Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[C:10](=[O:29])[C:11]4[C:16]([C:17]([CH3:19])([CH3:18])[C:8]=3[O:7][C:6]=2[CH:30]=1)=[CH:15][C:14]([O:20][CH2:21][C@H:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)=[CH:13][CH:12]=4.[Na+].[I-:32].CN[C@@H]1CCCC[C@H]1NC>C(OCC)(=O)C.[Cu]I>[CH3:27][C:24]1([CH3:28])[O:23][C@@H:22]([CH2:21][O:20][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:29])[C:9]2[C:5]4[CH:4]=[CH:3][C:2]([I:32])=[CH:30][C:6]=4[O:7][C:8]=2[C:17]3([CH3:18])[CH3:19])[CH2:26][O:25]1
Reactant: [I-]
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2oc4cc(Br)ccc4c2C3=O)O1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2oc4cc(I)ccc4c2C3=O)O1
Reaction time: 48 h
Yield: 96.5 %

Procedure:
To 3-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one (15 mg, 0.032 mmol), CuI (6.2 mg, 0.032 mmol), NaI (9.6 mg, 0.064 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.01 ml) were added and the mixture was stirred for 48 hrs under nitrogen atmosphere. The reaction solution was diluted with ethyl acetate. The organic layer was washed with saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane) to obtain 8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-iodo-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one (16 mg, 97%), which was then deprotected according to the method of A-14-2 to give the title compound.
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1Cl)=[S:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O>CS(C)=O>[C:1]([C:5]1[S:6][C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]([Cl:14])=[CH:13][C:8]=2[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=S)Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1

Procedure:
A mixture of 94 g of N-tert-butylthiocarbonyl-2,5-dichloro-4-nitroaniline, described in Example 1, in 360 ml of dimethylsulphoxide and 160 ml of triethylamine is heated at 140° for 10 hours under nitrogen. The reaction mixture is cooled and poured into water. The solid obtained is filtered and washed with water and air-dried to yield 2-tert-butyl-5-chloro-6-nitrobenzothiazole, melting at 65°-69°.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22](B(O)O)=[C:21]([O:29][CH3:30])[CH:20]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[CH2:11]([C:9]1[N:10]=[C:3]2[C:2]([C:20]3[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][C:21]=3[O:29][CH3:30])=[N:7][CH:6]=[CH:5][N:4]2[C:8]=1[C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH3:12]
Reactant: COc1cc(C)cc(C)c1B(O)O
Reactant: CCCC(=O)c1c(CC)nc2c(Cl)nccn12
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CCCC(=O)c1c(CC)nc2c(-c3c(C)cc(C)cc3OC)nccn12
Yield: 77.5 %

Procedure:
1-(8-Chloro-2-ethylimidazo[1,2-a]pyrazin-3-yl)-1-butanone (226 mg, 0.90 mmol) and 4,6-dimethyl-2-methoxybenzeneboronic acid (198 mg, 1.1 mmol) were dissolved in a mixed solvent of 1,2-dimethoxyethane (4.5 mL) and water (0.75 mL). Barium hydroxide octahydrate (347 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium complex (79 mg, 0.068 mmol) were added thereto, and the mixture was heated under reflux for 4 hours under nitrogen atmosphere. After being allowed to cool, the reaction mixture was filtered and washed with ethyl acetate. Then, the filtrates were combined and washed with a 1N aqueous sodium hydroxide solution. It was extracted with ethyl acetate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give 1-[2-ethyl-8-(2-methoxy-4,6-dimethylphenyl)imidazo[1,2-a]pyrazin-3-yl]-1-butanone (245 mg) as a white amorphous.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[NH2:42][C:43]1[CH:44]=[N:45][C:46]([NH:49][C:50]2[CH:51]=[C:52]([CH:58]=[CH:59][CH:60]=2)[C:53]([O:55][CH2:56][CH3:57])=[O:54])=[N:47][CH:48]=1>C(Cl)Cl.CN(C=O)C>[CH2:56]([O:55][C:53](=[O:54])[C:52]1[CH:58]=[CH:59][CH:60]=[C:50]([NH:49][C:46]2[N:45]=[CH:44][C:43]([NH:42][C:14](=[O:16])[C:13]3[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:1])([F:23])[F:22])[CH:4]=4)[CH:10]=[CH:11][C:12]=3[Cl:18])=[CH:48][N:47]=2)[CH:51]=1)[CH3:57]
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cccc(Nc2ncc(N)cn2)c1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cccc(Nc2ncc(NC(=O)c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3Cl)cn2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 42.8 %

Procedure:
To a solution of intermediate 1 (Example 2) (280 mg, 0.8 mmol) in anhydrous CH2Cl2 (15 mL), 2-chloro-4,6-dimethoxy-1,3,5-triazine (180 mg, 1 mmol) and 4-methylmorpholine (250 mg, 2.5 mmol) were added. After the reaction mixture was stirred at room temperature for 75 minutes, intermediate 6 (Example 11) (110 mg, 0.4 mmol) in anhydrous DMF (2.5 mL) was added into the solution. The solution was stirred under argon for overnight. The residue was dissolved in CH2Cl2 (20 mL) and washed with aqueous saturated NaHCO3 solution (20 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic phase was dried (Na2SO4) and the solvent was removed. The crude product was purified by silica gel column with CHCl3 to 10% CH3OH/CHCl3 as eluents to give the final product as a pale yellow solid (100 mg, 21%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12]Cl>>[Cl:12][C:2]1[CH:3]=[C:4]([S:7]([OH:10])(=[O:8])=[O:9])[CH:5]=[CH:6][C:1]=1[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: ClCl
Product: Cc1ccc(S(=O)(=O)O)cc1Cl

Procedure:
In a typical process for preparing an aqueous solution of an alkali metal salt of 2-chloro-5-amino-4-toluene sulfonic acid, toluene is first reacted with sulfuric acid to produce para-toluene sulfonic acid as the principal product. The sulfonic acid is then reacted with chlorine to produce 2-chloro-para-toluene sulfonic acid as a principal product which is reacted with a mixture of 50 percent nitric acid and 50 percent sulfuric acid to produce 2-chloro-5-nitro-para-toluene sulfonic acid. The nitrated product is then neutralized in an aqueous lime slurry which is subsequently filtered. The aqueous nitrated product is then iron reduced to form an amine and the reaction mixture is neutralized with sodium hydroxide to a pH of about 9.5-10.5 and the resulting solution is subsequently filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:28]([C:23]2([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:29])=[N:7][CH:6]=1
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Reactant: COc1ccc(C2(C(=O)O)CCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C(=O)Nc3ncc(Cc4ccccc4Cl)s3)CCCC2)cc1
Reaction time: 16 h

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (45 mg, 0.20 mmol) and 1-(4-Methoxy-phenyl)-cyclopentanecarboxylic acid (44 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL) containing triethylamine (84.1 L, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography. ESI-MS m/z calc. 426.1. found; 427.2 (M+1)+ Retention time 3.97 minutes. 1H NMR (400 MHz, MeOD) d 1.62-1.84 (m, 4H), 1.95-2.17 (m, 2H), 2.41-2.62 (m, 2H), 3.78 (s, 3H), 4.22 (s, 2H), 6.90 (d, J=8.8 Hz, 2H), 7.03-7.49 (m, 7H).
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:7]([Cl:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].ClC1C(=O)N(CC2CC2)C=CC=1O>>[Cl:19][C:7]1[C:6](=[O:20])[N:5]([CH2:1][CH:2]2[CH2:4][CH2:3]2)[CH:10]=[CH:9][C:8]=1[O:11][S:12]([C:15]([F:16])([F:17])[F:18])(=[O:14])=[O:13]
Reactant: CCCCn1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1=O
Agent: O=c1c(Cl)c(O)ccn1CC1CC1
Product: O=c1c(Cl)c(OS(=O)(=O)C(F)(F)F)ccn1CC1CC1

Procedure:
Intermediate D5 was prepared following the same procedure used for the synthesis of intermediate D4, but using intermediate 3-chloro-1-cyclopropylmethyl-4-hydroxy-1H-pyridin-2-one as starting material.
Reaction SMILES: [C:1]([C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[C:7]([O:36][CH2:37][CH3:38])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45]>>[ClH:25].[C:1]([C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]2[N:15]([C:33]([N:42]3[CH2:43][CH2:44][NH:39][C:40](=[O:45])[CH2:41]3)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:18]=2)=[C:7]([O:36][CH2:37][CH3:38])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)c(OCC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)c(OCC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1
Product: Cl

Procedure:
4-[(4S,5R)-2-(4-tert-Butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12f) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 637.4 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[CH3:17])=[N:9][CH:10]=1)=[O:4].[CH2:18]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](Cl)=[N:27][N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:26][N:27]=3)[CH2:13][C@H:12]2[CH3:17])=[N:9][CH:10]=1)=[O:4]
Reactant: Clc1nnc(Cc2ccccc2)c2ccccc12
Reactant: COC(=O)c1cnc(N2CCNC[C@H]2C)cn1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)C[C@H]2C)cn1
Yield: 18.2 %

Procedure:
(R)-2-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (150 mg, 0.63 mmol), 1-benzyl-4-chloro-phthalazine (161.75 mg, 0.635 mmol) are added into a microwave vial followed by NMP (3.3 mL) and triethylamine (0.265 mL, 1.91 mmol). The vial is sealed and irradiated in the microwave at 180° C. for 30 min. The crude material is directly purified via flash chromatography on silica gel (40-100% EtOAc in heptane). Desired product is then washed with water and lyophilized to afford the title compound (52 mg, 18% yield).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][CH3:22]
Reactant: COc1ccccc1S
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1ccccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.5 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.6 mmol of 2-methoxybenzenethiol, and 1.6 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 170°-172° C. dec.). 1H NMR (DMSO-d6) δ 3.76 (bs, 5 H), 5.44 (dd, 1 H), 6.26 (t, 1 H), 6.85 (m, 1 H), 6.91 (t, 1 H), 7.34-7.50 (m, 10 H).
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC([CH2:14][N:15](C)[C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[C:21]([C:30]4[CH:35]=[C:34]([NH2:36])[C:33]([F:37])=[CH:32][C:31]=4[Cl:38])[C:22](=[O:29])[N:23]3[CH:26]([CH3:28])[CH3:27])=[CH:18][N:17]=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O>[NH2:36][C:34]1[C:33]([F:37])=[CH:32][C:31]([Cl:38])=[C:30]([C:21]2[C:22](=[O:29])[N:23]([CH:26]([CH3:27])[CH3:28])[C:24]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16]([NH:15][CH3:14])[CH:25]=3)[CH:35]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2Cl)c(=O)n3C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1Cl)c(=O)n2C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.9 %

Procedure:
TFA (5.55 g, 48.7 mmol) was added to 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one (0.78 g, 1.62 mmol) and the reaction was stirred for 90 min at RT. Water (50 mL) was added and the reaction mixture was carefully treated with solid Na2CO3 until it was faintly basic. The solution was extracted with EtOAc (2×), and the combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography (MeOH/DCM) to afford 3-(5-amino-2-chloro-4-fluorophenyl)-1-isopropyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.42 g, 72% yield) as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.60 (s, 1H), 7.17 (d, J=11.2 Hz, 1H), 6.95 (q, J=4.8 Hz, 1H), 6.71 (d, J=9.6 Hz, 1H), 6.41 (s, 1H), 5.30 (s, 2H), 5.08 (br s, 1H), 2.84 (d, J=4.8 Hz, 3H), 1.49 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 361.0 [M+H]+.
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].O[N:11]=[C:12](Cl)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>CO>[CH3:6][C:4]1[O:5][N:11]=[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:3]=1[C:2]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(C)=O
Reactant: ON=C(Cl)c1ccncc1
Agent: [Na]
Solvent: CO
Product: COC(=O)c1c(-c2ccncc2)noc1C
Temperature: 0 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
Sodium (0.400 g, 0.0166 mol) was added to anhydrous methanol under nitrogen. After complete dissolution, the reaction vessel was cooled to 0° C. and methyl acetoacetate (1.8 ml, 0.166 mol) added. A solution of N-hydroxy-4-pyridine carboximidoyl chloride (2 g, 0.0128 mol; prepared according to Kocevar, M., Synth. Commun., 1988, 18(12), 1427) was added dropwise over 20 minutes. The reaction was stirred at 25° C. for 16 h, and quenched with acetic acid (1 ml). The methanol was removed in vacuo and the product partitioned between EtOAc and water. The organic layer was collected, dried over MgSO4, and evaporated. The residue was chromatographed on silica eluting with 20% EtOAc/hexane→EtOAc to obtain the title compound as a beige solid (1.2 g). 1H NMR (400 MHz, CDCl3) δ 8.73–8.71 (m, 2H), 7.57–7.56 (m, 2H), 3.80 (s, 3H), 2.77(s, 3H).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([N:8]1[C:16](OC)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[C:9]1[CH:19]=[CH:20][C:21]1[S:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[N+:25]=1[CH2:26][CH3:27])[CH3:7].[CH2:32]([N:34]1[C:38](=[O:39])[CH2:37][S:36][C:35]1=[S:40])[CH3:33].C(N(CC)CC)C>CO>[CH2:32]([N:34]1[C:38](=[O:39])[C:37](=[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[CH:19][CH:20]=[C:21]3[N:25]([CH2:26][CH3:27])[C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[S:22]3)[N:8]2[CH2:6][CH3:7])[S:36][C:35]1=[S:40])[CH3:33]
Reactant: CCn1c(C=Cc2sc3ccccc3[n+]2CC)c2ccccc2c1OC
Reactant: CCN1C(=O)CSC1=S
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN1C(=O)C(=c2c3ccccc3c(=CC=C3Sc4ccccc4N3CC)n2CC)SC1=S

Procedure:
2-[2-(2-Ethyl-3-methoxyisoindol-1-yl)vinyl]-3-ethylbenzothiazolium perchlorate (0.5 g) and 3-ethylrhodanine (0.3 g) were dissolved in a 1:1 acetronitrile/methanol solution. Triethylamine was added and the reaction mixture heated to reflux for 10 minutes. The dyes which separated out was dissolved in chloroform and passed through a column of silica gel. After recrystallization from a mixture of chloroform and methanol the dye melted at 252°-253° C. pyridine/methanol λ max 661 nm.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH:16]([CH3:20])[C:17]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: CC(Cl)C(=O)Cl
Reactant: OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 90.4 %

Procedure:
Benzyl alcohol (242 mL, 253 g, 2.34 mol) and pyridine (204 mL, 204 g, 2.57 mol) were dissolved in methylene chloride (2.5 L) and cooled to 0° C. 2-Chloropropanoyl chloride (250 mL, 327 g, 2.57 mol) was added dropwise keeping the temperature between 00° C. and 5° C. After addition the mixture was allowed to warm to RT overnight. The mixture was washed with 20% aqueous citric acid (2.5 L), saturated aqueous NaHCO3 (2.5 L), brine (2.5 L), dried (MgSO4), filtered and concentrated in vacuo. The resulting brown liquid (450 g) was dissolved in a small amount of methylene chloride and filtered through a short path of silica gel. After concentration, the crude was purified via bulb-to-bulb distillation (2*10−2 mbar, 90-95° C.) affording the title compound as a pale yellow liquid (420 g, 90%). 1H-NMR: (CDCl3, 300 MHz): δ ppm 1.75 (d, 3H, CH3), 4.45 (q, 1H, CHCl), 5.25 (s, 2H, CH2Ar), 7.40 (m, 5H, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1)[C:5]([NH2:7])=[O:6].Br[CH2:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].CN(C)[C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][C:52]=2N(C)C)C=CC=1.[I-].[Na+]>C(#N)C.CN(C=O)C>[C:36]1([CH2:35][O:34][C:32](=[O:33])[CH2:31][N:1]([C:2]2[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]=[C:4]([C:5](=[O:6])[NH2:7])[CH:3]=2)[CH2:31][C:32](=[O:33])[O:34][CH2:44][C:53]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(C(N)=O)c1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(N)=O)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Yield: 43.2 %

Procedure:
A mixture of 3.0 g (7.4 mmol) of 3-amino-5-(octadecyloxy)benzamide, 3.6 ml (22 mmol) of benzyl bromoacetate, 4.0 g (18.5 mmol) of 1,8-bis(dimethylamino)naphthalene and 0.3 g (2.1 mmol) of sodium iodide in 60 ml of acetonitrile and 20 ml of DMF was stirred and heated at reflux under argon for 48 hours. The solvents were removed at reduced pressure and the residue was dissolved in ethyl acetate. The extract was washed with 0.05N HCl, with NaHCO3 solution, dried and concentrated at reduced pressure to a solid. Purification by HPLC using 20% ethyl acetate-toluene gave 2.24 g (43% yield, mp 112°-114°) of N-[(3-carbamoyl)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[CH:5]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:6][CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.CCO>CO>[Cl:1][C:2]1[C:3]2[C:4]3[C@@H:5]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:6][CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.[Cl:1][C:2]1[C:3]2[C:4]3[C@H:5]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:6][CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCOC(=O)CC1CCCc2sc3ncnc(Cl)c3c21
Solvent: CCO
Solvent: CO
Product: CCOC(=O)C[C@@H]1CCCc2sc3ncnc(Cl)c3c21
Product: CCOC(=O)C[C@H]1CCCc2sc3ncnc(Cl)c3c21
Yield: 37 %
Yield: 37 %

Procedure:
The enantiomers of racemic ethyl 2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-13-yl]acetate (1.4 g, 4.50 mmol, 1.00 equiv) in MeOH (10 mL) were separated by preparative chiral HPLC under the following conditions: column: Chiralpak IC 0.46*25 cm, 5 um; mobile phase, Hex (0.1% TEA): EtOH=70:30; UV detection at 254 nm. The product-containing fractions were collected and evaporated to remove solvents under reduced pressure to give 520 mg (37%) of ethyl 2-[(13R)-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-13-yl]acetate 170.1 (first peak) as a white solid and 520 mg (37%) of ethyl 2-[(13S)-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-13-yl]acetate 170.2 (second peak) as a white solid, respectively.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O>>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CO
Product: COC(=O)Cc1cccc(O)c1

Procedure:
(3-Hydroxy-phenyl)-acetic acid (5.0 g, 32.86 mmol) is stirred in methanol (100 mL) and concentrated (98%) sulfuric acid (3.0 mL) is added. The mixture is heated to reflux 18 hr. The reaction is cooled and concentrated. The residue is diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated to yield the title compound as an orange oil, 5.46 g, 100%. MS M++1 167. The structure is confirmed by 1H NMR spectroscopy.