Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:17]([O:20][CH2:21][CH2:22]O)[C:18]#[CH:19].C(N(CC)CC)C>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O:16][CH2:22][CH2:21][O:20][CH2:17][C:18]#[CH:19])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)COc1ccc(Cl)c2cccnc12
Reactant: C#CCOCCO
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: C#CCOCCOC(=O)COc1ccc(Cl)c2cccnc12
Yield: 16.4 %

Procedure:
5.0 g (0.021 mol) of 5-chloroquinolin-8-oxyacetic acid are heated at 70° C. in 70 ml of thionyl chloride for one hour. The excess thionyl chloride is then distilled off in vacuo and the residue is suspended in 150 ml of carbon tetrachloride. 2.10 g (0.021 mol) of 2-propargyloxyethanol are added dropwise to this suspension, 2.30 g (0.023 mol) of triethylamine are then added dropwise and the mixture is heated under reflux for 12 hours. The suspension is then washed with in each case 70 ml of 2N HCl and 5 percent strength sodium hydroxide solution, the organic phase is dried over magnesium sulfate and the solvent is stripped off in vacuo. The residue is recrystallized from n-heptane. 1.1 g (16.3% of theory) of 2-(propargyloxy)ethyl 5-chloroquinolin-8-oxyacetate of melting point 53° C. are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1([CH2:30][C@@H:31]2[NH:36][C@@H:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:34][CH2:33][CH2:32]2)[CH2:29][CH2:28][CH2:27][CH2:26]1.[C:41](=[O:44])([O-:43])[O-].[Na+].[Na+]>ClCCl>[C:10]([OH:12])(=[O:11])/[CH:9]=[CH:4]\[C:41]([OH:43])=[O:44].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:36]2[C@@H:31]([CH2:30][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)[CH2:32][CH2:33][CH2:34][C@@H:35]2[C:37]([O:39][CH3:40])=[O:38])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)[C@H]1CCC[C@H](CN2CCCC2)N1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1CCC[C@H](CN2CCCC2)N1C(=O)Cc1ccc(Cl)c(Cl)c1
Product: O=C(O)/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3,4-dichlorophenylacetic acid (0.325 g) and carbonyldiimidazole (0.26 g) in dry dichloromethane (10 ml) was stirred at ambient temperature for 1 h. A solution of the product of stage (ii) (0.30 g) in dry dichloromethane (10 ml) was added and the mixture was stirred at ambient temperature for 2 days. The reaction mixture was poured into 2M sodium carbonate solution (50 ml) and extracted with dichloromethane (250 ml). The organic extract was washed with 2M sodium carbonate solution (30 ml), dried and evaporated in vacuo. The residue (0.58 g) was purified by flash chromatography eluting with dichloromethane, methanol and ammonia (200:8:1) as eluant to give the free base of the title compound as a gum (0.76 g). The gum was dissolved in ethyl acetate (50 ml) and treated with a solution of maleic acid (60 mg), in ethyl acetate to give a solid which was crystallised from ethyl acetate to give the title compound as a white solid (0.2 g) m.p. 160°-1°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28].O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH:17][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])[C:11]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-amino-6-chloro-2-fluoro-benzoic acid benzyl ester (48, 1.20 g, 4.3 mmol) in methylene chloride (28 mL) was added pyridine (0.52 mL, 6.4 mmol) and propane-1-sulfonyl chloride (0.685 g, 4.8 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated with silica gel column chromatography to give a colorless oil (49, 960 mg, 58.0%). MS (ESI) [M−H+]−=384.1.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[Mn]([O-])(=O)(=O)=O.FC1C=C(C)C=CC=1[N+:26]([O-])=O.[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]N>C1(C)C=CC=CC=1>[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][C:2]1[C:3]([NH2:26])=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=[Mn](=O)(=O)[O-]
Solvent: Cc1ccccc1
Product: Nc1c(C(=O)O)ccc([N+](=O)[O-])c1Cc1ccccc1Cl

Procedure:
The procedure of Example 1(ii) was followed. From 6.25 g (33.8 mmol) of 3-fluoro-4-nitrobenzoic acid (mp 168°-169° C.; prepared by the method of F. C. Schmelkes and M. Rubin, J.A.C.S., 66, 1631 (1944), by permanganate oxidation of 3-fluoro-4-nitrotoluene) 11.96 g (84.5 mmol) of 2-chlorobenzylamine and 100 mL of toluene refluxed for 24 hours was obtained, after workup and crystallization from methanol, 8.4 g (82%) of 3-[(2-chlorophenyl)methyl]-amino-4-nitrobenzoic acid; mp 221°-223° C.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.[CH3:50][C:51]1[N:52]=[CH:53][C:54]([CH2:57][NH2:58])=[N:55][CH:56]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:58][CH2:57][C:54]4[CH:53]=[N:52][C:51]([CH3:50])=[CH:56][N:55]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:48][CH:49]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1cnc(CN)cn1
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(-n3cnn(Cc4ccc(F)cc4)c3=O)nc2C)cn1
Yield: 64 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with (5-methylpyrazin-2-yl)methanamine, the title compound was obtained as a white solid in 64% yield: mp 188-189° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.53 (s, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 7.43-7.33 (m, 2H), 7.10-6.99 (m, 2H), 6.97 (t, J=4.8 Hz, 1H), 4.98 (s, 2H), 4.72 (d, J=4.8 Hz, 2H), 2.66 (s, 3H), 2.58 (s, 3H); MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(OCC)(=O)C>C(Cl)Cl>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Brc1cccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cccnc1)O2
Reaction time: 18 h

Procedure:
Rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 4,6 g, was reacted as described in Example 4 with 4.74 g of 3-bromopyridine. The reaction time was extended to 18 hours. The product was isolated by chromatography over 150 g of silica gel using 10% (v/v) of ethyl acetate in methylene chloride for elution. Crystallization of the combined clean fractions from ethyl acetate/hexane gave off-white crystals with m.p. 172°-175° C. The analytical sample was recrystallized from tetrahydrofuran/hexane and had m.p. 175°-178° C.
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[S:3][C:2]=1[NH:10][C:11]([C:13]1[C:18]2[NH:19][C:20]([NH:22][C:23]([C:25]3[N:26]=[CH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])=[N:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:12].N1C=CC=CC=1.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl.C(OCC)(=O)C>[C:41]([N:6]1[CH2:7][CH2:8][C:9]2[N:1]=[C:2]([NH:10][C:11]([C:13]3[C:18]4[N:19]=[C:20]([NH:22][C:23]([C:25]5[N:26]=[CH:27][C:28]6[C:33]([CH:34]=5)=[CH:32][CH:31]=[CH:30][CH:29]=6)=[O:24])[NH:21][C:17]=4[CH:16]=[CH:15][CH:14]=3)=[O:12])[S:3][C:4]=2[CH2:5]1)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Nc1nc2cccc(C(=O)Nc3nc4c(s3)CNCC4)c2[nH]1)c1cc2ccccc2cn1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2c(C(=O)Nc3nc4c(s3)CN(C(=O)c3ccccc3)CC4)cccc2[nH]1)c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of 30 mg (0.063 mmol) of isoquinoline-3-carboxylic acid [7-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide (Example 198) in DCM (2 mL) was added pyridine (0.5 mL) and benzoyl chloride (0.05 mL). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20 mL), the organic phase was washed with sat. aq. Na2CO3 solution, dried over Na2SO4, and concentrated under reduced pressure. The crude product was dissolved in DCM (0.5 mL), hexane was added (4 mL), and the resulting precipitate was filtered and dried to provide 17 mg (47%) of isoquinoline-3-carboxylic acid [4-(5-benzoyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 574 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[NH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:19][C:20]3[CH:21]=[C:22]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=3)=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(S(N)(=O)=O)c2)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 3-amino-benzenesulfonamide as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.91 (s, 1H), 8.17 (d, 1H), 8.11 (s, 1H), 7.70 (d, 1H), 7.54 (t, 1H), 7.48 (d, 1H), 7.39 (br, 2H), 7.05-6.98 (2H), 6.37 (s, 1H), 4.00 (t, 2H), 3.85 (s, 3H) and 2.98 (t, 2H); MS (ESI) (M+H)+ 399.
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:38]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([Cl:53])[CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:3]([NH:5][C:6]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:7]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][C:18](=[O:25])[NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11]1)=[O:4].C(N(CC)CC)C.Cl[C:62]([O:64][CH3:65])=[O:63]>ClCCl>[Cl:53][C:47]1[CH:46]=[C:45]([C@@H:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@H:2]([NH:1][C:62]([O:64][CH3:65])=[O:63])[C:3]([NH:5][C:6]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:7]=2[CH2:8][CH2:9][C@H:10]2[O:15][CH2:14][C@@H:13]([CH2:16][O:17][C:18](=[O:25])[NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:12]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:11]2)=[O:4])[CH:50]=[CH:49][C:48]=1[O:51][CH3:52]
Reactant: COc1ccc([C@@H](c2ccccc2)[C@H](N)C(=O)Nc2cccc(F)c2CC[C@@H]2CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO2)cc1Cl
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)[C@H](c1ccccc1)c1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the product from step 3 (80 mg, 0.1 mmol) in dichloromethane (2 mL) was added triethylamine (0.02 mL, 0.16 mmol) and methyl chloroformate (0.01 mL, 0.12 mmol). The mixture was stirred at ambient temperature for 6 h, then diluted with dichloromethane (10 mL) and washed with aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-100% EtOc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=825.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([S:13](Cl)(=[O:15])=[O:14])[CH:8]=2)[N:3]=1.[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21].C(N(CC)C(C)C)(C)C>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([S:13]([O:21][CH2:20][C:19]([F:23])([F:22])[F:18])(=[O:15])=[O:14])[CH:8]=2)[N:3]=1
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)c(Cl)nc2cc1Cl
Reactant: OCC(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=S(=O)(OCC(F)(F)F)c1cc2nc(Cl)c(Cl)nc2cc1Cl

Procedure:
To a stirred mixture of 470 g (1.42 mole) of 2,3,7-trichloro-6-quinoxalinesulfonyl chloride and 153 g (1.53 mole) of 2,2,2-trifluoroethanol in 3 liters of anhydrous tetrahydrofuran are added 183 g (1.42 mole) of N,N-diisopropylethylamine. The resulting mixture is heated under reflux with exclusion of moisture for 24 hours. The solvent is removed under reduced pressure to obtain a residue which is dispersed in one liter of diethyl ether. The resulting mixture is washed twice with 500 ml of water then dried over magnesium sulfate, and filtered. The filtrate obtained therefrom is evaporated to give crude product which is recrystallized first from cyclohexane and then from 2-propanol to give 112 g (20%) of nearly colorless crystals having a melting point of 142°-144°.
Reaction SMILES: [OH:1][C:2]([CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])([CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[C:3](O)=[O:4].O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:46]([O:53][NH2:54])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:46]([O:53][NH:54][C:3](=[O:4])[C:2]([OH:1])([CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)CC(O)(CS(=O)(=O)c2ccc(-c3ccccc3)cc2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)CC(O)(CS(=O)(=O)c2ccc(-c3ccccc3)cc2)C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-phenylbenzenesulfonyl)propionic acid (0.6 g, 1.2 mmol) in 50 mL of methylene chloride is added 1-hydroxybenzotriazole monohydrate (0.185 g, 1.36 mmol), O-benzylhydroxylamine hydrochloride (0.218 g, 1.36 nmol), diisopropylethylamine (0.177 g, 1.36 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.262 g, 1.36 mmol), in that order. The clear, colorless solution is stirred overnight at ambient temperature. Methylene chloride is removed under reduced pressure and the residue is partitioned between ethyl acetate and water. The organic phase is washed with several portions of 1N HCl and then with aqueous potassium bicarbonate. It is dried over magnesium sulfate, filtered, concentrated, and chromatographed on silica gel. Elution with 1:1 ethyl acetate:hexanes affords the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[CH3:11][O:12][C:13]1[C:18](B(O)O)=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.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:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:18]1[C:13]([O:12][CH3:11])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ncccc1B(O)O
Reactant: O=Cc1ccc(F)c(Br)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: C1COCCO1
Product: COc1ncccc1-c1cc(C=O)ccc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.9 mmol), (2-methoxypyridin-3-yl)boronic acid (1.2 g, 7 mmol) and sodium hydrogen carbonate (1.5 g, 15 mmol) was stirred in dioxane (20 mL) and water (8 mL). The mixture was degassed for 10 minutes, then tetrakis(triphenylphosphine)palladium (0) (0.130 g, 0.1 mol) was added. The reaction mixture was stirred at 100° C. for 1 hour then cooled and concentrated in vacuo. The resulting residue was partitioned between EtOAc (60 mL) and water (15 mL), dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography eluting with 20% EtOAc in heptane to afford the title compound as a white solid (0.85 g).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Br)[C:3](Cl)=[O:4].Cl.[NH2:10][CH2:11][C:12]#[N:13].C(N(CC)CC)C.[H-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][CH:2]1[CH2:6][CH2:7][N:13]([CH2:12][C:11]#[N:10])[C:3]1=[O:4]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: N#CCN
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#CCN1CCC(Br)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.7 %

Procedure:
To a solution of 2,4-dibromobutanoyl chloride (3.6 g, 14 mmol) in DCM (100 mL) and 2-aminoacetonitrile hydrochloride (1.3 g, 14 mmol) was added triethylamine (5.7 mL, 41 mmol) at 0° C. The mixture was stirred at ambient temperature for 24 h. To the resulting material was added methylene chloride and it was washed with water and then brine. The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The resulting residue was taken up in toluene (130 mL) and at 0° C. was added sodium hydride (545 mg, 13.6 mmol, 60% in mineral oil) portion-wise over 20 minutes. The reaction was stirred at ambient temperature for 60 h. The mixture was diluted with ethyl acetate and then poured into ice water. The organic layer was separated, washed with brine, dried over sodium sulfate, and purified via flash column chromatography (ethyl acetate:hexane, 0:100 to 100:0) to provide a brown oil (730 mg, 26% yield). 1H NMR (400 MHz, CDCl3) δ 4.37-4.50 (m, 2H), 4.10-4.28 (m, 1H), 3.70 (dq, J=7.6, 2.0 Hz, 1H), 3.51-3.59 (m, 1H), 2.65-2.79 (m, J=7.0 Hz, 1H), 2.33-2.50 (m, 1H).
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.[C:23]1([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[ClH:35]>O1CCOCC1.O>[Cl-:35].[OH:1][CH:2]([CH2:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:22][N+:32]1[CH:33]=[CH:34][C:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:30][CH:31]=1
Reactant: O=C(c1ccc(OCC2CO2)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(-c2ccncc2)cc1
Reactant: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(OCC(O)C[n+]2ccc(-c3ccccc3)cc2)cc1)c1ccc([N+](=O)[O-])cc1
Product: [Cl-]
Temperature: 70 °C
Yield: 50 %

Procedure:
A solution of 2.06 g (6.88 mmol) of 4-(2,3-epoxypropoxy)-4'-nitrobenzophenone in 50 ml of dioxan and 25 ml of water was treated with 1.06 g (6.88 mmol) of 4-phenylpyridine and stirred at 70° C. while adding 1N HCl at a pH less than 8. After stirring at 70° C. for 18 hours the mixture was cooled to 20° C., treated with 300 ml of water and extracted three times with 200 ml of chloroform. The organic phase was dried and concentrated. The residue was recrystallized from acetone. There was obtained 1-[2-hydroxy-3-[p-(p-nitrobenzoyl)phenoxy]propyl]-4-phenylpyridinium chloride in 50% yield, m.p. 240° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][C@H:16]([OH:18])[CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([N:19]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]2.CI.[H-].[Na+].[C:40](OCC)(=O)C>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][C@H:16]([O:18][CH3:40])[CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([N:19]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[N:9]2
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)C2=N[C@@]3(c4ccccc4F)C[C@H](O)CC[C@H]3CS2)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)C2=N[C@@]3(c4ccccc4F)C[C@H](OC)CC[C@H]3CS2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl(±)-[(4aR*,7R*,8aS*)-8a-(2-fluorophenyl)-7-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]-(4-methoxybenzyl)carbamate obtained in Preparation Example 58-(9) (541 mg) was dissolved in DMF (5 mL). Methyl iodide (113 μL, specific gravity: 2.28 g/cm3) was added and then the mixture was cooled in an ice bath under a nitrogen atmosphere. Sodium hydride (60%, 55 mg) was added, followed by stirring for one hour and 45 minutes. Thereafter, methyl iodide (113 μL, specific gravity: 2.28 g/cm3) and sodium hydride (60%, 55 mg) were added, and the mixture was warmed to room temperature and stirred for one hour and 45 minutes. Thereafter, methyl iodide (113 μL, specific gravity: 2.28 g/cm3) was further added, followed by stirring for 13 hours. Ethyl acetate and water were added to the reaction solution, followed by further stirring. Then, the aqueous layer was separated. The organic layer was sequentially washed with a saturated ammonium chloride solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (409 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.[Na+]>CO>[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH:6][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of D-alanine methyl ester hydrochloride (3.0 g, 21.5 mmol) in methanol (10 mL) is added benzaldehyde (2.3 mL, 22.6 mmol). The reaction mixture is stirred at room temperature for 3 hours. The solvent is then evaporated. To the resultant residue is added acetic acid (15 mL) and methanol (1 mL) followed by portionwise addition of sodium cyanoborohydride (1.35 g, 21.5 mmol) at room temperature. The mixture is stirred overnight, and then the solvent is evaporated. The remaining residue is diluted with water (75 mL) and basified with Na2CO3. The mixture is extracted with ethyl acetate (3×75 mL). The combined organic extracts are washed with brine (50 mL), dried (Na2SO4), and the solvent is evaporated to give N-benzyl-D-alanine methyl ester.