Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]([O:15]CC)=[O:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of ethyl 1-(4-nitrophenyl)cyclopropanecarboxylate (3.0 g) obtained in Step A of Example 145 in ethanol (50 mL) was added 1M aqueous sodium hydroxide solution (25 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and 1M hydrochloric acid was added thereto at 0° C. The resulting solid was collected by filtration to give the title compound (2.5 g).
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(O)(=O)C>C(O)C>[CH2:1]([S:7][C:8]1[N:13]=[C:12]([CH2:14][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1COCCN1
Reactant: CCCCCCSc1nc(C=O)cc(C(F)(F)F)n1
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCSc1nc(CN2CCOCC2)cc(C(F)(F)F)n1

Procedure:
2-Hexylsulfanyl-6-trifluoromethyl-pyrimidine-4-carbaldehyde (0.5 g, 1.7 mmol) and morpholine (0.16 mL, 1.9 mmol) were dissolved in ethanol (5 mL) and acetic acid (0.5 mL) and treated with borane-pyridine complex (0.19 mL, 1.9 mmol) for 4 h at 20° C. The reaction mixture was evaporated to dryness. Extraction: 2×AcOEt, 1×10% aqueous Na2CO3. One obtained a mixture of the expected product and the reduced aldehyde which was more polar. This mixture was separated by chromatography on Si-amine from Silicycle with a gradient of heptane/ethyl acetate from 10:1 up to 1:1. Gave 220 mg (35%) of a colorless oil. MS: m/z=364 (M+H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20]Br)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][S:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(S)nc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCSc1ccc([N+](=O)[O-])cn1

Procedure:
A heterogeneous solution of 2-mercapto-5-nitropyridine (96 mg, 0.62 mmol), N-tert-butoxycarbonyl-amino-2-bromoethane (0.14 g, 0.63 mmol), and K2CO3 (0.42 g, 3.0 mmol) in acetone (10 mL) was heated at 60° C. for 15 h. The cooled reaction mixture was filtered through Celite®, concentrated, and then purified by silica gel chromatography to give N-tert-butoxycarbonyl-amino-2-(5-nitro-2-pyridinylthio)ethane (37), which was treated with trifluoroacetic acid (5 mL) in dichloromethane (5 mL) at room temperature for 30 min. The reaction mixture was concentrated and then residue was suspended in dichloromethane, washed with saturated NaHCO3 followed by brine, dried over anhydrous MgSO4 and concentrated to give 1-amino-2-[(5-nitro-2-pyridinyl)thio]ethane (38) as a tan solid which was used without further purification. 1H NMR (DMSO-d6): δ 9.21 (d, J=3.0 Hz, 1H), 8.41 (dd, J=2.4 and 8.7 Hz, 1H), 7.81 (bs, 2H), 7.65 (d, J=8.7 Hz, 1H), 3.44 (t, J=6.6 Hz, 2H), 3.12 (t, J=6.6 Hz, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=1)[NH:11][C:12]1[C:13]2[CH:20]=[C:19]([C:21](OCC)=[O:22])[NH:18][C:14]=2[N:15]=[CH:16][N:17]=1>O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=1)[NH:11][C:12]1[C:13]2[CH:20]=[C:19]([CH2:21][OH:22])[NH:18][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: CCOC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: OCc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Under a N2 atmosphere, 1.4 g (37 mmol) of lithium aluminum hydride are added in portions to 5.70 g (18 mmol) of 4-(3-chloroanilino)-6-ethoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine. After stirring at 50° C. for 2 h, 100 ml of water are added dropwise to the reaction mixture and it is filtered through Celite. Water is added to the filtrate and the mixture is extracted 3 times with ethyl acetate. The organic phases are washed 3 times with water and brine, dried (MgSO4) and evaporated. Recrystallization from isopropanol yields 4-(3-chloroanilino)-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=8.2; TLC-Rf=0.11 (CH2Cl2/methanol [10:1]); MS: (M)+=274.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:10])[NH:7][CH:8]=1)([O-])=O>C(O)C.O.[Pd].[C]>[NH2:1][C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:10])[NH:7][CH:8]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c[nH]1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1c[nH]c(C(=O)O)c1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
4-Nitro-2-pyrrolecarboxylic acid (0.5 g, 3.2 mmol) in ethanol (10 ml) and water (20 ml) was hydrogenated over Pd/carbon (10%, 100 mg) at atmospheric pressure. After two hours the reaction was over, the catalyst was filtered off over diatomaceous earth, and the ethanol evaporated; the resulting aqueous solution was freeze dried to give the title compound (0.35 g, 88%). NMR (DMSO-d6) δ 6.13 (s, 1H); 6.28 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=O)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)[C:2]#[CH:3].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(O)(=O)C>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)[C:2]#[CH:3]
Reactant: C#CCn1ccc2cc(C=O)ccc21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#CCn1ccc2cc(CN3CCCC3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 250 mg (1.37 mmol) 1-prop-2-ynyl-1H-indole-5-carbaldehyde and 200 μL (2.37 mmol) pyrrolidine in 50 mL THF is adjusted to pH 5 with glacial acetic acid, combined with 550 mg (2.47 mmol) NaBH(OAc)3 and stirred for 24 h at RT. 20 mL of saturated K2CO3 solution are added, the mixture is extracted with 50 mL EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)OC(C)(C)C)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the N-t-butyloxycarbonyl-3-nitro-α-methylbenzylamine (1.79 g, 6.74 mmol) in dimethylformamide (50 1 mL) was added tin(II) chloride dihydrate (9.12 g, 40.4 mmol) and the reaction was stirred at room temperature for 48 hours. The dimethylformamide was removed under vacuum, residue resuspended in dichloromethane (100 ml), washed with brine (100 mL), filtered through a celite pad, and solvent removed to provide the crude aniline.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[C:20]([F:33])[CH:19]=1>C(OCC)C>[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([S:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])=[C:20]([F:33])[CH:19]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: CCCN(CCC)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Solvent: CCOCC
Product: CCCN(CCC)SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2.6 g of 2,6-difluorobenzoyl isocyanate in 15 ml of diethyl ether was added over 30 seconds to 5.4 g of 38C. The solution was stirred at ambient temperature for 2.5 hours after which a slight precipitate formed. 50 ml of petroleum ether was added, and the resulting suspension was cooled in a freezer (-5° to 0° C.) for 3 hours. The precipitate which formed was filtered off and recrystallised from a 1:1 v:v mixture of diethyl ether and petroleum ether, to give 2.3 g of 38, as white crystals, m.p.: 118°-121° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[NH:28][CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:51][N:52]=[C:53]=[O:54]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:53](=[O:54])[NH:52][CH3:51])[CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Reactant: CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
A solution containing 35 (228 mg, 0.4 mmol), DIPEA (104 mg, 0.8 mmol) in DCM (5 mL) was cooled to 0° C. Methyl isocyanate (35 mg, 0.6 mmol) was added. After 3 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with saturated aqueous NaHCO3, 1N HCl, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude 40 (230 mg) which was used without further purification. Mass spectrum, m/z [630.1] (M+H)+.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:19])=[C:7]([CH3:18])[C:8]=1[C:9]1[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[N:10]=1)=[C:2]=[O:3].[NH:20]1[CH2:27][CH2:26][CH2:25][C@@H:21]1[C:22]([OH:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:7]1[C:8]([C:9]2[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[N:10]=2)=[C:4]([NH:1][C:2]([N:20]2[CH2:27][CH2:26][CH2:25][C@@H:21]2[C:22]([OH:24])=[O:23])=[O:3])[S:5][C:6]=1[CH3:19]
Reactant: O=C(O)[C@H]1CCCN1
Reactant: Cc1sc(N=C=O)c(-c2nc(C(F)(F)F)no2)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1sc(NC(=O)N2CCC[C@@H]2C(=O)O)c(-c2nc(C(F)(F)F)no2)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.3 %

Procedure:
To a solution of 5-(2-isocyanato-4,5-dimethyl-thiophen-3-yl)-3-trifluoromethyl-[1,2,4]-oxadiazole (178 mg, 0.615 mmol) in CH2Cl2 (10 mL) were added D-proline (142 mg, 1.23 mmol) and triethylamine (0.128 mL, 0.923 mmol) at 25° C. and the reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with 2N aqueous HCl solution (15 mL) followed by H2O (20 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified using silica gel column chromatography using a gradient of CH2Cl2:MeOH (100:0 to 95:5) to furnish the desired compound as an off-white solid (120 mg, 48%). MS (ESI): m/z=403.4 (M−H)−.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:29])[CH2:26][O:25][C:24](=O)[N:23]2C)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C(O)C>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]([NH:23][CH3:24])([CH3:29])[CH2:26][OH:25])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C(=O)OC[C@@]1(C)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CN[C@@](C)(CO)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Temperature: 120 °C
Yield: 9.5 %

Procedure:
A mixture of (R)-4-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-3,4-dimethyl-oxazolidin-2-one (80 mg, 0.2 mmol) in 4.2 M of LiOH aqueous (1.5 mL, 6 mmol) and ethanol (1.5 mL) was heated at 120° C. for 5 hrs. The solvent was concentrated and the residue was washed with water to give white precipitate. The crude was purified with silica gel column eluted with 2 M NH3 in MeOH and DCM from 0 to 8% to give 7 mg of product, 10%. ESI-MS (M-30)+: 339.30, room temperature 1.57 min. 1H NMR (400 MHz, CDCl3) δ: 7.76˜7.70 (m, 3H), 7.51 (d, 1H), 7.17˜7.12 (m, 2H), 4.27 (m, 1H), 3.88 (d, 1H), 3.71 (d, 1H), 2.32˜2.23 (m, 5H), 1.89 (d, 2H), 1.62 (s, 3H), 1.44 (m, 2H), 1.25˜1.05 (m, 3H), 0.90 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[F:12])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cc(C(F)(F)F)ccc1F
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)c1cc(Cl)ccc1O
Yield: 77.9 %

Procedure:
Using 5-chlorosalicylic acid and 2-fluoro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:19]=[CH:20][C:21]3[C:26]([C:4]=2[NH:3]1)=[CH:25][CH:24]=[CH:23][CH:22]=3.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(NC(C2C=CC(N3C(=O)CC(=O)NC4C5C(C=CC3=4)=CC=CC=5)=CC=2)=O)C=CC=CC=1>>[CH2:27]([NH:34][C:14]([C:13]1[CH:17]=[CH:18][C:10]([N:6]2[C:7](=[O:9])[CH2:8][C:2](=[O:1])[NH:3][C:4]3[C:26]4[C:21]([CH:20]=[CH:19][C:5]2=3)=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:11][CH:12]=1)=[O:15])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Reactant: NCc1ccccc1
Agent: O=C1CC(=O)N(c2ccc(C(=O)Nc3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(C(=O)NCc3ccccc3)cc2)c2ccc3ccccc3c2N1
Yield: 56 %

Procedure:
By using 4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoic acid obtained in Example 102, (4), and benzylamine, the title compound (yield 56%) was obtained in the same manner as that of Example 102, (5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@@H:20]3[C@@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:28]([NH:32][C:33](=[O:40])[NH:34][C@H:35]([CH3:39])[C:36](O)=[O:37])([CH3:31])([CH3:30])[CH3:29].C(OC(=O)NCCCC(N1CCC(N2N=C(C3C=CC(OC)=C(OC)C=3)[C@@H]3[C@@H](CC=CC3)C2=O)CC1)=O)(C)(C)C>>[C:28]([NH:32][C:33]([NH:34][C@@H:35]([CH3:39])[C:36]([N:25]1[CH2:26][CH2:27][CH:22]([N:13]2[N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C@@H:20]3[C@@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14]2=[O:21])[CH2:23][CH2:24]1)=[O:37])=[O:40])([CH3:31])([CH3:30])[CH3:29]
Reactant: C[C@@H](NC(=O)NC(C)(C)C)C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: COc1ccc(C2=NN(C3CCN(C(=O)CCCNC(=O)OC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCN(C(=O)[C@H](C)NC(=O)NC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from compound 5c and (R)-2-(3-tert-butyl-ureido)-propionic acid (N-boc-L-alanine) as described for compound 5b. M. p. 153-154° C.
Reaction SMILES: [Br:1][C:2]([Br:9])([Br:8])[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:12])=O>CN(C)C=O>[Br:1][C:2]([Br:9])([Br:8])[CH2:3][CH2:4][C:5]([Cl:12])=[O:6]
Reactant: O=C(O)CCC(Br)(Br)Br
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(Br)(Br)Br
Reaction time: 3 h
Yield: 95 %

Procedure:
324.8 g (1.0 mol) of 4,4,4-tribromobutyric acid are warmed with 600 g of thionyl chloride and 1 ml of dimethylformamide, first for 2 hours at 40° C. and then for 3 hours at 75° C. The excess thionyl chloride is then distilled off and the residue is rectified under a high vacuum. 326.0 g (95% of theory) of 4,4,4-tribromobutyric acid chloride with a boiling point of 71° to 73° C./0.05 mm Hg are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.C(N(CC)CC)C.Cl[CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>C(Cl)Cl>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[O:19][CH2:18][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCOc1ccc2ccccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1COc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-Chloropyrimidine-2-one hydrochloride (5 mmol) and triethylamine were stirred together in CH2Cl2 (30 ml). When all the solid had dissolved there was added a solution of 2-chloromethoxynaphthalene [see Preparation 13] (5 mmol) in CH2Cl2 (10 ml) with stirring at room temperature for 5 minutes. The mixture was stirred at room temperature for 24 hours before the solvent was distilled off. The residue was triturated with water, extracted into CHCl3, dried (MgSO4) and evaporated to give a mixture of the title compound and the O-alkylated isomer in the ratio 4:1. Yield 1.27g (86%). The O-isomer was removed from the product by extraction with ether followed by recrystallization of the N-isomer from acetone m.p. 168° C. 1H NMR (CDCl3 δ): 5.85 (s, CH2), 7.10-8.1 (m, 8H. Ar+ H-4), 8.48 (H-6, d7 =4Hz) IR (KBr, cm -1): 1675 (CO).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH3:9][S:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[C:15]=2[N:16]=1>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[C:15]=2[N:16]=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(Cl)c1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 54.1 %

Procedure:
To a suspension of 79 mg (3.30 mmol) of sodium hydride in 2 mL of benzene was added 225 mg (2.75 mmol) of methyl glycolate and a solution of 320 mg (0.91 mmol) of 2-(methylthio)-4-chloro-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidine in 2 ml of benzene. The mixture was then heated at 60° C. After 24 hours the reaction was cooled to ambient temperature and an additional 40 mg of sodium hydride and 110 mg of methyl glycolate were added. After 3 days, the reaction was partitioned by the addition of 2 mL of 2 M sodium hydrogen sulfate and 20 mL of ethyl acetate. The organic phase was washed with 10 mL of water, dried with sodium sulfate and concentrated. The product was purified by flash chromatography (30 g silica, methylene chloride-heptane gradient 2:1 to 100:0) to provide 200 mg (54%) of [[2-(methylthio)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.26 (t, J=7.4 Hz, 3H), 2.53 (s, 3H), 2.56 (q, J=7.4 Hz, 2H), 3.79 (s, 3H), 5.05 (s, 2H), 5.35 (s, 2H), 6.31 (s, 1H), 6.92 (d, J=6.7 Hz, 1H), 7.08 (s, 1H), 7.21 (m, 2H)
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)=[C:5]([C:22]([NH2:24])=[O:23])[CH:4]=1)#[CH:2].[C:25]([O:31][CH2:32][N:33]=[N+:34]=[N-:35])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CN(C=O)C.O>[C:25]([O:31][CH2:32][N:33]1[CH:2]=[C:1]([C:3]2[S:7][C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[N:10]=3)=[C:5]([C:22]([NH2:24])=[O:23])[CH:4]=2)[N:35]=[N:34]1)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Reactant: C#Cc1cc(C(N)=O)c(Nc2cccc(CN3CCOCC3)n2)s1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1cc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCOCC4)n3)s2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Ethynyl-2-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (86 mg, 0.25 mmol) and azidomethyl pivalate (59 mg, 0.38 mmol) were combined in DMF (1.0 mL). CuSO4.5H2O (6.3 mg, 0.025 mmol) in water (0.2 mL) and sodium ascorbate (20 mg, 0.10 mmol) in water (0.2 mL) were added, and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated to dryness, combined with MeOH and silica gel, and evaporated. Flash chromatography (dry load, 0-10% MeOH/EtOAc) afforded the title compound as a yellow solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6][NH2:7].[F:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH:7][CH2:6][CH2:5][C:4]#[C:3][Si:2]([CH3:9])([CH3:8])[CH3:1])=[O:19]
Reactant: O=C(O)c1cccc(Cc2cccc(F)c2)c1
Reactant: C[Si](C)(C)C#CCCN
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: CN(C)C=O
Product: C[Si](C)(C)C#CCCNC(=O)c1cccc(Cc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.3 %

Procedure:
A mixture of 4-(trimethylsilyl)but-3-yn-1-amine (0.184; 1.30 mmol), 3-(3-fluorobenzyl)benzoic acid, (0.200 g; 0.869 mmol), HATU (0.363 g; 0.955 mmol) and N,N-diisopropylethylamine (0.374 mL; 2.17 mmol) in DMF (20 mL) was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was washed with water, dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) to afford 0.13 g (42%) of 3-(3-fluorobenzyl)-N-(4-(trimethylsilyl)but-3-ynyl)benzamide which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[CH2:9])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[CH2:9])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: C=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1C(=O)O
Yield: 90 %

Procedure:
Methyl 2-[1-(4-chloro-3-nitrophenyl)ethenyl]benzoate (0.95 g, 3.0 mmol) was suspended in methanol (45 mL) and 2N sodium hydroxide (100 mL), and stirred at 65° C. for two hours. The reaction mixture was concentrated and acidified to pH of 4, and then extracted with ethyl acetate (3×50 mL). The combined extract was washed with water (100 mL), brine solution (100 mL), dried over sodium sulfate, filtered and concentrated to give 2-[1-(4-chloro-3-nitrophenyl)ethenyl]benzoic acid (0.81 g, 2.7 mmol, 90% yield). 1H NMR (400 MH, CDCl3): 7.92-7.91 (d, 1H), 7.85-7.83 (dd 1H), 7.70-7.67 (d, 1H), 7.66-7.62 (dt, 1H), 7.54-7.50 (dt, 1H), 7.38-7.35 (m, 2H), 5.93 (s, 1H), 5.37 (s, 1H); MS (EI) for C15H10ClNO4: 302 (M−).