Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:3].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])[CH3:3]
Reactant: C[C@H](O)[C@@H](CCc1ccccc1O)n1cnc(C(N)=O)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@@H](CCc1ccccc1OCCCCCCN1C(=O)c2ccccc2C1=O)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.1 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-hydroxyphenyl)-3-pentyl]imidazole-4-carboxamide (0.11 g), 1-bromo-6-phthalimidohexane (0.47 g) and potassium carbonate (0.42 g) in N,N-dimethylformamide (5 ml) was stirred overnight at room temperature. The mixture was taken up in ethyl acetate, washed three times with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a white powder of 1-{(2S,3R)-2-hydroxy-5-[2-(6-phthalimidohexyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide (6-1) (219 mg).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([S:7]([O-])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+].S(Cl)([Cl:14])=O.N1C2C(=CC=CC=2)C=C1.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]1([CH3:10])[C:2]([S:7]([Cl:14])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1S(=O)[O-]
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc2[nH]ccc2c1
Solvent: ClCCl
Product: Cc1ccccc1S(=O)Cl
Reaction time: 0.5 h

Procedure:
Toluenesulfinyl chloride was prepared according to Org. Syn., IV, 937 on half the scale described (that is, on 0.1 mole sodium toluenesulfinate). The crude sulfinyl chloride (15.2 g) was added dropwise to 11 g of indole dissolved in dichloromethane (200 ml) at 0° C. in the presence of 20 g of sodium bicarbonate. After 30 min at room temperature, the reaction mixture was washed well with saturated sodium bicarbonate solution, the phases separated and the organic phase dried and evaporated. The crude material was applied to a short silica gel column. Elution with dichloromethane removed a large amount of non-polar material. The product was removed with ethyl acetate. Upon recrystallization from ethyl acetate, the compound had melting point 120.5-121.5 (dec.) (corr.).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH:7]([OH:10])[CH2:8]Br)[O:4][N:3]=1.[CH2:11]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:8][CH:7]([C:5]2[O:4][N:3]=[C:2]([Br:1])[CH:6]=2)[OH:10])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC(CBr)c1cc(Br)no1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCO
Product: OC(CN1CCC(Cc2ccccc2)CC1)c1cc(Br)no1

Procedure:
A solution of 6.0 g of 1-(3-bromoisoxazol-5-yl)-2-bromoethanol and 11.7 ml of 4-benzylpiperidine in 150 ml of ethanol was refluxed for 2 hours.
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[C:23]3[S:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:29]C(OC(C)(C)C)=O)[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>Cl.O1CCOCC1>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[C:23]3[S:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH2:29])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1cccs1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)c1cccs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1-(2-Toluoylmethyl) -2-oxo-3-tert-butoxycarbonylamino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(l.0 g) was dissolved in 4N HCl-dioxane (10 ml), the mixture was stirred at 60° C. for one hour. The reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby obtain 0.81 g of the title compound as a light yellow crystal (Yield: 100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=O.ClC(OCC1C=CC=CC=1)=O.ClC(OCC)=O.[CH2:23]([NH2:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(N(CC)CC)C>[CH2:23]([NH:30][C:3](=[O:5])[CH2:2][NH2:1])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCN
Reactant: NCC(=O)O
Agent: CCOC(=O)Cl
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)CN

Procedure:
As above from glycine and benzyl chloroformate (N-benzyloxycarbonylglycine has m.p. 119°-121° C.), then triethylamine, ethyl chloroformate and n-heptylamine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]1([OH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O[CH2:40][C:41]1[CH:42]=[C:43]([N:47]([CH2:53][C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)[S:48]([CH2:51][CH3:52])(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=1>C1COCC1.CCOC(C)=O>[O:38]([CH2:40][C:41]1[CH:42]=[C:43]([N:47]([CH2:53][C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)[S:48]([CH2:51][CH3:52])(=[O:49])=[O:50])[CH:44]=[CH:45][CH:46]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(CO)c1
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(COc2ccccc2)c1
Reaction time: 72 h

Procedure:
To a solution of triphenylphosphine (0.141 g, 0.539 mmol) in 3.5 mL THF was added diethylazodicarboxylate (0.165 g, 0.539 mmol). After 5 min phenol (0.061 g, 0.646 mmol) was added as a solution in 2 mL THF. After 5 min N-(3-(hydroxymethyl)phenyl)-N-(ethanesulfonyl)pyrid-3-ylmethylamine (0.165 g, 0.539 mmol) was added as a solution in 2 mL THF and the reaction was stirred for 3 days. The mixture was diluted with EtOAc, washed with 1 N NaOH and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with 4:1 to 2:1 DCM/EtOAc to give the title compounds as a clear oil. 1H NMR: 8.48 (d,J=1.5 Hz, 1H), 8.36 (s,1H), 7.64 (d,J=7.8 Hz, 1H), 7.36-7.23 (m,5H), 7.19 (m,2H), 6.95 (t,J=7.8 Hz, 1H), 6.91 (d,J=7.8 Hz, 1H), 5.01 (s,2H), 4.84 (s,2H), 3.03 (q,J=7.6 Hz, 2H), 1.39 (t,J=7.6 Hz, 3H). MS calcd. 382.1; MS (M+1) 383.1.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][N:7]([CH3:11])[C:8]([NH2:10])=[NH:9].[F:12][C:13]([F:18])([F:17])[C:14](O)=O>>[CH3:11][N:7]1[C:8]([NH2:10])=[N:9][C:14]([C:13]([F:18])([F:17])[F:12])=[N:6]1
Reactant: O=C(O)C(F)(F)F
Reactant: CN(N)C(=N)N
Agent: O=S(=O)(O)O
Product: Cn1nc(C(F)(F)F)nc1N

Procedure:
1-Amino-1-methyl guanidine sulphate (12.3 g) and trifluoroacetic acid (16 ml) were heated at reflux for 96 h. Excess trifluoroacetic acid was removed by distillation and the residue was basified with sodium bicarbonate and extracted with ethyl acetate. The extract was dried and evaporated to give a white solid (7.2 g) which was recrystallised from a mixture of methyl acetate (8 ml) and petroleum ether (b.p. 60°-80°) (20 ml) to give the title compound as a white powder (5.1 g) m.p. 165°-166°.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[C:34]([O:35][CH3:36])[CH:33]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: COc1ccc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cc1OC

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3,4-dimethoxyphenylboronic acid, 5-(3,4-dimethoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=73%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5](=[CH:11][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].BrN1C(=[O:24])CCC1=O>[W].C(Cl)(Cl)(Cl)Cl>[CH:1]([C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5](=[CH:11][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:24]
Reactant: CCOC(=O)c1ccc(C)cc1C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(C=O)cc1C(=O)OCC

Procedure:
A mixture of one equivalent of diethyl 4-methylphthalate, two equivalents of N-bromosuccinimide and carbon tetrachloride is irradiated with a 500 W tungsten lamp for three hours. The mixture is filtered and the solution is shaken with excess sodium carbonate solution. Evaporation of the organic phase gives diethyl 4-formylphthalate. This aldehyde is combined with excess nitroethane, toluene and a catalytic amount of benzyl amine. The mixture is heated on a steam bath for 48 hours and evaporated in vacuo to give diethy 4-(2-nitropropen-1-yl)phthalate.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH:22]=[CH2:23])[CH:15]=2)([CH3:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[OH-].[K+].Cl>CO>[CH:21]([C:16]1[CH:15]=[C:14]([C:11]([C:6]2[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([CH:1]=[CH:2][CH3:3])[CH:5]=2)([CH3:12])[CH3:13])[CH:19]=[CH:18][C:17]=1[OH:20])=[CH:22][CH3:23]
Reactant: C=CCc1cc(C(C)(C)c2ccc(O)c(CC=C)c2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC=Cc1cc(C(C)(C)c2ccc(O)c(C=CC)c2)ccc1O
Temperature: 110 °C

Procedure:
400 ml of methanol is slowly added with stirring to a mixture of 3 mols of 2,2-bis-(3-allyl-4-hydroxyphenyl)-propane (A1) and potassium hydroxide pellets. The mixture is afterwards carefully heated to 110° C. with the distilling off of 116 ml of methanol. The reaction solution is subsequently held, with reflux cooling, for a further 6 hours at 110° C. The reaction solution is then cooled, neutralised with conc. HCl, and extracted with methylene chloride. The extract is dried, and completely evaporated to dryness to thus yield essentially pure 2,2-bis-[3-(1-propenyl)-4-hydroxyphenyl]-propane (A2), which at room temperature is a very highly viscous yellow liquid. The structural formula A2 is confirmed by microanalysis and H-NMR, MS and UV spectroscopy, as well as by means of gel-permeation chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].[N+:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]>CN(C)C=O.O.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>[NH2:1][C:2]1[C:3]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:4][C:5]([Br:9])=[CH:6][C:7]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:28]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Nc1c(I)cc(Br)cc1S(=O)(=O)O
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: CN(C)C=O
Solvent: O
Product: Nc1c(-c2cccc([N+](=O)[O-])c2)cc(Br)cc1S(=O)(=O)O
Temperature: 70 °C
Yield: 80.4 %

Procedure:
To a solution of 1.9 g (5 mmol) of 2-amino-5-bromo-3-iodobenzenesulphonic acid and 1.6 g (15 mmol) of sodium carbonate in 25 ml of dimethylformamide and 12.5 ml of water are added successively, under a nitrogen atmosphere, 0.231 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium (0) and 1.42 g (8.5 mmol) of 3-nitrobenzeneboronic acid. The reaction medium is heated for 2 hours at 70° C. and is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on an RP 18 reverse-phase column, eluting with an acetonitrile/water mixture (1:9). 1.5 g of compound are obtained in sodium sulphonate form.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[OH-].[NH4+:12]>O1CCOCC1>[NH2:2][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:12])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Cyano-benzyl bromide (4.00 g) was combined with 1,4-dioxane (2 mL) and conc. aq. ammonium hydroxide (30 mL). The reaction mixture was sealed with a teflon plug and stirred overnight at ambient temperature. The reaction mixture was concentrated to dryness in vacuo. The crude material consisted of a mixture of the desired mono- and undesired bis-benzyl adducts. The undesired product was removed by repeated precipitation from hot methanol, enriching the desired product in the filtrate. After three cycles, pure title compound was isolated as the hydrobromide salt (2.38 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:22])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][S:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:16]=2[NH:22][C:10]1=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSc1c(N)cccc1N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CSc2c(N)cccc2NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-3-(2,6-diamino-phenylsulfanyl)-propionic acid (1.0 g, 3.1 mmol) in DMF (12 mL) was added DIEA (1.6 mL, 9.1 mmol), HOBT.H2O (859 mg, 6.2 mmol) and HBTU (2.3 g, 6.2 mmol). The mixture was stirred under an atmosphere of N2 at room temperature for 3 h. The reaction was poured into H2O and extracted with EtOAc. The organic extracts were combined, washed with 0.5 M HCl, H2O, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography by silica gel chromatography to give the title compound (560 mg, 59%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4](NC(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.C(OC(OC(C)(C)C)N(C)C)(C)(C)C.CCOCC>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)CCc1ccccc1

Procedure:
A solution of 3.50 g of (S)-4-carboxymethyl)alpha-[[(1,1-dimethylethoxy)carbonyl]amino]benzenepropanoic acid methyl ester in 40 mL of dry toluene and 10 mL of dimethylformamide di-t-butyl acetal was heated to a bath temperature of 80° C. for 4 hours. After cooling, the mixture was diluted with 100 mL of ether and was washed with water and saturated sodium chloride solution and was dried over magnesium sulfate. The residue obtained after filtration and evaporation was chromatographed over 150 g of silica gel, eluting with 20% ethyl acetate-hexane to give 2.663 g of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-]2-(1,1-dimethylethoxy) 2-oxoethyl]benzenepropanoic acid methyl ester.
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][N:31]=1)[C:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:21])[CH3:15].[B:32](OC)([O:35]C)[O:33]C.[Cl-].[NH4+].Cl>C1COCC1>[CH:23]([N:22]([CH:26]([CH3:28])[CH3:27])[C:20]([C:19]1[CH:29]=[CH:30][N:31]=[C:17]([O:16][CH2:14][CH3:15])[C:18]=1[B:32]([OH:35])[OH:33])=[O:21])([CH3:25])[CH3:24]
Reactant: COB(OC)OC
Reactant: CCOc1cc(C(=O)N(C(C)C)C(C)C)ccn1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOc1nccc(C(=O)N(C(C)C)C(C)C)c1B(O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of N,N,N′,N′-tetramethylethylenediamine (7.46 ml, 49.4 mmol) in THF (105 ml) at −78° C., sec-butyl lithium (35.3 ml, 49.4 mmol, 1.4 M in cyclohexane) was added. 2-Ethoxy-N,N-diisopropylisonicotinamide (8.25 g, 33.0 mmol) in THF (10 mL) was added slowly over 5 min. After 15 min, trimethyl borate (11.23 ml, 101 mmol) was added and after an additional 30 min, the mixture was allowed to warm to 0° C. To this mixture, aqueous ammonium chloride (saturated, 35 mL) and hydrochloric acid (1 M, 140 mL) were added. The reaction mixture was then allowed to warm to room temperature. After 1 h, the aqueous layer was extracted with CH2Cl2 (140 mL). The organic extract was then washed with aqueous sodium hydroxide (1M, 2×120 mL). The combined aqueous extracts were washed with CH2Cl2 (100 mL), acidified with hydrochloric acid (12 M), and extracted with CH2Cl2 (2×120 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound as a white solid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[O:7])[CH3:4]>CO>[CH2:3]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[OH:13])=[O:7])[CH3:4]
Reactant: CCOC(=O)C1CCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CCCC1O
Temperature: 0 °C
Yield: 69.5 %

Procedure:
1st method: 10 g of sodium borohydride are added to a solution of 62.4 g (0.4 mole) of 2-oxo-cyclopentylcarboxylic acid ethyl ester in 200 ml of methanol cooled to 0° C. When the reaction, which is followed by thin layer chromatography, is completed, the reaction mixture is poured with caution into an aqueous solution saturated with NaH2PO4. By extracting with ethyl ether and subsequently evaporating off the solvent, a residue is obtained which is purified by under vacuum distillation yielding 44 g of 2-hydroxy-cyclopentylcarboxylic acid ethyl ester (b.p. 87° C./0.3 mmHg).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC1C(C)=C(C)C(C)=C(C)C(C)=[C-]PC=1>O>[CH2:13]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cc1[c-][pH]cc(C)c(C)c(C)c(C)c1C
Solvent: O
Product: CCOC(=O)c1ccc(NCc2ccccc2)cc1

Procedure:
A mixture of 16.5 g. of ethyl p-aminobenzoate, 8.55 g. of benzyl bromide and 45 ml. of hexamethylphosphorimide are heated in an oil bath at 110° C. for 20 hours. The mixture is diluted with water, chilled, filtered and the solid washed with water to give tan crystals, m.p. 90°-93° C. A sample is recrystallized from ethanol to give tan crystals, m.p. 96°-97° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2.C(N(CC)CC)C>CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To the solution of 4-chloro-2-methylthio-5-pyrimidine carboxylic acid ethyl ester (5 g) and 5-aminoindazole (3.15 g) in methanol (70 ml) was added triethylamine (3.5 ml), and then the solution was reacted at 30° C. for 3 hr. The reaction mixture was cooled at room temperature, stirred at 20° C. for 1 hr. Then the reaction mixture was filtered and washed with methanol (20 ml). The obtained solid was dried at 40-50° C. in vacuo to obtain the desired compound (6.15 g, 87%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]([NH:20]C(C)(C3C=CC=CC=3)C)=[O:19])=[CH:16][N:17]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]([NH2:20])=[O:19])=[CH:16][N:17]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2ncc(C(=O)NC(C)(C)c3ccccc3)s2)cn1
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)Nc1ccc(-c2ncc(C(N)=O)s2)cn1
Reaction time: 8 h

Procedure:
2-(6-{[(Ethylamino)carbonyl]amino}pyridin-3-yl)-N-(1-methyl-1-phenylethyl)-1,3-thiazole-5-carboxamide (Intermediate 18, 53 mg, 0.129 mmol) was dissolved in TFA (1 mL) and the solution was stirred overnight. TFA was removed under reduced pressure and the crude was partitioned between aqueous sodium bicarbonate and EtOAc. The layers separated and the organic layer was washed with water and brine. During the work up process the product precipitated which was collected by filtration. Washed with water and EtOAc and dried (0.020 g). MS (ESP): 292 (M+H+) for C12H13N5O2S; NMR: 1.09 (t, 3H), 3.16-3.22 (m, 2H), 7.56 (d, 1H), 7.65 (brs, 1H), 7.83 (brs, 1H), 8.15-8.23 (m, 2H), 8.40 (s, 1H), 8.77 (s, 1H), 9.51 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[Cl:34]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=3[Cl:34])[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)c(Cl)c1
Reaction time: 0.08 h
Yield: 37.8 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 200 mg, 0.882 mmol) was dissolved in DMSO (4.4 mL). Sodium tert-butoxide (102 mg, 1.059 mmol) was then added to give a brown solution. After 5 minutes, 1-(bromomethyl)-2-chloro-4-(methylsulfonyl)benzene (250 mg, 0.882 mmol) was added dropwise. The reaction mixture was stirred for 18 hours. Additional sodium tert-butoxide (0.5 eq) was added and the reaction mixture was stirred for an additional 18 hours. The reaction mixture was subsequently diluted with ethyl acetate and was washed with aqueous saturated NH4Cl (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was loaded onto an ISCO® silica gel cartridge (12 g) and eluted with an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow oil (143 mg, 37%). ESI-MS m/z [M+H]+ calc'd for C17H18Cl2N4O3S, 430.3. found 431.3.