Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C:14]1[C:15]([OH:28])=[C:16]([S:21]([N:24]([O:26][CH3:27])[CH3:25])(=[O:23])=[O:22])[C:17]([Cl:20])=[CH:18][CH:19]=1>C(O)C>[Cl:20][C:17]1[C:16]([S:21]([N:24]([O:26][CH3:27])[CH3:25])(=[O:22])=[O:23])=[C:15]([OH:28])[C:14]([NH:13][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])=[CH:19][CH:18]=1
Reactant: CON(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.83 g, 1.2 equiv) in ethanol (30 ml) was treated with TEA (1.54 g, 1.1 equiv) and the reaction mixture was heated to 45° C. 3-Amino-6-chloro-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (3.7 g, 1 equiv) was added portion wise over 30 minutes, with vigorous stirring, maintaining the reaction mixture at 45′C. The reaction mixture was stirred at 45° C. for 1 hour and then allowed to cool to RT. The solvent was removed in vacuo and the residue was partitioned between EtOAc (600 ml) and water (2×200 ml). The aqueous portion was separated and extracted with EtOAc (3×200 ml) and the combined organic extracts were washed with water (3×200 ml) and allowed to stand over night. The resulting solid was collected by filtration and dried in vacuo to afford the title compound. The mother liquor was evaporated to give a yellow/brown oily solid which was triturated with ethanol (100 ml). The solid was collected by filtration, washed with EtOH and dried in vacuo to afford the title compound; [M+H]+ 390.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].[CH3:24][C:25]1[C:26]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:8]=1[C:9]([N:38]1[CH2:39][CH2:40][N:35]([C:26]2[C:25]([CH3:24])=[CH:30][C:29]([C:31]([F:34])([F:32])[F:33])=[CH:28][N:27]=2)[CH2:36][CH2:37]1)=[O:10]
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCS1(=O)=O
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2N2CCCS2(=O)=O)CC1
Yield: 52.8 %

Procedure:
Using 2,4-bis(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (200 mg) described in Preparation Example 34 and 1-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine (136 mg) described in Preparation Example 84 and by the reaction and treatment in the same manner as in Example 87, the title compound (172 mg) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:15]([C:19]1[N:20]=[C:21]([SH:24])[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[N:20]=[C:21]([S:24][CH2:2][C:3]([N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][CH2:6]2)=[O:4])[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: CC(C)(C)c1csc(S)n1
Product: CC(C)(C)c1csc(SCC(=O)N2CCCc3ccccc32)n1
Yield: 37 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 4-tert-butylthiazole-2-thiol as the nucleophile to yield 34 (37%): MS: m/z+347.2 [M+H]+. Anal. Calcd (found) for C18H22N2OS2: C, 62.39; (62.60), H, 6.40; (6.43), N, 8.08; (8.06), S, 18.50; (18.39).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19][OH:20])=[O:5])[CH3:2].I[CH3:22]>[Ag]=O>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH2:8][C@H:7]1[CH2:19][O:20][CH3:22])=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: O=[Ag]
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COC
Reaction time: 288 h
Yield: 42.8 %

Procedure:
To a solution of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxymethyl-cyclopentanecarboxylic acid ethyl ester (Example 68/69 step 4, epimeric mixture, 509 mg) in iodomethane (24 g) was added silver oxide (3.9 g) in several portions over 8 days. After 12 days at room temperature, the reaction mixture was concentrated in vacuo, diluted with dichloromethane, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/EtOAc (1:0 to 9:1 v/v) as eluant to afford the title compound (228 mg, 43%) as light yellow oil. MS (EI): 317.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:10][CH:9]2[CH2:11][CH:3]1[CH:4]1[CH:8]2[C:7](=[O:12])[NH:6][C:5]1=[O:13].CC(O)C>S(=O)(=O)(O)O.O.CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:7]1(=[O:12])[CH:8]2[CH:4]([CH:3]3[CH2:11][CH:9]2[CH2:10][C:2]3=[O:1])[C:5](=[O:13])[NH:6]1
Reactant: O=C1NC(=O)C2C3CC(CC3O)C12
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=C1CC2CC1C1C(=O)NC(=O)C21
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Chromium trioxide (2.7 g) was dissolved in concentrated sulfuric acid (2.3 mL) and water (10 mL). 12.17 mL of this solution was added dropwise to a 0° C. solution of rac-(3aS,4R,5S,7R,7aR)-5-hydroxyhexahydro-1H-4,7-methanoisoindole-1,3-dione (4.21 g) (prepared by modification of the procedures in Japanese Patent Publication JP 8-333368, Dec. 17, 1996) in 20 mL of acetone. After 1 hr, 2-propanol (20 mL) was added, and the reaction was stirred 30 min (orange color dissipates). The reaction was filtered through celite and concentrated in vacuo. Silica gel chromatography eluting with 98:2 CH2Cl2:MeOH afforded 4 g of the titled compound as a white solid.
Reaction SMILES: [CH2:1]([O:6][P:7](=[S:20])([O:14][CH2:15][CH2:16][CH2:17][CH2:18]C)[O:8][CH2:9][CH2:10][CH2:11][CH2:12]C)[CH2:2][CH2:3][CH2:4]C.C(OP(=S)(OCCCCCCC)OCCCCCCC)CCCCCC.C(OP(=S)(OCCCCCCCC)OCCCCCCCC)CCCCCCC.C(OP(=S)([O-])[O-])CCCCCCCCCCCC.C(OP(=S)(OCCCCCCCCCCCC)OCCCCCCCCCCCC)CCCCCCCCCCC.C(OP(=S)(OCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCC)CCCCCCCCCCCCCC.C(OP(=S)(OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCC.C(OP(=S)([O-])[O-])CCCCCCCCCCCCCCCCCCCCCC>>[CH2:15]([O:14][P:7](=[S:20])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:6][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCCOP(=S)(OCCCCC)OCCCCC
Agent: CCCCCCCCCCCCCCCCCCCCCCCOP([O-])([O-])=S
Agent: CCCCCCCCCCCCCCCCCCOP(=S)(OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC
Agent: CCCCCCCCCCCCCCCOP(=S)(OCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCC
Product: CCCCOP(=S)(OCCCC)OCCCC

Procedure:
tripentylphosphorothioate; triheptylphosphorothioate; trioctylphosphorothioate; tridecylphosphorothioate; tridodecylphosphorothioate; tripentadecylphosphorothioate; trioctadecylphosphorothioate; trieicosylphosphorothioate;
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:3]=1[C:4]([NH:6][C:7](=[NH:19])[CH2:8][O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:5].CC([O-])(C)C.[K+]>>[Cl:24][C:21]1[CH:22]=[N:23][C:2]2[N:19]=[C:7]([CH2:8][O:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[NH:6][C:4](=[O:5])[C:3]=2[CH:20]=1
Reactant: N=C(COCCc1ccccc1Cl)NC(=O)c1cc(Cl)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=c1[nH]c(COCCc2ccccc2Cl)nc2ncc(Cl)cc12

Procedure:
In analogy to the procedure described in example 78.4, 2,5-dichloro-N-{2-[2-(2-chloro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide was treated with KOtBu to obtain 6-chloro-2-[2-(2-chloro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one as off-white crystals. MS: m/e=350.3 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([CH3:19])([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:20])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])([CH3:19])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Nc1ccccc1N
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A mixture of 2-methyl-2-(2-nitro-phenylamino)-propionic acid tert-butyl ester (638 mg, 2.3 mmol), 10% Pd/C (110 mg) in EtOH (25 mL) under H2 atmosphere at room temperature was stirred for 30 min. The reaction mixture was filtered and the organic layer was concentrated to give the desired 2-(2-amino-phenylamino)-2-methyl-propionic acid tert-butyl ester (570 mg, 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH:13][C:18](=[O:19])[O:20][CH2:21][CH3:22])=[CH:8][CH:7]=1
Reactant: CC(C)=CCSc1ccc(OCCN)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)NCCOc1ccc(SCC=C(C)C)cc1

Procedure:
Following the procedure of Example 13, 2-[4-(3-methyl-2-butenylthio)phenoxy]ethylamine is prepared and is reacted with ethyl chloroformate to give ethyl N-{2-[4-(3-methyl-2-butenylthio)phenoxy]ethyl}carbamate (compound 43, Table A).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ncoc1CSCCN
Reactant: O=C(N=C=S)c1ccccc1
Product: Cc1ncoc1CSCCNC(=S)NC(=O)c1ccccc1

Procedure:
5-[(2-Aminoethyl)thiomethyl]-4-methyloxazole is reacted with benzoyl isothiocyanate by the procedure of Example 18 to give N-benzoyl-N'-[2-((4-methyl-5-oxazolyl)methylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-((4-methyl-5-oxazolyl)methylthio)ethyl]thiourea.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](Cl)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Al+3].[Cl-].[Cl-].[Cl-]>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:12](=[O:13])[CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:18][CH:17]=1
Reactant: O=C(Cl)CCc1ccc([N+](=O)[O-])cc1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Yield: 61.2 %

Procedure:
A procedure similar to step 2 of Example 1 was used. 3-(4-nitro-phenyl)-propionyl chloride prepared in the step 2 of Example 6 and fluorobenzene were used as starting materials, and anhydrous AlCl3 was used as catalyst. The obtained product was a white solid in a yield of 61.2%, mp: 122-124 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.19 (2H, t, J=7.28 Hz), 3.32 (2H, t, J=7.28 Hz), 7.14 (2H, t, 3JFH=3JHH=8.40 Hz, ArH), 7.42 (2H, d, J=8.40 Hz, ArH), 7.99 (2H, dd, 3JHH=7.84, 4JFH=5.60 Hz, ArH), 8.16 (2H, d, J=8.40 Hz, ArH); EI-MS m/e (%): 273.1 (M+, 55), 123.0 (100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=3)[C:8]=2[C:9](Cl)=[N:10][CH:11]=1)=[O:5])[CH3:2].[NH4+].[Cl-]>O1CCOCC1.C1COCC1.CN(C=O)C.O.C(OCC)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cccc([N+](=O)[O-])c3)csc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-chloro-3-(3-nitro-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (398 mg, 1.01 mmol) (from Example 2 supra) in 1,4-dioxane (20 mL), THF (10 mL) and DMF (10 mL) was added NH4Cl (810 mg, 15.14 mmol) in water (6 mL). Zinc powder (783 mg, 12 mmol) was then added in several portions and the reaction was stirred at room temperature for a total of 4 hours. The resulting mixture was diluted with ethyl acetate (800 mL), washed with water (100 mL) and then brine (100 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (hexanes/EtOAc, 60/40 to 30/70) to give 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 339.1 mg, 100%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[Si](C)(C)C.Cl.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[O:21].[C:35]([S:38][CH:39]1[CH2:43][N:42]([C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=2)=[O:45])[CH:41]([C:57](O)=[O:58])[CH2:40]1)(=[O:37])[CH3:36].CN1CCOCC1.ClC(OCC(C)C)=O.NC1C=CC=CC=1>C1COCC1>[C:35]([S:38][C@@H:39]1[CH2:43][N:42]([C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=2)=[O:45])[C@H:41]([C:57](=[O:58])[NH:16][C:17]2[CH:34]=[CH:33][CH:32]=[C:19]([C:20](=[O:21])[NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:18]=2)[CH2:40]1)(=[O:37])[CH3:36]
Reactant: Nc1cccc(C(=O)NS(=O)(=O)c2ccccc2)c1
Reactant: CC(=O)SC1CC(C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: Nc1ccccc1
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)S[C@H]1C[C@@H](C(=O)Nc2cccc(C(=O)NS(=O)(=O)c3ccccc3)c2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
Di-isopropylethylamine (2.0 ml) followed by chlorotrimethylsilane (0.73 ml) was added to a stirred solution of 3-amino-N-phenylsulfonylbenzamide hydrochloride (1.8 g, 5.7 mM) in THF (distilled from CaH2 ; 25 ml) under an argon atmosphere. The solution was allowed to stand for 30 minutes then cooled to -10 C. Meanwhile 4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-carboxypyrrolidine (1.84 g, 5 mM) dissolved in tetrahydrofuran (25 ml) was treated with N-methylmorpholine (1.1 ml, 10 mM). This solution was cooled to -15° C. with stirring under an argon atmosphere, and treated with isobutyl chloroformate (0.66 ml, 5 mM) in one portion. After 20 minutes, this solution was added to the solution of the trimethylsilyl derivative of the aniline (prepared above). When the addition was complete, the mixture was stirred for 15 minutes and the solvent evaporated. The residue was partitioned between ethyl acetate (200 ml) and 1M aqueous hydrochloric acid (100 ml). The ethyl acetate layer was washed with hydrochloric acid, brine and dried giving (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-phenylsulfonylcarbamoylphenylcarbamoyl)pyrrolidine as a gum which was crystallised from EtOH (2.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:32][CH:33]([CH3:35])[CH3:34])=[C:28]([CH:31]=1)[C:29]#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:29]([C:28]1[CH:31]=[C:24]([CH:25]=[CH:26][C:27]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: CC(C)Oc1ccc(CCl)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.7 %

Procedure:
tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (461 mg, 1.60 mmol) was dissolved in DMF (3.0 mL) and 5-(chloromethyl)-2-isopropoxybenzonitrile (337 mg, 1.60 mmol) and cesium carbonate (533 mg, 1.60 mmol) were added. The reaction mixture was stirred at room temperature for 2 days and partitioned between ethyl acetate and water. The organics were removed and the aqueous mixture was extracted two times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residual oil was dissolved in methanol (10 mL) and cooled to 0° C. The precipitate was collected by filtration and triturated with 10% ethyl acetate/hexanes to provide the title compound (462 mg). LCMS m/z=461.5 [M+H]+; NMR (400 MHz, DMSO-d6) δ ppm 1.31 (d, J=6.1 Hz, 6H), 1.44 (s, 9H), 2.15-2.25 (m, 1H), 2.51-2.68 (m, 2H), 2.71-2.81 (m, 1H), 3.53-3.61 (m, 1H), 3.91-3.99 (m, 1H), 4.04-4.13 (m, 1H), 4.78 (septet, J=6.1 Hz, 1H), 5.02 (s, 2H), 5.99 (s, 1H), 6.74 (dd, J=8.7, 2.4 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 7.70 (dd, J=8.7, 2.3 Hz, 1H), 7.76 (d, J=2.1 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([CH3:13])=[N:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[CH2:16]([OH:22])[CH2:17][CH2:18][CH2:19][C:20]#[CH:21].C(N(CC)CC)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([C:21]#[C:20][CH2:19][CH2:18][CH2:17][CH2:16][OH:22])[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1
Reactant: C#CCCCCO
Reactant: COc1cc(Br)ccc1-n1cnc(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C#CCCCCO)ccc1-n1cnc(C)n1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A mixture of 1-(4-bromo-2-methoxyphenyl)-3-methyl-1H-1,2,4-triazole (3.00 g), 5-hexyn-1-ol (2.45 mL), dichlorobis(triphenylphosphine)palladium(II) (786 mg), copper(I) iodide (213 mg) and triethylamine (110 mL) was stirred at 70° C. for 14 hr, allowed to cool to room temperature, and diluted with ethyl acetate, and the mixture was filtered through celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.80 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[Si:12](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CN=C1>CN(C=O)C>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[Si:12]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C1CCc2ccc(O)cc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2c(c1)C(=O)CC2)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
6-Hydroxy-1-indanone was prepared according to the procedure described by Nayak & Chakraborti, Tetrahedron Lett., 38, 8749-8752 (1997). A mixture of 6-hydroxy-1-indanone (5.00 g, 33.8 mmol), tert-butyldiphenylsilyl chloride (23.1 g, 84.2 mmol), and imidazole (6.90 g, 101.4 mmol) in degassed DMF (100 mL) was heated at 60° C. for 18 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with a gradient of hexane—10% to 15% EtOAc, to yield the titled product.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[C:6](/[Br:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](/[Br:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: CCOC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the product of Step A and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-bromo-3-oxo-3-ethoxy-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =-70.5°±2° (c=0.7% in chloroform).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[O:11]=[CH:12][C:13](OCC)=O.FC1C=C2C(=CC=1F)NC(=O)C=N2.FC1C(F)=CC=C2C=1N=CC(=O)N2>>[F:8][C:7]1[C:2]([F:1])=[C:3]2[C:4]([N:9]=[CH:13][C:12](=[O:11])[NH:10]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=O
Reactant: Nc1ccc(F)c(F)c1N
Agent: O=c1cnc2c(F)c(F)ccc2[nH]1
Agent: O=c1cnc2cc(F)c(F)cc2[nH]1
Product: O=c1cnc2ccc(F)c(F)c2[nH]1
Yield: 64.3 %

Procedure:
3,4-Difluorobenzene-1,2-diamine (4.6 g, 31.6 mmol) and ethyl oxoacetate (50 wt % in toluene, 13.0 mL, 63.2 mmol) were reacted as described for Intermediate 152 to give 3.7 g of product as an off white solid, mixture with 30% of the regioisomer 5,6-difluoroquinoxalin-2(1H)-one. The mixture was carried on to the next step.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30](OC)([O:32]C)[CH3:31])=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:1][C:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:30](=[O:32])[CH3:31])=[CH:28][CH:29]=3)=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: COC(C)(OC)c1ccc(COC(=O)N2CCN(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(COC(=O)N2CCN(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
A mixture of 4-(1,1-dimethoxyethyl)benzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (600 mg, 1.23 mmol), 1 N hydrochloric acid (10 ml, 10 mmol) and THF (15 ml) was stirred at room temperature for 2 hours, then neutralized with a saturated sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The oranic phase was washed with water and then with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, diethyl ether was added, and the precipitates were filtered off to afford 4-acetylbenzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (558 mg, yield 99%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>O1CCOCC1>[NH2:6][C:5]1[CH:7]=[C:8]([NH:16][CH2:15][CH2:13][OH:14])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: NCCO
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: Nc1cc(NCCO)c(Cl)cc1[N+](=O)[O-]

Procedure:
0.11 mole (22.8 g) of 4,5-dichloro-2-nitroaniline is added to a solution of 0.55 mole (33.3 ml) of ethanolamine in 70 ml of dioxane. The reaction mixture is heated for 6 hours in refluxing dioxane. After dilution with water and neutralization with concentrated hydrochloric acid, the expected product precipitates.