Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[Br:20][C:21]1[CH:22]=[C:23]([C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]#[N:42])=[N:28]S(C(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=1.Cl>O1CCCC1.O>[Br:20][C:21]1[CH:22]=[C:23]([C:27]2([C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:13])[C:35]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]([NH2:42])=[N:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: Fc1cccnc1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1ccccc1C#N
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: NC1=NC(c2cccc(Br)c2)(c2ccncc2F)c2ccccc21
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a −78° C. solution of diisopropylamine (0.77 mL, 5.50 mmol) in tetrahydrofuran (10 mL) was n-butyllithium (2.5 M in hexane, 2.20 mL, 5.50 mmol) added, the mixture was stirred 0.5 h and then a solution of 3-fluoropyridine (0.47 mL, 5.50 mmol) in tetrahydrofuran (2 mL) was added and after another 0.5 h N-[(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide (Scheme #5, N) (1.95 g, 5.0 mmol) in tetrahydrofuran (5 mL) was added. After 1.5 h at −78° C. water was added, the mixture was extracted with ethyl acetate, the organic phase was dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (40 mL) and treated with hydrochloric acid (2 M in diethylether, 5 mL, 10.0 mmol) over night. After evaporation, the residue was partitioned between aqueous saturated sodium bicarbonate and chloroform, the organic phase was dried over magnesium sulfate and evaporated. Purification of the residue by column chromatography using a stepwise gradient of methanol in chloroform (0-10%) as the eluent gave the title compound (1.22 g, 64%). 1H NMR (CDCl3) δ 8.43 (d, J=2.78 Hz, 1 H), 8.35 (d, J=5.05 Hz, 1 H), 7.76 (d, J=8.08 Hz, 1 H), 7.60-7.50 (m, 3 H), 7.45-7.37 (m, 2 H), 7.37-7.33 (m, 1 H), 7.20-7.13 (m, 2 H), 5.37 (br s, 2 H); MS (AP) m/z 382, 384 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19]C(=O)COC4C=CC=CC=4)[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH:35]C(=O)C)[CH3:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C1C=CC=CC=1.CO>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH2:19])[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH2:35])[CH3:31])=[O:11])=[CH:40][CH:41]=1)([O-:3])=[O:2]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: C[C@@]1(COC(N)=O)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylic acid p-nitrobenzyl ester (1.17 g, 2.0 mmol) in methylene chloride (10 ml) at -40° was charged with dimethylaniline (1.03 ml, 8.0 mmol) and phoshorous pentachloride (0.92 g, 4.4 mmol). The solution was stirred at -35° to -40° for 30 minutes and cold (~-35°) methanol (4.1 ml, 100 mmol) was added dropwise. The pale green solution was stirred at -35° to -40° for 2 hours and then quenched into ice-water (10 ml). The pH was adjusted to 1.7 with conc. ammonia and the layers were separated. The aqueous was washed with CH2Cl2 (5 ml), combined with a water back-extract (5 ml), and stirred with CH2Cl2 (10 ml) during pH adjustment to 6.5 with ammonia. The organic phase was withdrawn, washed (5 ml, H2O), combined with a back-extract (CH2Cl2, 10 ml), dried (4 A sieves), filtered, concentrated to 4 ml and diluted with heptane (10 ml). The suspension was concentrated to 8 ml and the liquids were decanted. The solids were treated with CH2Cl2 (4 ml) and heptane (10 ml) in the same fashion, and the product was washed with heptane and dried to an off-white solid (0.28 g) 34%; nmr 100 MHz CDCl3 --D2O δ8.24 (2, d, J=8.5 Hz, 1/2pNB AB), 7.56 (2, d, J=8.5, pNB AB), 5.68 (1, brd J=4, C5 --H), 5.32 (2 s, benzyl CH2), 4.76 (1, s, C3 --H) 4.55 (HOD overlapping C6 --H d), 4.16 and 3.97 (2, ABq J=11.5 C2 --CH2 --O), 1.43 (3, s, C3 --C3), with 2.36 ##STR79##
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.CN1CCCC1=O.[OH-].[K+].[C:44]1([SH:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O>[C:44]1([S:50][C:2]2[CH:34]=[CH:33][C:5]3=[N:6][N:7]([C:9]4[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)([CH3:25])[CH3:24])[C:10]=4[OH:32])[N:8]=[C:4]3[CH:3]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 90 °C
Yield: 94.7 %

Procedure:
To a stirred mixture of 75 g of 5-chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octyl-phenyl)-2H-benzotriazole and 105 g of N-methylpyrrolidone heated at 90° C. is added first 44.3 g of 45% aqueous potassium hydroxide solution over a 15-minute period then 20.4 g of thiophenol over another 15 minutes. The reaction mixture is then heated at 170-175° C. for four hours with water being removed by distillation. After cooling to 100° C., xylene and water are added and the resultant mixture is made acidic with 15% aqueous hydrogen chloride solution. The organic layer is separated and washed with water and then concentrated. The crude product residue is recrystallized from methanol to yield 82 g of the title compound as a pale yellow solid melting at 124-125° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])([CH:16]([CH3:18])[CH3:17])[O:12][C:11]2=[O:24])[CH3:9])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:29]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:19][CH2:20][C:21]([O:23][CH3:29])=[O:22])([CH:16]([CH3:17])[CH3:18])[O:12][C:11]2=[O:24])[CH3:9])=[CH:4][CH:3]=1
Reactant: CO
Reactant: CC(C)C1(CCC(=O)O)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCC1(C(C)C)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazinan-6-yl)propanoic acid (41 mg, 0.1 mmol) in MeOH (10 mL) was added SOCl2 (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h, concentrated, and purified by preparative TLC to give methyl 3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazinan-6-yl)propanoate (42 mg, 96% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:13]=[CH:12][C:11]([I:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)[CH2:2][CH3:3].[NH2:15][C:16]1[C:17]([CH2:24][CH3:25])=[N:18][NH:19][C:20]=1[C:21]([NH2:23])=[O:22]>>[NH2:23][C:21]([C:20]1[C:16]([NH:15][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([I:14])[CH:12]=[N:13][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])=[C:17]([CH2:24][CH3:25])[NH:18][N:19]=1)=[O:22]
Reactant: CCc1n[nH]c(C(N)=O)c1N
Reactant: CCCOc1ncc(I)cc1C(=O)O
Product: CCCOc1ncc(I)cc1C(=O)Nc1c(C(N)=O)n[nH]c1CC

Procedure:
The title compound was prepared from 2-propoxy-5-iodonicotinic acid (see Preparation 2(h) and 4-amino-3-ethyl-1H-pyrazole-5-carboxamide (prepared as described in WO 98/49166) according to the method described in Preparation 2(g)(i).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[I-:11].[Na+]>CC(C)=O>[I:11][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10]
Reactant: OCCOCCOCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: OCCOCCOCCI
Reaction time: 16 h
Yield: 53 %

Procedure:
One hundred grams (0.59 mole) of 2-[2-(2-chloroethoxy)ethoxy]-ethanol (Aldrich 16,297-3) was added to a solution of 450 g. (3 mol) of sodium iodide in 2.5 l acetone and stirred, in the dark, for 5 hours at reflux and then at room temperature for 16 hours. The precipitate was filtered and the acetone evaporated off at 30° C. The residue was dissolved in chloroform, extracted with saturated sodium chloride solution, and then with saturated sodium bisulfate solution. The chloroform extract was dried (MgSO4) and evaporated at room temperature to yield 137 g. (53%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:17][C:18]1[N:19]=[C:20]([NH:23][CH2:24][CH2:25][NH2:26])[S:21][CH:22]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:9][C:2]([F:1])([CH3:8])/[CH:3]=[CH:4]/[C:5]([NH:26][CH2:25][CH2:24][NH:23][C:20]1[S:21][CH:22]=[C:18]([CH3:17])[N:19]=1)=[O:7]
Reactant: CC(F)(F)/C=C/C(=O)O
Reactant: Cc1csc(NCCN)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1csc(NCCNC(=O)/C=C/C(C)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.7 %

Procedure:
(E)-4,4-Difluoropent-2-enoic acid (31 mg, 0.23 mmol) was dissolved in DCM (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N′-(4-methylthiazol-2-yl)ethane-1,2-diamine hydrochloride (24 mg, 0.15 mmol) and diisopropylethylamine (88 μl, 0.5 mmol) dissolved in DCM (2 ml) and the resulting mixture was stirred at room temperature for three hours. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 11 mg of a solid (0.04 mmol, 27%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)(=[O:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:20].[F:21][C:22]([F:33])([F:32])[CH2:23][O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26]>C1(C)C=CC=CC=1>[CH3:1][N+:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)(=[O:12])=[O:13])=[CH:10][C:5]=2[N:4]([CH2:23][C:22]([F:33])([F:32])[F:21])[C:3]=1[CH3:20].[F:29][C:28]([F:31])([F:30])[S:25]([O-:27])(=[O:26])=[O:24]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1nc2cc(S(=O)(=O)N3CCOCC3)ccc2n1C
Solvent: Cc1ccccc1
Product: Cc1n(CC(F)(F)F)c2cc(S(=O)(=O)N3CCOCC3)ccc2[n+]1C
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Yield: 68.3 %

Procedure:
In 20 ml of a toluene solution, 5.9 g of 1,2-dimethyl-5-morpholinosulfonylbenzimidazole synthesized by a method described in Japanese Patent Publication No. 43-10252, end 6.5 g of 2,2,2-trifluoroethyl-trifluoromethanesulfonate were heated in reflux for 24 hours. After the resulting mixture was allowed to cool to room temperature, the supernatant was separated; to the reaction mixture was added an ethyl acetate solution and dispersed, and the product was collected by filtration and washed to obtain 7.2 g of a quartenary salt.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][C@@H:35]1[C@@H:40]2[CH2:41][C@@H:37]([CH2:38][CH2:39]2)[C@@H:36]1[CH2:42][OH:43]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][C@H:35]2[C@@H:36]([CH2:42][OH:43])[C@H:37]3[CH2:41][C@@H:40]2[CH2:39][CH2:38]3)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: N[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1CO
Product: CON=C1C[C@@H](C(=O)N[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2CO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and [(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the title compound was obtained in 64% purity by HPLC. MS(ESI+): m/z=462.
Reaction SMILES: C(Br)(Br)(Br)[Br:2].[F:6][C:7]1[CH:8]=[C:9]([C@H:13]([C@@H:15]2[O:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16]2)O)[CH:10]=[CH:11][CH:12]=1.[F:28][C:29]1[CH:30]=[C:31]([C@@H:35]([C@H:37]2[O:42][CH2:41][CH2:40][N:39]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:38]2)O)[CH:32]=[CH:33][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:2][C@@H:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=1)[C@@H:15]1[O:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16]1.[Br:2][C@H:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=1)[C@H:37]1[O:42][CH2:41][CH2:40][N:39]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:38]1
Reactant: BrC(Br)(Br)Br
Reactant: O[C@@H](c1cccc(F)c1)[C@@H]1CN(Cc2ccccc2)CCO1
Reactant: O[C@H](c1cccc(F)c1)[C@H]1CN(Cc2ccccc2)CCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc([C@@H](Br)[C@@H]2CN(Cc3ccccc3)CCO2)c1
Product: Fc1cccc([C@H](Br)[C@H]2CN(Cc3ccccc3)CCO2)c1
Reaction time: 0.5 h
Yield: 34 %

Procedure:
A solution of carbon tetrabromide (3.3 g, 9.96 mmol) in dichloromethane (4 ml) was added dropwise over 5 min to a stirred solution of (R)-[3-fluorophenyl][(2R)-4-benzylmorpholin-2-yl]methanol and (S)-[3-fluorophenyl][(2S)-4-benzylmorpholin-2-yl]methanol (2.0 g, 6.64 mmol) and triphenylphosphine (2.61 g, 9.96 mmol) in dichloromethane (40 ml) at room temperature under nitrogen. After 30 min, the reaction solution was washed with saturated aqueous sodium bicarbonate (50 ml). The dichloromethane layer was dried, filtered and evaporated to a red liquid (8.5 g). Trituration with diethyl ether (40 ml) crystallised triphenylphoshine oxide that was then removed by filtration. The filtrate was evaporated to a yellow oil and was purified by chromatography on silica eluting with ethyl acetate:hexane 20:80 to give a colourless oil of (2R)-2-[(S)-bromo(3-fluorophenyl)methyl]-4-benzylmorpholine and (2S)-2-[(R)-bromo(3-fluorophenyl)methyl]-4-benzylmorpholine (0.811 g, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1C(O)=O.C(=O)(O)[O-].[Na+].[Br:32]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:32][C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:23])=[CH:10][N:9]=2)[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C(=O)O)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
Combined 5-methoxy-1-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (329.5 mg, 0.914 mmol) and sodium bicarbonate (307 mg, 3.66 mmol) in DMF (3 mL) then added 1-bromopyrrolidine-2,5-dione (163 mg, 0.914 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 30 minutes and then diluted with water (15 mL) to give a suspension. The suspension was filtered, rinsed with water (3×5 mL), and dried in vacuo to give the title compound (302 mg, 84% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.28 (m, 2H) 1.62 (dd, J=12.88, 1.77 Hz, 2H) 1.80 (dddt, J=14.78, 11.12, 7.39, 3.44, 3.44 Hz, 1H) 3.16-3.23 (m, 2H) 3.23-3.31 (m, 2H) 3.81-3.89 (m, 2H) 4.05 (s, 3H) 7.79 (dd, J=8.59, 0.76 Hz, 1H) 7.84 (s, 1H) 8.38 (dd, J=8.46, 2.40 Hz, 1H) 8.75 (t, J=5.81 Hz, 1H) 8.96 (dd, J=2.53, 0.76 Hz, 1H). MS m/z [M+H]+ 395.3, 397.3.
Reaction SMILES: [OH:1][C:2]([CH3:32])([CH3:31])[CH2:3][C@@:4]1([CH:28]([CH3:30])[CH3:29])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:25]([C:22]2[N:21]=[CH:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:32])[CH3:31])([CH:28]([CH3:29])[CH3:30])[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)=[CH:24][N:23]=2)=[O:26])[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: CC(C)[C@@]1(CC(C)(C)O)CCN([C@@H](C)c2ccc(-c3cnc(C(=O)O)nc3)cc2)C(=O)O1
Product: CC(C)[C@@]1(CC(C)(C)O)CCN([C@@H](C)c2ccc(-c3cnc(C(=O)NC4CC4)nc3)cc2)C(=O)O1

Procedure:
The title compound was prepared from 5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrimidine-2-carboxylic acid and cyclopropylamine following a procedure analogous to that described in Example 25 Step 7.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([O:24][P:25]([CH:30](O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23].N1C=CC=CC=1>C(Cl)Cl>[CH2:22]([O:24][P:25]([CH:30]([Br:1])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23]
Reactant: BrBr
Reactant: CCOP(=O)(OCC)C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
90 g of bromine, dissolved in 250 ml of methylene chloride, were added dropwise to a solution of 131 g (0.5 mole) of triphenylphosphine in 500 ml of methylene chloride at 30° to 35° C., moisture being excluded. The mixture was subsequently stirred at room temperature for 1 hour, a solution of 122 g (0.5 mole) of α-hydroxybenzyl-phosphonic acid diethyl ester in 250 ml of methylene chloride was then added dropwise at -20° C. in the course of 1 hour, the mixture was subsequently stirred at -20° C. for 1 hour and 40 g of pyridine, dissolved in 250 ml of methylene chloride, were then added dropwise at -20° C. in the course of one hour. The mixture was subsequently stirred for 20 hours, whereupon the temperature rose slowly to +20° C. The reaction mixture was transferred to a pear-shaped flask and the solvent was distilled off under a waterpump vacuum. The residue was extracted by stirring with one liter of ether and the undissolved triphenylphosphine oxide was filtered off (120 g of triphenylphosphine oxide=86% of theory). The mother liquor was concentrated in vacuo and the residue distilled under a high vacuum. 112 g (72% of theory) of α-bromobenzylphosphonic acid diethyl ester were obtained as a light yellow oil with a boiling point of 110° C./0.01 mm Hg and a purity of 95.9% (gas chromatogram).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([CH:11]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])[CH3:10].CN(C=O)C>O>[Br:8][C:18]1[CH:17]=[CH:16][C:15]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[C:14]([O:13][CH2:12][CH:11]([CH2:9][CH3:10])[CH2:29][CH2:30][CH2:31][CH3:32])[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC(CC)COc1ccccc1OCC(CC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc(Br)cc1OCC(CC)CCCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
Solid NBS (26.21 g, 0.147 mol) was added to an ice cold CH2Cl2 solution (250 mL) of 1b under N2 in the absence of light. Just enough DMF was added (30 mL) to dissolve the NBS. The reaction mixture was allowed to warm to room temperature and then stirred for 12 h. The mixture was then poured into water. The organic layer was washed with a saturated LiCl solution and water. After drying with MgSO4 the solvent was removed under reduced pressure. The remaining oil was distilled (160° C./0.01 mmHg) to yield 4-bromo-1,2-di(2-ethylhexyloxy)benzene (2b) in 96% yield as a colorless oil.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Br:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]1>>[Br:24][C:20]1[CH:19]=[C:18]([F:25])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:40][CH2:39][CH2:38][CH2:37][N:34]3[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]3)=[O:29])[S:14][N:13]=2)=[C:22]([F:23])[CH:21]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: NC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)Oc1ccccc1
Product: CN1CCN(CCCNC(=O)Nc2snc(OCc3c(F)cc(Br)cc3F)c2C(N)=O)CC1

Procedure:
The title compound was prepared from [3-(4-bromo-2,6-difluoro-benzyloxy)-4-carbamoyl-isothiazol-5-yl]-carbamic acid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 1. MS (APCI, m/z): 547 and 549 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][CH2:16][CH:15]([OH:18])[O:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:39]1(=[O:53])[N:43]([CH2:44][CH2:45][CH2:46]O)[C:42](=[O:48])[C:41]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:40]12>ClCCl>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C@H:13]2[CH2:17][CH2:16][C@@H:15]([O:18][CH2:46][CH2:45][CH2:44][N:43]3[C:39](=[O:53])[C:40]4=[CH:52][CH:51]=[CH:50][CH:49]=[C:41]4[C:42]3=[O:48])[O:14]2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Reactant: COc1cc(C2CCC(O)O2)cc(OC)c1OC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc([C@H]2CC[C@@H](OCCCN3C(=O)c4ccccc4C3=O)O2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Compound 105 (1.14 g, 4.49 mmol) was dissolved in 4 mL dichloromethane. Triethylamine (681.4 mg, 6.73 mmol) was added to this solution. The reaction mixture was cooled with an ice bath and trifluoroacetic anhydride (1.41 g, 6.73 mmol) was added in a dropwise manner. The reaction mixture was stirred at 0° C. for 30 minutes and then 3-phthalimidylpropanol (106) (2.4 g, 13.26 mmol) was added. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NaHCo3 solution and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution, dried over MgSO4, filtered and evaporated in vacuo to an oil which was purified by column chromatography (silica, 2:1 hexane/ethyl acetate) (107: 522 mg (trans); 108: 271 mg (cis); 1:1 mixture of 107 and 108: 110 mg; total yield 46%). 1H NMR (CDCl3): 107: 1.70(m,1H); 1.82(m,1H); 2.00(m,2H); 2.02(m,1H); 2.28(m,1H); 3.46(m,1H); 3.83(s,3H); 3.84(m,3H); 3.88(s,6H); 4.99(t,1H); 5.30(dd,1H); 6.56(s,2H); 7.72(m,2H); 7.85(m,2H). 108: 1.95(m,3H); 2.00(m,2H); 2.20(m,1H); 3.51(m,1H); 3.83(s,3H); 3.85(m,2H); 3.88(s,6H); 3.92(m,1H); 4.90(m,1H); 5.16(dd,1H); 6.60(s,2H); 7.72(m,2H); 7.84(m,2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[OH-].[Na+].[OH:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O.[CH3:17][N:18]=[C:19]=[S:20]>C(O)C>[CH3:17][NH:18][C:19]([N:2]1[CH2:3][CH2:4][S:5][CH:11]1[C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[OH:8])=[S:20]
Reactant: O=Cc1ccccc1O
Reactant: NCCS
Reactant: CN=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNC(=S)N1CCSC1c1ccccc1O
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
To a solution of cysteamine hydrochloride (11.3 g) in ethanol (250 ml) is added sodium hydroxide (4.0 g), and the mixture is stirred for 30 minutes under argon gas. A solution of 2-hydroxybenzaldehyde (12.2 g) in ethanol (40 ml) is added to the mixture, and the mixture is refluxed for 4 hours. To the mixture is added methyl isothiocyanate (7.9 g), and the mixture is further refluxed for 4 hours. After distilling off the solvent under reduced pressure, a mixture of water and ethanol is added to the resulting residue, and the insoluble crystals are collected by filtration. The crystals thus obtained are washed with water and ethanol and recrystallized from ethanol to give N-methyl-2-(2-hydroxyphenyl)thiazolidine-3-carbothioamide (7.9 g, yield: 31.1%).