Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[ClH:12].[CH2:13]([O:15]CC)[CH3:14]>C(O)C.O1CCCC1>[ClH:12].[S:10]1[C:11]2[C:3]([C:1](=[NH:2])[O:15][CH2:13][CH3:14])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=[N:9]1
Reactant: CCOCC
Reactant: N#Cc1cccc2nnsc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=N)c1cccc2nnsc12
Reaction time: 24 h

Procedure:
7.2 g of 7-cyanobenzo-1,2,3-thiadiazole are dissolved at 45° C. in 60 ml of absolute ethanol and 20 ml of tetrahydrofuran, and the solution is cooled to 0° C. and saturated with gaseous hydrochloric acid in the course of 1 hour at 0° C. to 15° C., with the exclusion of moisture. The reaction mixture is then stored for 24 hours in the refrigerator, treated with 70 ml of absolute diethyl ether and allowed to stand for another 4 days in the refrigerator. The solid is then filtered off, washed with diethyl ether and dried. This gives 9.4 g of compound 5.2 in the form of beige crystals of m.p. 270°-272° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:31])[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)C=Cc1cccc(F)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cccc(F)c1
Yield: 99.7 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.0 g), triethylamine (1.4 mL), 3-fluorocinnamic acid (1.6 g), WSC.HCl (1.9 g), and methylene chloride (60 mL), to give the captioned compound (2.9 g, 99%) as an oily product.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:9]([O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C(OCc2ccccc2)CCC1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a round bottomed flask equipped with Dean-Stark apparatus was added 1,3-cyclohexanedione (60.0 g), toluene (450 ml), p-toluenesulfonic acid monohydrate (1.35 g) and benzyl alcohol (52.6 g, 487). The resulting solution was heated to reflux temperature for 12 hr. The reaction mixture was cooled to room temperature and then washed with saturated aqueous sodium carbonate solution (2×100 ml). The organic layer was then washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo, affording a brown oil (94.9 g) which crystallised upon standing for 17 hr. The crude crystalline material was slurried in isopropyl ether (20 ml). The mixture was filtered and the crystalline material was washed with ice cold isopropyl ether (3×30 ml), then with cold petroleum ether (2×20 ml). The resulting peach-colored crystalline solid was dried overnight under reduced pressure, furnishing the title compound (74.4 g, 76%). m/z (ES+) 203 (M+H+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:18])[N:3]=1.O.[C:20](#[N:22])[CH3:21]>C1(N)CCCCC1>[CH:21]1([CH2:20][NH:22][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH2:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[C:4]([NH2:18])[N:3]=2)[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]1
Reactant: CC#N
Reactant: Nc1nc(Cl)nc2c1ncn2CC1CCOCC1
Solvent: NC1CCCCC1
Solvent: O
Product: Nc1nc(NCC2CCCCC2)nc2c1ncn2CC1CCOCC1

Procedure:
A solution of 2-chloro-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (150 mg) in cyclohexylamine (363 ul) was heated in the microwave at 170° C. for five minutes. The crude reaction mixture was subjected to C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford a white solid (98 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12](B(O)O)=[CH:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1ccccc1-c1ccccc1)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 34.2 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.46 g, 10.0 mmol), 2-biphenylboronic acid (Aldrich; 1.94 g, 10.0 mmol), copper(II) acetate (1.81 g, 10.0 mmol) and triethylamine (1.4 mL, 10.0 mmol) in 1,2-dichloroethane (10 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 5-40% ethyl acetate/hexanes, to give N′-biphenyl-2-yl-N-methyl-hydrazinecarboxylic acid tert-butyl ester (1.02 g, 34%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)=[O:4].CN([CH:20]=[O:21])C.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[CH:20]=[O:21])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc(OC)ccc2c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(C=O)c(OC)ccc2c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 62.8 %

Procedure:
To a stirred solution of 6-methoxy-2-naphthoic acid methyl ester (10.3 g, 47.6 mmol) in DMF (36.9 mL, 476 mmol) at 5° C. was added POCl3 (44.4 mL, 476 mmol) dropwise. The reaction mixture was heated to 80° C. After 2 days at this temperature, the reaction was poured into ice/H2O (400 mL). The solution was made basic with addition of solid Na2CO3. The resulting mixture was extracted with EtOAc (2×400 mL). The organic layer was washed with brine (80 mL) and dried (MgSO4). After concentration, the residue was recrystallized from MeOH:H2O to afford the product (7.30 g, 63%) as a solid; 1H NMR (DMSO-d6) δ3.91 (s, 3H), 4.11 (s, 3H), 7.72 (d, J=9.3 Hz, 1H), 8.10 (dd, J=2.0, 9.0 Hz, 1H), 8.53 (d, J=9.2 Hz, 1H), 8.66 (d, J=1.8 Hz, 1H), 9.17 (d, J=9.0 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][OH:23])=[CH:4][C:3]=1[F:24].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10][C@H:9]2[CH2:22][O:23][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:4][C:3]=1[F:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CO)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (4.50 g) in THF (41.7 mL) were added triethylamine (3.49 mL) and methanesulfonyl chloride (1.94 mL) under ice-cooling, and the mixture was stirred for 3 hr. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.01 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:32]=[CH:31][C:25]([O:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl[C:53](=[O:60])[CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:32]=[CH:31][C:25]([O:26][CH2:27][CH2:28][CH2:29][NH:30][C:53](=[O:60])[CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:33]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: NCCCOc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Reactant: COC(=O)CCC(=O)Cl
Product: COC(=O)CCC(=O)NCCCOc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1

Procedure:
41 mg of 3-(4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}phenoxy)propylamine obtained in Example 16 and 12 μL methyl 4-chloro-4-oxobutyrate were reacted in the same manner as in Example 17, to give 24 mg of the title compound as a colorless amorphous.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([C:9]([CH3:23])([CH:21]=[CH2:22])[C:10](N1[C@@H](C(C)C)COC1=O)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH:26]O.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([C:9]([CH3:23])([CH:21]=[CH2:22])[C:10]([OH:11])=[O:26])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: OO
Reactant: C=CC(C)(C(=O)N1C(=O)OC[C@@H]1C(C)C)C(C)O[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(C)(C(=O)O)C(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.4 %

Procedure:
A cooled (0° C.) solution of (S)-3-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoyl}-4-isopropyl-oxazolidin-2-one (1.729 g, 4.677 mmol) in tetrahydrofuran/water (60 mL, 2:1) was subsequently treated with hydrogen peroxide (30% aqueous, 2.4 mL, 23.385 mmol) and lithium hydroxide monohydrate (392.4 mg, 9.355 mmol). After stirring for 2 days at room temperature, hydrogen peroxide (30% aqueous, 2.4 mL, 23.385 mmol) and lithium hydroxide monohydrate (400 mg, 9.535 mmol) were added at 0° C. After stirring at room temperature for 4 days, the reaction was quenched with solid sodium metabisulfite (18 g). After stirring for 1 h at room temperature, the pH was adjusted with hydrochloric acid (1 M) to pH 2 at 0° C. The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 7:3 to afford the title compound (488.0 mg, 40%) as a yellow solid and as a single pair of enantiomers along with unreacted (S)-3-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoyl}-4-isopropyl-oxazolidin-2-one (431.5 mg, 25%, LCMS (m/z) 370.1 [M+H], Tr=3.93 min) as the other single pair of enantiomers as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 0.12 (s, 6H), 0.92 (s, 9H), 1.18 (d, J=6.0 Hz, 3H), 1.34 (s, 3H), 3.99 (q, J=6.2 Hz, 1H), 5.18 (d, J=17.8 Hz, 1H), 5.28 (d, J=10.5 Hz, 1H), 6.22 (dd, J=17.6, 11.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:52])[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@@H:25]3[CH2:29][C@H:28]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[C@@H:27]([OH:35])[C@H:26]3[OH:36])=[C:18]([NH:37][CH2:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:53]1(C)[C:54](S(O)(=O)=O)=CC=C[CH:58]=1.[OH-].[NH4+]>CC(C)=O.COC(OC)(C)C>[CH2:1]([O:8][C:9](=[O:52])[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@H:25]3[C@H:26]4[C@H:27]([O:35][C:53]([CH3:54])([CH3:58])[O:36]4)[C@@H:28]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH2:29]3)=[C:18]([NH:37][CH2:38][CH:39]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of {(R)-1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid benzyl ester (0.63 g, 0.89 mmol) in acetone (10 ml) and 2,2-dimethyloxypropane (5 ml) is treated with toluenesulfonic acid (ca.60 mg) and then stirred at room temperature overnight. The mixture is basified using ammonium hydroxide and the solvent is removed in vacuo. The crude product is partitioned between DCM and water and the organic portion is washed with brine, dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. [MH+ 745].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:22]=[C:23]([CH:34]=O)[NH:24][C:25]=1[C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:34][C:23]4[NH:24][C:25]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])=[C:21]([CH3:20])[CH:22]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C=O)[nH]c1C(=O)N1CCOCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 87 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrol[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 4-methyl-5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (66.7 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 105 mg (87%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.16 (br s, 1H, NH), 11.74 (br s, 1H, NH), 8.78 (br s, 1H), 8.27 (s, 1H), 7.74 (dd, J=2.2 & 6.5 Hz, 1H), 7.71 (s, 1H), 7.52 (m, 1H), 7.38 (t, J=9.1 Hz, 1H), 6.74 (s, 1H), 3.65 (m, 4H, 2×CH2z), 3.54 (m, 4H, 2×CH2), 2.15 (s, 3H, CH3). MS 483 [M++1].
Reaction SMILES: CN(C)[CH:3]=[O:4].C1([C@@H](N)C)C=CC=CC=1.[CH2:15]([O:22][C@@H:23]([CH3:27])[C:24](O)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(Cl)(Cl)=O>CO>[CH2:15]([O:22][C@@H:23]([CH3:27])[C:24]([O:4][CH3:3])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](OCc1ccccc1)C(=O)O
Reactant: CN(C)C=O
Agent: C[C@H](N)c1ccccc1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](C)OCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Dimethyl formamide (0.5 ml) was added to a mixture of (S)-1-phenylethanamine salt of (S)-2-(benzyloxy)propanoic acid compound of formula-13a obtained in step-c) of above examples-9 &. 10 (200 g) and methanol (600 ml) and the reaction mixture was cooled to 0-5° C. Thionyl chloride (58.4 ml) was slowly added to the reaction mixture at 0-5° C. over a period of 1 hour and stirred for 1 hour at 0-10° C. After completion of the reaction, the reaction mixture was quenched with water and extracted with dichloro methane. Both aqueous and dichloro methane layers were separated, dichloro methane layer was washed with 10% sodium chloride and water. Distilled off the solvent completely from dichloro methane layer to get title compound. Yield: 129 g; Chiral purity: 99.5%
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:19][CH:20]=O>CO.O>[Cl:12][C:4]1[N:3]2[CH:19]=[CH:20][N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: O=CCCl
Reactant: COC(=O)c1ccc(Cl)nc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(Cl)n2ccnc12
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a stirred suspension of methyl 2-amino-6-chloro-3-pyridinecarboxylate (2 g, 10.72 mmol) and sodium bicarbonate (900 mg, 10.72 mmol) in a mixture of methanol (40 mL) and water (20 mL) was added chloroacetaldehyde (50% wt. solution in water, 2.9 mL, 22.51 mmol). The resultant mixture was heated at reflux for 5 hours when more chloroacetaldehyde (50% wt. solution in water, 1.45 mL, 11.25 mmol) was added and heating at reflux continued for 16 hours. The majority of the solvent was then removed in vacuo and the residue was partitioned between ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate (150 mL). The organic phase was separated and the aqueous phase was back extracted with ethyl acetate (150 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (100 g) using a 0-100% ethyl acetate-cyclohexane+0-20% methanol gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (1.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:9])[C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)cnc1COc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2COc2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(4-chlorophenoxy)methyl]nicotinic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][O:18]C)=[O:16])=[C:11]([F:20])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[C:28](SCC)(=[S:30])[CH3:29]>CN(C=O)C>[C:28]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][OH:18])=[O:16])=[C:11]([F:20])[CH:10]=2)[CH2:4]1)(=[S:30])[CH3:29]
Reactant: CONC(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Reactant: CCSC(C)=S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=S)NC[C@H]1CN(c2ccc(C(=O)NO)c(F)c2)C(=O)O1

Procedure:
A solution of 5-(S)-aminomethyl-3-[4′-(N-methoxyamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one (0.053 ml, 0.47 mmol), triethylamine (0.12 ml, 0.84 mmol) and ethyl dithioacetate (0.87 ml, 7.6 mmol) in DMF (0.75 ml) was stirred at r.t. for 48 h. Solvent was removed under vacuum, and the crude material purified by silica gel PTLC (eluent: 5% MeOH in ethyl acetate). White crystalline solid (100 mg, 70%). HPLC Rt=4.6 min. MS (m/z): [M+H]+=342.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[C:12]([F:23])=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1.[H-].[Na+].[CH3:27]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:11]2[C:12]([F:23])=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1
Reactant: CI
Reactant: CN1C(=O)COc2cc(F)c(C(=O)Cc3ccc(Br)cc3Cl)cc21
Agent: [H-]
Agent: [Na+]
Product: CC(C(=O)c1cc2c(cc1F)OCC(=O)N2C)c1ccc(Br)cc1Cl

Procedure:
In analogy to Example 1, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-acetyl]-7-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with sodium hydride and methyl iodide to give the title compound as a light brown foam. MS (m/e, ISP neg. ion)=426.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][N:7]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:6]=2[CH:5]=[C:4]([C:23]([OH:25])=O)[CH:3]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:36]=[CH:37][C:27]([NH:26][C:23]([C:4]2[CH:3]=[C:2]([Cl:1])[C:10]3[O:9][CH2:8][N:7]([S:11]([C:14]4[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=4[O:21][CH3:22])(=[O:13])=[O:12])[C:6]=3[CH:5]=2)=[O:25])=[CH:28][CH:29]=1)[CH3:35]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2c(Cl)cc(C(=O)O)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2cc(Cl)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CO3)cc1

Procedure:
Reaction of 7-chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic acid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave 4-{[7-chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester. Light yellow solid, MS (ISP)=551.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[I-].[Na+].[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:17]=1)=[N:13][C:14](=[S:16])[N:15]=2)([O-:7])=[O:6].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35])=[O:26]>CN(C)C=O.O>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[NH:27][C:25](=[O:26])[N:24]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:16][C:14]1[NH:13][C:12]2[CH:17]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=[CH:10][C:11]=2[N:15]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)=NC(=S)N=2
Reactant: CCCCCCCN(CCCCCBr)C(=O)Nc1ccc(F)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCN(CCCCCSc1nc2ccc([N+](=O)[O-])cc2[nH]1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 337 %

Procedure:
Part E. To a suspension of sodium hydride (0.04 g, 60% mineral oil dispersion, 0.001 mol; washed free of mineral oil with hexane) and sodium iodide (0.15 g; 0.0011 mol) in N,N-dimethylformamide (10 mL) under a nitrogen atmosphere, cooled to 0°, a solution of 6-nitrobenzimidazol-2-thione (0.975 g; 0.005 mol) in N,N-dimethylformamide (5 mL) was added slowly. The reaction mixture was stirred for 30 minutes and then a solution of N-(5-bromopentyl)-N'-(2,4-difluorophenyl)-N-heptylurea (0.42 g, 0.001 mol) in N,N-dimethylformamide (5 mL) was added. The reaction mixture was stirred for 1 hour and then allowed to warm to ambient temperature and stirred an additional 24 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and concentrated to give a viscous oil. The product was purified by flash chromatography on silica gel eluting with hexane:ethyl acetate (75:25::v:v) to give the title compound (1.2 g, 0.00337 mol) as a solid, mp 120°-122°. 1H NMR (DMSO-d6) δ13.25 (bs,1H), 8.27 (bs,1H), 8.05 (d,1H,J=7.6 Hz), 7.91 (s,1H), 7.57 (d,1H,J=7.6 Hz), 7.4-7.3 (m,1H), 7.25-7.12 (m,1H), 7.0-6.8 (m,1H), 3.37-3.16 (m,6H), 1.85-1.72 (m,2H), 1.6-1.35 (m,6H), 1.27-1.1 (m,8H), 0.83 (t,3H,J=6.8 Hz).