Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COc1ccc(CCCC(=O)OC(C)(C)C)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)CCCc1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of tert-butyl 4-(2-chloro-4-methoxyphenyl)butanoate (1.73 g) in dichloromethane (10.0 mL) were added under ice-cooling, and a 1 M solution of boron tribromide in dichloromethane (12.2 mL), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure and basified by the addition of a saturated aqueous sodium hydrogen carbonate solution, and 1 M hydrochloric acid was added thereto until the liquid became acidic. The precipitated insoluble material was collected by filtration and dried under reduced pressure to obtain 4-(2-chloro-4-hydroxyphenyl)butanoic acid (647 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(O)(C)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[CH3:8]
Reactant: Nc1ccccc1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: CC(C)O
Product: Cc1c(Cl)ncnc1Nc1ccccc1
Yield: 85.1 %

Procedure:
To a mixture of 4,6-dichloro-5-methylpyrimidine (2.27 g, 13.9 mmol) and aniline (1.0 g, 10.7 mmol) in isopropanol (15 mL) was added concentrated aqueous hydrochloric acid (1.5 mL) and heated to reflux for 2.5 h. The mixture was then concentrated and the residue triturated with ethyl acetate:isopropanol 4:1. The solid was collected by filtration and washed with additional ethyl acetate:isopropanol 4:1 then dried to give 6-chloro-5-methyl-N-phenylpyrimidin-4-amine (2.0 g, 67% yield). 1H NMR (400 MHz, d6-DMSO): 8.85 (s, 1H), 8.26 (s, 1H), 7.60 (d, 2H), 7.35 (tr, 2H), 7.11 (tr, 1H), 2.31 (s, 3H). MS (EI) for C11H10ClN3: 220 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)([C:11]2[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([Cl:18])[CH:12]=2)[N:3]=1.[CH3:26]OC1C=C([Mg]Br)C=CC=1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:17][C:15]1[CH:16]=[C:11]([C:4]2([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([NH2:1])=[N:3]2)[CH:12]=[C:13]([Cl:18])[N:14]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: NC1=NC(c2cccc(O)c2)(c2cc(Cl)nc(Cl)c2)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(C2(c3cc(Cl)nc(Cl)c3)N=C(N)c3ccccc32)c1
Reaction time: 0.83 h
Yield: 89.3 %

Procedure:
(E)-N-((2-cyanophenyl)(2,6-dichloropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (Scheme #19, B, 0.69 g, 1.81 mmol) was dissolved in dry tetrahydrofuran (20 mL) at 0° C. to which a solution of 3-methoxyphenylmagnesium bromide (1.0 M in tetrahydrofuran, 5.44 mL, 5.44 mmol) in tetrahydrofuran was added. The reaction was stirred for 50 minutes and then quenched by addition of saturated aqueous ammonium chloride (25 mL), then further diluted with saturated aqueous sodiumhydrogen carbonate and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated. The residue was dissolved in methanol (20 mL) and treated with hydrochloride (1.0 M in diethyl ether, 3.63 mL, 3.63 mmol) for 1.5 h and then treated with saturated aqueous sodiumhydrogen carbonate and washed with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated. Purification by flash chromatography using ethyl acetate afforded 0.621 g (89% yield) of the title compound. 1H NMR (CDCl3) δ 7.59-7.43 (m, 4 H), 7.29-7.20 (m, 3 H), 6.89-6.87 (m, 3 H), 3.75 (s, 3 H). MS (AP) m/z 384 [M+1]+.
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.O=[C:33]1[CH2:39][CH:38]2[N:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]([CH2:36][CH2:37]2)[CH2:34]1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:28]([CH2:27][C:23]1([N:21]2[CH:22]=[C:18]([C:17]3[C:12]4[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:19]=[N:20]2)[CH2:24][N:25]([CH:33]2[CH2:34][CH:35]3[N:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:38]([CH2:37][CH2:36]3)[CH2:39]2)[CH2:26]1)#[N:29]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(N1CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (2.6 g, 6.3 mmol) in THF (30 mL) were added tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.3 g, 6.3 mmol), N,N-diisopropylethylamine (4.4 mL, 25 mmol) and sodium triacetoxyborohydride (2.2 g, 10 mmol). The mixture was stirred at room temperature overnight and quenched by addition of 20 mL of brine. The solution was extracted with EtOAc. The extract was dried over anhydrous Na2SO4. After removing solvent, the residue was purified by combiflash column eluting with 30-80% EtOAc in hexanes to give the desired product tert-butyl 3-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate. LC-MS: 619.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11]C)=[CH:9][C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].Br.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cc(Cl)cc(C(=O)[O-])c1N
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(O)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of 2-amino-5-chloro-3-methoxybenzoate (2.76 g, 12.8 mmol), 48% aqueous solution of hydrobromic acid (25 mL) and glacial acetic acid (1 mL) was heated to reflux for 48 h. The reaction mixture was cooled down to room temperature, treated with saturated solution of Na2CO3 to pH6, concentrated and purified by column chromatography (silica gel, 90:10 dichloromethane/methano 1) to afford 2-amino-5-chloro-3-hydroxybenzoic acid (0.84 g, 35%) as a light brown solid: MS (ESI+) m/z 188 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[C@H:3]1[NH:14]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:14][C@@H:3]1[C:4](=[O:13])[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[O:8][C@@H:2]1[CH3:1]
Reactant: C[C@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1Oc2ccccc2NC(=O)[C@H]1N
Yield: 98.4 %

Procedure:
To a solution of tert-butyl (2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (0.65 g, 2.22 mmol, Eq: 1.00) in DCM (11.2 mL) at 0° C. was added TFA (12.7 g, 8.26 mL, 111 mmol, Eq: 50.00). After 1 h the mixture was concentrated, the residue dissolved in 50 mL DCM and washed with sat. NaHCO3. The NaHCO3 mixture was extracted with DCM and the combined extracts dried over Na2SO4, filtered and concentrated to afford the title compound (0.42 g, 96%) as a yellow foam which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:22])[CH2:7][C:6]=2[CH:23]=1.[BH4-].[Na+].O>CO>[OH:22][CH:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:15](=[C:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][C:6]=2[CH2:7]1
Reactant: O=C1Cc2cc(Cl)ccc2C(=C2CCNCC2)c2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1Cc2cc(Cl)ccc2C(=C2CCNCC2)c2ncccc21
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
Mix the title compound of Example 6 (400 mg, 1.23 mmol) in CH3OH (20 mL) at 0° C. under an argon atmosphere, and add in 3 portions NaBH4 (total 231 mg, 6.10 mmol). After 30 minutes, pour the mixture into water and extract (3X) with ethyl acetate. Combine the organic portions, wash with brine, dry over sodium sulfate, filter and concentrate in vacuo. Triturate the solid with isopropyl ether/ethyl acetate to give the title compound as a white solid (351 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[C:29]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:29]([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:28]=1
Reactant: O=C=Nc1ccc(Cl)cc1Oc1ccccc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(Cl)cc4Oc4ccccc4)cc3)cc2C1=O
Yield: 96 %

Procedure:
The compound of example 43 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 4-chloro-2-phenoxy phenyl isocyanate.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl>[N:14]1([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a stirred solution of 3-(chlorosulfonyl)benzoic acid (1.10 g, 5.00 mmol) in DCM (10 mL) was added piperidine (1.49 g, 17.5 mmol) at 0° C., and the resulting solution stirred for 30 minutes. The volatiles were then removed in vacuo and the residue treated with aqueous 1N KHSO4. The aqueous phase was then extracted with ethyl acetate (×3), and the combined organic phases dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 3-(piperidin-1-ylsulfonyl)benzoic acid (1.22 g, 4.52 mmol, 90%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[CH2:5]([O:7][C:8]([CH2:10][O:11][CH2:12][C:13]([NH:15][NH2:16])=[O:14])=[O:9])[CH3:6]>O1CCCC1>[CH3:1][NH:2][C:3]([NH:16][NH:15][C:13]([CH2:12][O:11][CH2:10][C:8]([O:7][CH2:5][CH3:6])=[O:9])=[O:14])=[S:4]
Reactant: CCOC(=O)COCC(=O)NN
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CCOC(=O)COCC(=O)NNC(=S)NC
Reaction time: 2 h

Procedure:
A solution of methyl isothiocyanate (3.52 g.) in dry tetrahydrofuran (20 ml.) was added during the course of 30 minutes to a suspension of ethoxycarbonylmethoxyacetohydrazide (8.50 g.) in absolute alcohol (50 ml.), and the resulting mixture was stirred for a further period of two hours. The solution was then filtered and the clear filtrate evaporated in vacuo. Trituration of the residue with dry diethyl ether then gave the compound CH3NHCSNHNHCOCH2OCH2COOEt as a white solid material (yield, 8.0 g.).
Reaction SMILES: I[CH2:2][C:3]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH:64][C:65]1[CH:77]=[CH:76][C:75]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:68](=[O:78])[C:67]=2[CH:66]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH2:46]([O:45][CH2:44][C:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:2][O:64][C:65]1[CH:77]=[CH:76][C:75]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:68](=[O:78])[C:67]=2[CH:66]=1)[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Reactant: CCCCCCCCCCCCCCCCCCOCC(CI)(COCCCCCCCCCCCCCCCCCC)COCCCCCCCCCCCCCCCCCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc2c(c1)C(=O)c1ccccc1-2
Temperature: 130 °C
Yield: 92.2 %

Procedure:
1-(3-Iodo-2,2-bis-octadecanoxymethyl-propoxy)octadecane (500 mg, 102 μmol) and 2-hydroxy-9-fluorenone (30 mg, 152 μmol) were dissolved in DMF (2 ml), potassium carbonate (21 mg, 152 μmol) was added, and the mixture was stirred at 130° C. After completion of the reaction, 0.5N hydrochloric acid (6 ml) was added, the precipitate was filtered, and the precipitate was washed with acetonitrile and water to give 2-(3-octadecyloxy-2,2-bis-octadecyloxymethyl-propoxy)-9-fluorenone (101 mg, 94 μmol).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2O)([O-:3])=[O:2].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:16][CH:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cccc2c1CCC2O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc2c1CCC2Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 4-nitro-2,3-dihydro-1H-inden-1-ol (252 mg, 1.41 mmol, 1.0 equiv) in dry toluene (2.5 mL) was added thionyl chloride (160 μL, 2.11 mmol, 1.5 equiv) dropwise by syringe. After stirring at 0° C. for 30 min, the reaction mixture was heated to 55° C. for 2 h. The reaction was allowed to cool to room temperature, washed twice with water, dried over sodium sulfate, filtered and concentrated in vacuo. The unpurified alkyl chloride (221 mg, 79%) was used without further purification.
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.Br[CH2:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13]>>[CH3:1][S:2][CH:3]1[N:6]([CH2:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])[C:5](=[O:7])[CH2:4]1
Reactant: CC(=O)CC(=O)CBr
Reactant: CSC1CC(=O)N1
Product: CSC1CC(=O)N1CC(=O)CC(C)=O

Procedure:
4-Methylthioazetidin-2-one (6.66 g., 57 mmole) and 1-bromopentan-2,4-dione (11.25 g., 63 mmole) were converted into the title compound using the process described in Example 1.1. The title compound was obtained as a colourless gum (3.13 g., 25% yield). νmax (CHCl3): 3400 (br.) (enol OH), 1760 (β-lactam C=O), 1720 (sh.) (ketone C=O), 1630 (sh.) and 1605 (enolic β-diketone C=O) cm-1. δ(CDCl3): 2.03 (s, 6H, COCH3 and SCH3), 2.97 (dd, J 16, J' 2 Hz, 1H, β-lactam CHH), 3.41 (dd, J 16, J' 5 Hz, 1H, β-lactam CHH), 3.60 (s, 0.4H, COCH2CO), 3.65 (d, J 17 Hz, 1H, NCHH), 4.18 (d, J 17 Hz, 1H, NCHH), 4.78 (dd, J 5, J' 2 Hz, 1H, β-lactam CH), 5.68 (s, 0.8H, olefinic H for enol), ca 14(v.broad, 0.8H, enolOH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[C:15]1([S:21]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 89.3 %

Procedure:
A solution of 5-nitroindole (1.62 g, 10 mmol) in 30 ml of dimethylformamide (DMF) was treated with 60% sodium hydride (0.44 g, 11 mmol) at room temperature. After 3 minutes, benzenesulfonyl chloride (1.766 g, 10 mmol) was added. The mixture was stirred at room temperature overnight and treated with 250 ml of water. A precipitate formed and was filtered to give a yellow solid which was pumped in vacuo to give 2.7 g (89%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[OH:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:31][CH2:30][CH2:29][CH2:28][OH:27])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: NCCCO
Product: O=C(NCCCO)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-hydroxypropylamine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(3-hydroxypropyl)terephthalamide. MS (Q1) 445 (M)+.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[C:39]1([Si:45](Cl)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:52]1([Si:45]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc([Si](c3ccccc3)(c3ccccc3)c3ccccc3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-Triphenylsilyl-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared as a colourless foam from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using triphenylsilylchloride instead of benzophenone).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ncccn4)cc3CC[C@@H]12
Yield: 23.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloropyrimidine (53 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 30 mg (23%) of the title compound as an oil. FDMS: m/e=339.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][C:9]1[N:13]2[CH2:14][CH2:15][CH2:16][N:17]=[C:12]2[S:11][C:10]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:6])[CH3:3]>C(O)C.Cl>[ClH:1].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][C:9]1[N:13]2[CH2:14][CH2:15][CH2:16][N:17]=[C:12]2[S:11][C:10]=1[C:18]([OH:20])=[O:19])=[O:6])[CH3:3]
Reactant: CCOC(=O)CCC1=C(C(=O)OC(C)(C)C)SC2=NCCCN21
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCC1=C(C(=O)O)SC2=NCCCN21
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.4 %

Procedure:
In saturated hydrogenchloride ethanol solution was suspended 13.4 g of tert-butyl 3-(2-ethoxycarbonylethyl)-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxylate hydrochloride obtained in Example 77, followed by stirring at room temperature for 18 hours. The precipitated crystals were collected by filtration and washed with diethylether to yield 5.63 g of the titled compound.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:28])[C@@H:5]([NH:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH3:7])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:5]([CH2:6][CH3:7])[CH:4]([OH:28])[CH:2]([CH3:3])[CH3:1]
Reactant: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)C(O)C(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of (3RS,4S)-2-methyl-4-(trityl-amino)-hexan-3-ol (0.36 g, 1 eq, 0.97 mmol) in DCM (20 mL) under an argon atmosphere at room temperature, was added CF3COOH (5 mL) dropwise, and the solution was stirred at this temperature for 1 h. The solvent was evaporated in vacuo, the residue was precipitated from Et2O (10 mL) with hexiane (90 mL) with stirfing to give a yellow oil. The solvent was decanted from the oil, and the oil was washed with hexane (20 mL) and dried in vacuo to afford the title compound as a light yellow oil. Yield: 0.13 g (100%). (50% de 3R,4S: 50% de 3S,4S) 1H-NMR (d6-DMSO, 250 MHz): δ 0.85-1.01 (m, 9H, NH2CH (CH2CH3)CH(CH(CH(CH3)2)OH), 1.44-1.76 (m, 2H, NH2CH(CH2CH3)CH (CH(CH3)2) OH), 2.94 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 3.17 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 3.40 (m, 1H, NH2CH(CH2CH3)CH (CH(CH3)2)OH), 7.54 (bs, 2H, NHCH(CH2CH3)CH(CH(CH3)2)OH).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:1]([NH:5][C:6]([NH:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:16][CH2:17]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=O
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: CCCCNC(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
Butyl isocyanate (33.9 g, 342 mmol) is added dropwise to a solution of 1-(phenylmethyl)-4-piperidinamine (65 g, 342 mmol) in methylene chloride (400 mL) at 0° C., and the mixture is stirred for 2 hr. The mixture is washed three times with water, dried over magnesium sulfate, and evaporated. Recrystallization of the residue from methylene chloride-hexane affords the title compound.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][CH:19]([CH3:22])[CH2:20][NH2:21]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:21][CH2:20][CH:19]([CH3:22])[CH3:18])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CC(C)CN
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CC(C)CNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), 2-methylpropan-1-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 0.4), 274 (11), 141 (15), 86 (bp), 72 (29), 57 (14).