Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1)[CH2:34][CH2:35][CH3:36]>ClCCl>[CH2:33]([O:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:46])=[CH:40][CH:39]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCOc1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of 1-butoxy-4-isocyanato-benzene (49.0 mg, 0.26 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol 3-yl]-piperidine-1-carboxylic acid (4-butoxy-phenyl)-amide as a white solid. (Yield 0.05 g, 41.7%).
Reaction SMILES: [H][H].[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH2:8]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:3][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: [H][H]
Reactant: c1ccccc1
Product: C=CCCCCCCCCCC

Procedure:
Nafion™ fiber (3.5 g., 0.006" diameter, 1200 equivalent weight, hydrogen form) was loosely packed into a 1 cm. diameter vacuum-jacketed column and dried at 150° C. for 2 hours in a stream of dry nitrogen. The column was fitted onto a 50 ml. round bottom flask equipped with a side arm for sampling. A condenser and drying tube were fitted above the catalyst column. Dodecene-1 (15.0 z.), dry benzene (15.0 g.) and marble boiling chips were added to the flask; reflux was established up to the condenser. Samples (0.2 ml.) were periodically withdrawn via the side arm and analyzed by gas chromatography. The results are shown in Table XV. The residual pot (refluxing flask) contents were distilled through a 1×12 cm. vigreaux column equipped with a reflux ratio take off. The results are shown in Table XVI and illustrate that the integrated reactor fractionator is preferred for obtaining monoalkylated products. Although the conversion is somewhat slower by the refluxing of the mixture up to the catalyst, this method provides that only dodecene and benzene are present at the catalyst surface, in a ratio determined by their contributory vapor pressures, resulting in specific conversion to dodecylbenzene with no polyalkylated benzenes produced.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.[C:13]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+]>O1CCCC1.CN(C)C=O>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][CH2:5]/[CH:4]=[CH:3]\[CH2:2][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClC/C=C\COC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C/C=C\COC1CCCCO1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
2-[4-Chloro-(Z)-2-butenyloxy]tetrahydro-2H-pyran (100 g) was dissolved in 2000 ml of dry tetrahydrofuran/600 ml of dry N,N-dimethylformamide. To the solution was added 100 g of diethyl malonate, and then 25 g of 60% sodium hydride with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=9:1) to provide 65.5 g of the objective compound as oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:19])[CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:19][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CBr
Reactant: CCC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COC(CC)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (1 g., 50% w/w suspension in mineral oil) was added gradually to a stirred solution of 1-[4-(4-chlorophenyl)phenyl]propanol (4.9 g.) in dry dimethylformamide (20 ml.), keeping the temperature below 40° C. After 2 hours stirring ethyl bromoacetate (2.3 ml.) was then added, keeping the temperature below 30° C. After stirring for 16 hours at room temperature, the mixture was poured into water (150 ml.), and the subsequent mixture was extracted with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated to give ethyl 2-{1-[4-(4-chlorophenyl)-phenyl]propoxy}acetate as an oil (5 g.).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH2:19]([O:21][CH:22]([C:24]1[S:25][CH:26]=[C:27]([C:29](O)=[O:30])[N:28]=1)[CH3:23])[CH3:20]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:27]3[N:28]=[C:24]([CH:22]([O:21][CH2:19][CH3:20])[CH3:23])[S:25][CH:26]=3)=[O:30])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CCOC(C)c1nc(C(=O)O)cs1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CCOC(C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 31.7 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-ethoxyethyl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (350 mg, 1.342 mmo) and 2-(1-ethoxyethyl)thiazole-4-carboxylic acid (661 mg, 3.28 mmol). The product purified by Flash-chromatography (reverse phase). Yield 31.7%. 1H-NMR (400 MHz; MeOD): δ 1.19-1.24 (m, 3H), 1.26 (dd, 3H), 1.51 (t, 3H), 3.48-3.58 (m, 1H), 3.58-3.66 (m, 1H), 4.33-4.46 (m, 2H), 4.52-4.62 (m, 1H), 4.72-4.79 (m, 1H), 6.77 (dd, 1H), 7.70-7.72 (m, 1H), 7.75-7.79 (m, 1H), 7.85-7.89 (m, 1H), 8.02 (m, 1H), 8.08 (d, 1H).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:9]=1)(C)(C)C.C(C1NC=CN=1)(C1[NH:25]C=CN=1)=O.N>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:20][N:17]1[CH2:18][CH2:19][N:14]([C:10]2[CH:9]=[C:8]([CH2:7][C:6]([NH2:25])=[O:5])[CH:13]=[CH:12][N:11]=2)[CH2:15][CH2:16]1
Reactant: CN1CCN(c2cc(CC(=O)OC(C)(C)C)ccn2)CC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cc(CC(N)=O)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[2-(4-Methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid tert-butyl ester (95 mg, 0.33 mmol) is dissolved in a mixture of TFA and CH2Cl2 (5 ml/5 ml) and stirred at RT. After 1 h at RT, TLC analysis indicated complete conversion of starting material. The solvent is removed by rotary evaporation, and replaced by dry DMF (1.5 ml). Under an atmosphere of argon, carbonyl diimidazole (58 mg, 0.36 mmol) is added. After 20 minutes at RT, TLC analysis indicated complete conversion of the carboxylic acid. An aqueous solution of ammonia (25%, 6 ml) is added at RT. After 15 minutes at RT, solvents are removed under high vacuum. The residue is dissolved in CH2Cl2/MeOH (9:1) and purified by FCC (CH2Cl2/MeOH, slow gradient from 95:5 to 40:60) to yield the title compound. 1H NMR (d4-MeOD, 400 MHz): δ 2.35 (s, 3H), 2.56 (m, 4H), 3.46 (s, 2H), 3.54 (m, 4H), 6.66 (d, J=6 Hz, 1H), 6.78 (s, 1H), 8.02 (d, J=6 Hz, 1H). ES+−MS: 235.3 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([NH2:36])=[O:35]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:13]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([NH2:36])=[O:35]
Reactant: NC(=O)CCCCCBr
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)OCO4)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)CCCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 mg (0.121 mmol) of 8-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (S13-1) was dissolved in DMF (2 mL). 47 mg (0.145 mmol) of Cs2CO3 and 117.4 mg (0.605 mmol) of 6-bromohexanamide (S13-2) were added and the mixture was stirred at rt for 2 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 10:1) to give 12.7 mg (20%) of DZ5-49-N9. 1H NMR (500 MHz, CDCl3/MeOH-d4): δ 8.13 (s, 1H), 7.31 (s, 1H), 6.97 (s, 1H), 5.98 (s, 2H), 4.13 (t, J=7.6 Hz, 2H), 2.14 (t, J=7.6 Hz, 2H), 1.71-1.80 (m, 2H), 1.55-1.65 (m, 2H), 1.28-1.39 (m, 2H); HRMS (ESI) m/z [M+H]+ calcd. for C18H20IN6O3S, 527.0362. found 527.0364.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH2:30][N:31]2[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([CH2:30][N:31]3[CH2:32][CH2:33][S:34](=[O:38])(=[O:37])[CH2:35][CH2:36]3)=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cc1nc(Cl)ccc1CN1CCS(=O)(=O)CC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1CN1CCS(=O)(=O)CC1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 4-[(6-chloro-2-methylpyridin-3-yl)methyl]thiomorpholine 1,1-dioxide (132 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([Cl:30])[CH:9]=1>>[Cl:30][C:10]1[CH:9]=[C:8]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:13]=[CH:12][C:11]=1[C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=2)[CH2:20][CH2:21]1)=[O:15]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3Cl)CC2)c(C)c1
Yield: 66.3 %

Procedure:
Using pyrrolidin-2-one (23 mg) and (4-bromo-2-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (100 mg) described in Preparation Example 119 and by the reaction and treatment in the same manner as in Example 1, the title compound (67 mg) was obtained.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[Br:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22](C)[CH:21]=2)=[N:11][N:10]=1>>[Br:4][C:5]1[CH:6]=[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][N:23]=[C:24]([C:1]([NH2:3])=[O:2])[CH:25]=3)=[N:11][N:10]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: NC=O
Reactant: Cc1cc(Cc2nnc(Nc3cccc(Br)c3)c3ccccc23)ccn1
Product: NC(=O)c1cc(Cc2nnc(Nc3cccc(Br)c3)c3ccccc23)ccn1
Yield: 10.6 %

Procedure:
The procedure used for the preparation of Example 1, but replacing N-methylformamide with formamide, was used to prepare the title compound (0.059 g, 0.13 mmol, 10.6% yield) from 1-(3-bromoanilino) 4-[(2-methyl-4-pyridyl)methyl]phthalazine (for preparation see Novartis patent WO98/35958, 11.02.98). 1H-NMR (DMSO-d6) 9.31 (s, 1H), 8.58 (d, J=7.7, 1H), 8.49 (d, J=5.3, 1H), 8.35 (s, 1H), 8.13 (d, J=7.5, 1H), 8.05 (broad s, 1H), 7.89 to 7.99 (m, 4H), 7.59 (broad s, 1H), 7.53 (dd, J=5.1, 1.5, 1H), 7.29 (t, J=8.0, 1H), 7.18 (d, J=7.8, 1H), 4.68 (s, 2H); MS ES 434/436 (M+H)+ w/1Br, calc. 433; TLC (1:4:15 v/v methanol-acetone-dichloromethane) Rf=0.59.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:31][C@@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[C:35]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH:36]=[CH:37][CH:38]=2)[CH2:33]1>CN(C)C=O>[CH3:48][N:45]1[CH2:46][CH2:47][N:42]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]3[C:34]=2[CH2:33][C@H:32]([NH:31][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:15][CH:14]=2)[CH2:41][CH2:40]3)[CH2:43][CH2:44]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCCCC4)cc2)CC3)CC1
Temperature: 75 °C
Reaction time: 17 h
Yield: 42.3 %

Procedure:
To a solution of 4-piperidinobenzoic acid (88 mg, 0.43 mmol; described in: Weringa, W. D.; Janssen, M. J. Recl. Trav. Chim. Pays-Bas 1968, 87 (12), 1372-1380) in anhydrous N,N-dimethylformamide (5 mL) was added 1,1'-carbonyldiimidazole (73 mg, 0.45 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 17 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent gave 75 mg (42% yield) of the title compound as white crystals: mp 196-198° C.; [α]21D 63° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 432 (2, M+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[NH3:11]>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH2:11])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: N
Reactant: COc1cnc(Cl)nc1Cl
Solvent: CO
Product: COc1cnc(Cl)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4 dichloro-5-methoxypyrimidine (0.45 g, 2.5 mmol) and ammonia in methanol (2N, 20 ml) was stirred at room temperature overnight. The mixture was then concentrated in vacuo and washed with water. The residue was purified by column chromatography (20-60% ethyl acetate/petroleum ether) to furnish the title compound as a white solid (211 mg). MS: [M+H]+=160
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:21][CH:20]([O:22][CH2:23][C:24](N4CCOCC4)=[O:25])[CH2:19][CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:21][CH:20]([O:22][CH2:23][CH:24]([OH:25])[CH3:32])[CH2:19][CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: O=C(COC1CCc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2C1)N1CCOCC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)COC1CCc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-((2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydro-1,3-benzoxazol-6-yl)oxy)-1-(morpholin-4-yl)ethanone (9.24 g) in THF (25 mL) was added methylmagnesium bromide (1 M THF solution, 31.0 mL). To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue in a mixed solvent of THF (10 mL)-methanol (10 mL) was added sodium tetrahydroborate (782 mg), and the mixture was stirred at room temperature for 10 min. the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.51 g).
Reaction SMILES: [Br:1]/[C:2](=[CH:5]\N(C)C)/[CH:3]=O.C(=O)([O-])[O-].[K+].[K+].Cl.[OH:16][C:17]([CH3:22])(C)[C:18]([NH2:20])=[NH:19]>C(O)C>[Br:1][C:2]1[CH:3]=[N:19][C:18]([C@@H:17]([OH:16])[CH3:22])=[N:20][CH:5]=1
Reactant: CC(C)(O)C(=N)N
Reactant: CN(C)/C=C(\Br)C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@H](O)c1ncc(Br)cn1
Temperature: 85 °C
Yield: 16 %

Procedure:
(Z)-2-bromo-3-(dimethylamino)prop-2-enal (11.5 g), potassium carbonate (13.4 g), ethanol (200 mL) and 2-hydroxy-2-methyl-propanamidine hydrochloride (12.1 g) were placed in a flask and the mixture heated at 85° C. overnight. The reaction mixture was cooled and the mixture filtered, washed with ethanol and the combined filtrates concentrated in vacuo with silica gel. This residue was purified by chromatography on silica, eluting with 0-50% ethyl acetate in heptane to give (1S)-1-(5-bromopyrimidin-2-yl)ethanol as a white solid (2.1 g, 16%). 1H NMR (CDCl3) δ 8.83 (s, 2H), 4.98 (m, 1H), 3.8 (m, 1H), 1.6 (d, J=6.6 Hz, 3H). Chiral HPLC: Column. Chirapak IC, 0.46 cm×25 cm; 20 min isocratic gradent; 5:95 EtOH:n-hexane+0.1% diethylamine) retention time=14.08 min. (racemic mixture: ˜14.5 min: S isomer; ˜17.5 min: R isomer).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][CH:15]1[CH2:19][CH2:18][C:17]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16]1.N1C=CC=CC=1>O>[CH2:16]1[C:17]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:18][CH2:19][CH:15]1[NH:14][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: NC1CCC2(CCCCC2)C1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1CCC2(CCCCC2)C1)c1cnc2ccccc2n1
Yield: 84.3 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 2-aminospiro(4.5)decane (150 mg, 0.79 mmol), pyridine (5 mL), and water (100 mL) yielding 206 mg (74%) of (236):
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: OB(O)c1ccccc1F
Reactant: COc1cccc(Sc2sc(CN(C)C(=O)OC(C)(C)C)cc2Br)c1
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: O
Solvent: COCCOC
Product: COc1cccc(Sc2sc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Temperature: 105 °C
Reaction time: 4 h
Yield: 74.5 %

Procedure:
tert-Butyl ({4-bromo-5-[(3-methoxyphenyl)thio]-2-thienyl}methyl)methylcarbamate (596 mg), (2-fluorophenyl)boronic acid (225 mg), sodium carbonate (341 mg) and tetrakis(triphenylphosphine)palladium (0) (155 mg) were suspended in a mixture of 1,2-dimethoxyethane (10 mL) and water (4 mL), and the suspension was stirred at 105° C. for 4 hr under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→9:1) to give the title compound as a colorless oil (yield 459 mg, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
A mixture of (2-chlorophenyl)acetic acid (15 g, 88 mmol) in cone. H2SO4 (100 mL) was cooled to −20° C. and treated (drop wise) with cone. HNO3 (9.4 g, 97 mmol). The resulting mixture was stirred at −20° C. for an additional 30 min. The reaction mixture was poured into the ice-water, and the mixture was extracted with EtOAc (3×200 mL), the combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to give (2-chloro-5-nitrophenyl)acetic acid (15 g, 79% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1 H), 8.35 (m, 1 H), 7.96 (m, 1 H), 4.12 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18].[ClH:19].N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:19])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18]
Reactant: Cl
Reactant: CC1(C)CC(=O)C(c2ccc(N)cc2Cl)C(=O)C1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(=O)C(c2ccc(Cl)cc2Cl)C(=O)C1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
A suspension of 5.00 g (0.0188 mol) of 2-(2'-chloro-4'-aminophenyl)-5,5-dimethyl-1,3-cyclohexanedione in 75 ml of water containing 4.0 ml of concentrated HCl was stirred and heated almost to boiling for 10 min., then cooled to 10° C. and an additional 7 ml of conc. HCl added and the solution cooled to 0°-5° C. A solution of 2.00 g (0.0282 mol) of sodium nitrite in 6.0 ml of water was added dropwise to the amine hydrochloride solution while maintaining the temperature at 0°-5° C. When all the NaNO2 solution had been added, the diazonium salt solution was stirred for 30 min. at 0° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([NH:11][C:12]1[O:13][C:14]([CH3:28])([CH3:27])[CH:15]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[S:16](=[O:19])(=[O:18])[N:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:29]C(C)([O-])C.[K+].CI>CN(C)C=O>[CH3:29][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]2[C:14]([CH3:28])([CH3:27])[O:13][C:12]([NH:11][C@H:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][CH2:2][OH:1])=[N:17][S:16]2(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1c1ccc(O)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C2C(C)(C)OC(N[C@@H](CCO)c3ccccc3)=NS2(=O)=O)cc1
Yield: 24.4 %

Procedure:
To a solution of 40 mg of 4-[2-((S)-3-hydroxy-1-phenylpropylamino)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-5-yl]phenol in 1 ml of N,N-dimethylformamide were added, at room temperature, 11 mg of potassium tert-butoxide and 28 mg of methyl iodide, and the reaction mixture was stirred at constant temperature for 3 hours. The reaction solution was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and lyophilized. This gave the product (10 mg) with a molecular weight of 418.5 g/mol (C21H26N2O5S); MS (ESI): m/e=419 (M+H+).