2:12][N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH:12][N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: Nn1cccc1
Reactant: CCCCN1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCN1CCC(Nn2cccc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A solution of 1-butyl-4-piperidone (6.2 g, 40 mmole) and 1-aminopyrrole (3.3 g, 40 mmole) in 100 ml of toluene was stirred at reflux overnight (about 16 hours). The mixture was cooled and then evaporated to an oil, which in turn was dissolved in 75 ml of isopropanol, and 22 ml of ethanol. To the solution was added NaBH4 (3.8 g, 100 mole). The mixture was stirred at 70° C. for 2 hours and then evaporated, stirred with water and extracted with ethyl acetate-ether. The organic extract was washed with water and saturated NaCl solution, dried (anhydrous MgSO4), filtered and evaporated to 13 g of an oil. This oil was purified by high pressure liquid chromatography (silica, 1% diethylamine/ethyl acetate) to give 8.2 g of an oil of 1-(n-butyl)-4-(1H-pyrrol-1-yl)aminopiperidine.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][C:7]=1[CH3:13].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][C:17]([CH2:16][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:14])=[C:7]([CH3:13])[CH:8]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)COc1ccc(S)cc1C
Reactant: BrCc1ccc(-c2ccccc2)cc1
Product: Cc1cc(SCc2ccc(-c3ccccc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 2C and 1E. MS m/z 379 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[CH:5]=[CH:4][N:3]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(C)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(-c2nc(NC(=O)Nc3ccccc3)sc2-c2ccnc(C)n2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of [5-(2-methyl-4-pyrimidinyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.8 mmol) in N,N-dimethylacetamide (10 mL) was added phenylisocyanate (0.29 mL, 2.7 mmol), and the mixture was stirred at 80° C. for 2 hrs. Into the reaction mixture was poured aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The resulting crystals were recrystallized from ethyl acetate-hexane to give the title compound (0.55 g, yield 78%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][OH:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].O>CS(C)=O>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:17]=[O:18])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Reaction time: 0.67 h

Procedure:
Triethylamine (17 ml) is added to a solution of (2S)-2-(tert-butoxycarbonyl)amino-3-phenyl-1-propanol (5.00 g, Reference compound No. 1-1) in dimethyl sulfoxide (100 ml). Then, a sulfur trioxide-pyridine complex (11.1 g) is added to the mixture, and the whole is stirred for 40 minutes. Water is added to the reaction mixture, and the whole is extracted with diethyl ether. The extract is washed with a saturated aqueous ammonium chloride solution, water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (4.48 g).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH2:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C1CCNCC1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].N.S(Cl)(Cl)(=O)=O>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH:17][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: N
Solvent: C1CCNCC1
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)c1ccc(S(=O)(=O)NCC(=O)NCC2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine (14.8 mg, 0.05 mmol) in CHC3 (2 mL) was treated with (piperidinomethyl)polystyrene resin (28 mg, 2.8 mmol/g), 4-isopropylbenzenesulfonyl chloride (1.5 equiv.) and stirred at 25° C. for 16 h. (Aminomethyl)polystyrene was added to scavenge the residual sulfonyl chloride and the reaction mixture was stirred at 25° C. for 16 h. Filtration and concentration afforded 1-(4-chlorobenzyl)-4-[{(4-isopropylphenylsulfonyl)glycyl}aminomethyl]piperidine (compound No. 869) (22.1 mg, 92%): The purity was determined, by RPLC/MS (86%); ESI/MS m/e 478 (M++H, C24H32ClN3O3S).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CCN(CC)CC.CCN=C=NCCCN(C)C.[Cl:31][C:32]1[CH:45]=[CH:44][C:35]([CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]2)=[CH:34][C:33]=1[O:46][CH2:47][CH3:48]>CN(C=O)C>[Cl:31][C:32]1[CH:45]=[CH:44][C:35]([CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([NH:43][C:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[NH:1][CH:2]=[CH:3]4)=[O:12])[CH2:39][CH2:38]2)=[CH:34][C:33]=1[O:46][CH2:47][CH3:48]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc4cc[nH]c34)CC2)ccc1Cl
Yield: 29.1 %

Procedure:
Indole-7-carboxlic acid (19 mg, 0.12 mmol), Et3N (20 μL, 0.15 mmol), EDCI (25 mg, 0.13 mmol) and 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine (27 mg, 0.1 mmol) were shaken in DMF (1.0 ml) for 16 h, after which time the solvent was evaporated and the residue purified by reversed phase HPLC (MeCN:H2O) affording the title compound (12 mg, 29%). MS: 412.4 (MH+)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([C:16](O)=[O:17])[C:6]=2[N:7]=1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([C:16]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:17])[C:6]=2[N:7]=1
Reactant: CCOCCn1nc(C(=O)O)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOCCn1nc(C(=O)NS(C)(=O)=O)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The carboxylic acid of Step 8 (1.0 g, 2.70 mmol), methanesulphonamide (330 mg, 3.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (660 mg, 3.5 mmol) and 4-dimethylaminopyridine (390 mg, 3.5 mmol) were dissolved in N,N-dimethylformamide (10 mL) and the reaction mixture stirred at room temperature for 60 hours. Additional methanesulphonamide (165 mg, 1.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (330 mg, 1.7 mmol) and 4-dimethylaminopyridine (195 mg, 1.7 mmol) were added and the reaction mixture stirred for a further 20 hours. Further methanesulphonamide (165±1.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (330 mg, 1.7 mmol) and 4-dimethylaminopyridine (195 mg 1.7 mmol) were added and the reaction mixture stirred for a final 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane (25 mL) and water (25 mL). The organic phase was separated, washed with water (2×25 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:acetic acid 100:0:0 to 96:3.5:0.5. The crude product was triturated in warm ethyl acetate (10 mL) to yield the title product, 290 mg.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:11]([OH:13])=O.O[N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[NH2:26].CCN(C(C)C)C(C)C>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]1[N:24]=[C:11]([C:10]2[CH:14]=[CH:15][C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:8]([CH3:7])[CH:9]=2)[O:13][N:26]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(N3CCOCC3)c(C)c2)n1

Procedure:
Oxalyl chloride (138 μL; 1.63 mmol; 3 eq.), Intermediate 35 (120 mg; 0.54 mmol; 1 eq.), Intermediate 1 (90 mg; 0.54 mmol, 1 eq.) and DIEA (280 μL; 1.63 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 95/5) afforded the title compound as a yellow solid.