Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]2([C:49]([NH:51][CH2:52][CH2:53][CH3:54])=[O:50])[C:48]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:42]3[C:37]2=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:28][CH:27]=1)([O-])=O.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:23][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]2([C:49]([NH:51][CH2:52][CH2:53][CH3:54])=[O:50])[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=3[C:43]3[C:48]2=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:28][CH:27]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCNC(=O)C1(CCCCc2ccc([N+](=O)[O-])cc2)c2ccccc2-c2ccccc21
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)C1(CCCCc2ccc(NC(=O)c3ccccc3Oc3ccccc3)cc2)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a solution of 2-phenoxybenzoic acid (Aldrich Chemical Co.) (111 mg, 0.518 mmol) and DMF (2 drops) in CH2Cl2 (1.5 mL) was added oxalyl chloride (389 μL, 2.0M in CH2Cl2, 0.777 mmol). The reaction bubbled for 10 min, then was stirred at RT under argon for 1.5 h. The reaction was concentrated in vacuo, and the resulting residue was dissolved in CH2Cl2 (1.5 mL) and added dropwise to a solution of Example 204 Part A compound (172 mg, 0.432 mmol) and triethylamine (90 μL, 0.648 mmol) in CH2Cl2 (1.5 mL) at 0° C. under argon. The reaction was stirred at 0° C. for 10 min, diluted with CH2Cl2 (20 mL), washed with saturated NaHCO3 (5 mL) and brine (5 mL), then dried over Na2SO4. Evaporation gave a yellow oil, which was dissolved in a minimum amount of CH2Cl2 and purified by flash chromatography on silica gel (50 g) eluting with 30% EtOAc/hexane to provide title compound (211 mg, 82%) as a yellow gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[F:9][B-:10]([F:13])([F:12])[F:11].[CH3:14][O+](C)C>C(Cl)Cl>[F:9][B-:10]([F:13])([F:12])[F:11].[CH3:14][N+:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ncccn1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1nccc[n+]1C

Procedure:
Starting material prepared by reaction of 2-methoxypyrimidine with trimethyloxonium tetrafluoroborate in CH2Cl2 at ambient temperature for 4 hours to give 1-methyl-2-methoxypyrimidinium tetrafluoroborate.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[CH2:60]([O:67][C:68]([NH:70][CH2:71][CH2:72][CH2:73][C@H:74]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C:75](OCC#N)=[O:76])=[O:69])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O.C(#N)C>[CH2:60]([O:67][C:68]([NH:70][CH2:71][CH2:72][CH2:73][C@@H:74]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C:75]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:76])=[O:69])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 28.6 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (67.9 mg, 0.107 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 5-(((benzyloxy) carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk66) (173 mg, 0.427 mmol) in acetonitrile (0.3 mL) were added to buffer A (18 mL), and the mixture was stirred at room temperature for 1.25 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk67) (30.1 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:14](=[O:16])[N:36]([CH2:35][CH2:34][O:33][CH3:32])[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: COCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2c(=O)n(CCOC)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 204.2 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.32 g) and triethylamine (0.59 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-methoxyethanamine (0.61 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), sodium methoxide (0.73 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.56 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13]OC(OC)N(C)C>CN(C)C=O>[CH3:13][N:7]1[C:8]2[C:3](=[C:2]([CH3:1])[N:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][C:6]1=[O:12]
Reactant: COC(OC)N(C)C
Reactant: Cc1nccc2[nH]c(=O)ccc12
Solvent: CN(C)C=O
Product: Cc1nccc2c1ccc(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture containing 4.5 g of 5-methyl-1,6-naphthyridin-2(1H)-one, 15 ml of dimethylformamide and 4 ml of dimethylformamide dimethyl acetal was stirred at room temperature overnight, then heated on a steam bath for 7 hours and then evaporated to dryness on a rotary evaporator. The solid residue was recrystallized from isopropyl alcohol and dried at 90°-95° C. to yield 3.5 g of 1,5-dimethyl-1,6-naphthyridin-2(1H)-one, m.p. 203°-205° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[CH:36]=1>CN(C)C=O.CN(C)C(=O)C>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:28]=[C:27]([NH:26][C:7]([C:5]5[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:48]=[CH:47][CH:46]=4)=[CH:36][N:35]3[N:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1cc(C(=O)O)n(CC(F)(F)F)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(CC(F)(F)F)n1
Yield: 86.2 %

Procedure:
In the same manner as in Example 18-4 and using 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid (269 mg, 1.29 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (278 mg, 86%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](O)=[O:9].S(Cl)([Cl:20])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([Cl:20])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Product: COc1cc(C=CC(=O)Cl)cc(OC)c1OC

Procedure:
0.86 gram (3.62 millimoles) of 3,4,5-trimethoxycinnamic acid and 16.3 grams (137 millimoles) of thionyl chloride were heated together at reflux temperature for 45 minutes to obtain 3,4,5-trimethoxycinnamoyl chloride. The reaction mixture was subjected to reduced pressure to vaporize excess thionyl chloride and to recover the acid chloride as residue. The acid chloride was purified by repeated dissolution in benzene and vaporizing the volatile matter. The purified acid chloride residue was dissolved in 15 milliliters of dry methylene chloride and the solution cooled to 0° C. To the solution was added a solution of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine and triethylamine in 15 milliliters of methylene chloride. The resulting mixture was allowed to warm to room temperature and then stirred overnight. As the end of this time, the mixture was diluted with methylene chloride and washed successively with 2N hydrochloric acid, aqueous sodium bicarbonate and brine and thereafter dried. The dried solution was subject to reduced pressure to remove the solvent and to obtain 1.84 grams of 4-(5H-dibenzo-[a,d]cyclohepten-5-yl) 1-(3,4,5-trimethoxyphenyl)prop-2-enoyl)piperidine as a light brown foamy solid. The latter was flash chromatographed on 80 grams of silica gel employing 40/60 ethyl acetate/hexane as eluant to obtain 1.06 grams of the product as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[CH2:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1COCCN1C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
Morpholine-3-carboxylic acid (10 g, 76 mmol) was dissolved in water (50 ml) and cooled to 5° C. A solution of 50% sodium hydroxide (6.10 g, 76 mmol) was added and the reaction mixture was cooled back to 5° C. An additional portion of 50% sodium hydroxide (7.93 g, 99 mmol) was then diluted to 22 mL with water and added to an addition funnel. Benzyl chloroformate (65.3 ml, 458 mmol) was added to a separate addition funnel and the two reagents were simultaneously added dropwise over about 30 minutes while maintaining the reaction temperature below 10° C. The pH of the mixture was about 6 when the addition was completed. Additional 50% NaOH (1.13 g, 14.3 mmol) was added to adjust pH to 9. The reaction was stirred at 10-15° C. for 2 hours. The reaction mixture was extracted with hexanes (2×30 ml) to remove excess benzyl chloroformate. EtOAc (50 ml) was added into the aqueous phase. The mixture was acidified to pH of about 0 with concentrated HCl (10 g). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×100 ml). The combined organic solution was concentrated to afford an oil. The product was further dried under high vacuum overnight to afford 21.2 g of crude 4-(benzyloxycarbonyl)morpholine-3-carboxylic acid which was used in the next step without further purification. [M−H] calculated for C13H15NO5, 264. found, 264
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([CH2:30][CH2:29][OH:33])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: C#CCCO
Reactant: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(-n3cc(CCO)nn3)ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 439 (0.29 mmol) and but-3-yn-1-ol (0.40 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 5:95 as the eluent to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(#N)C.C(OCC)C>[Cl:12][C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Solvent: CC#N
Product: Cc1c(O)ccc(Cl)c1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
2-Methyl-3-nitrophenol (25.5 g), N-chlorosuccinimide (44.5 g), and trifluormethanesulfonic acid (50.0 g) were combined in dry acetonitrile (500 mL) and allowed to stir under an atmosphere of nitrogen at 75° C. for 1.5 hr. The reaction mixture was cooled to room temperature, diluted with ethyl ether (650 mL), washed with water, 10% sodium bisulfite solution, water, and finally saturated sodium chloride solution. Evaporation of the solvent afforded a crude material which was flash chromatographed on silica and eluted with acetone:hexane (1:9) to afford 16.8 g as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.C(Cl)(=O)C([Cl:17])=O.[CH2:20]([O:22][C:23]([N:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=2)[CH2:26]1)=[O:24])[CH3:21].C(N(CC)CC)C>ClCCl.CN(C=O)C>[ClH:17].[CH2:20]([O:22][C:23]([N:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:10]([C:8]3[S:9][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=4[CH:7]=3)=[O:12])=[CH:33][N:32]=2)[CH2:26]1)=[O:24])[CH3:21]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2cc(Br)ccc2s1
Reactant: CCOC(=O)N1CC[C@H](Nc2ccc(N)cn2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CC[C@H](Nc2ccc(NC(=O)c3cc4cc(Br)ccc4s3)cn2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a suspension of 5-bromobenzothiophene-2-carboxylic acid (109 mg, 0.42 mmol) in dichloromethane (5 mL) was added oxalyl chloride (2M in dichloromethane, 0.5 mL) and one drop of DMF. The mixture was stirred at room temperature for 1 hr and solvents were evaporated. The residue was diluted with benzene (10 mL) and then concentrated to dryness. The residue was dissolved in dichloromethane (5 mL) and treated with (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester (106 mg, 0.42 mmol) in dichloromethane (5 mL) containing triethylamine (0.1 mL). The mixture was stirred at room temperature for 1 hr and solvents were evaporated. The residue was extracted with ethyl acetate and saturated ammonium chloride solution. Organic layer was washed with brine and dried over sodium sulfate. Solvents were evaporated and the residue was treated with methanol (1 mL) and hydrogen chloride in ether. Solvents were evaporated and the residue was treated with ether. The precipitate was filtered and washed with ether to give a light pink solid as (S)-3-{5-[(5-bromo-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester hydrochloride (100 mg, 48.3% yield). LCMS for C21H21BrN4O3S calcd. (m/e) 488, observed 489 (M+H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1.C(O)(=O)C.C(N(CC)CC)C.[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([O:43][CH2:44][CH3:45])[C:41]=1[F:42])[CH:37]=O)[CH3:32].C([BH3-])#N.[Na+]>C(O)C>[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([O:43][CH2:44][CH3:45])[C:41]=1[F:42])[CH2:37][N:3]1[CH2:4][CH2:5][CH:6]([NH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:8]1)[CH3:32]
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Reactant: CC(=O)Nc1cccc(NC2CCNCC2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(Nc3cccc(NC(C)=O)c3)CC2)cc(OCC)c1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a solution of N-[3-(piperidin-4-ylamino)-phenyl]-acetamide dihydrochloride (61.2 mg, 0.2 mmol, 1.0 equiv; intermediate B1), acetic acid (60.1 mg, 1.0 mmol, 5.0 equiv) and triethylamine (40.5 mg, 0.4 mmol, 2.0 equiv) in ethanol (1 mL) was added 3,5-diethoxy-4-fluoro-benzaldehyde (53.1 mg, 0.25 mmol, 1.25 equiv; intermediate E5, vide infra) and the mixture stirred at 50° C. After 1 h, sodium cyanoborohydride (15.1 mg, 0.24 mmol, 1.2 equiv), dissolved in ethanol (1 mL), was added and the mixture stirred at 50° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 19.9 mg (23%) of the title compound. MS (ISP): 430.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([O:13][CH3:14])[C:4]=1[C:15]([OH:17])=O.C(Cl)(=O)C([Cl:21])=O>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([O:13][CH3:14])[C:4]=1[C:15]([Cl:21])=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2ccccc2c(OC)c1C(=O)O
Product: COc1cc2ccccc2c(OC)c1C(=O)Cl

Procedure:
The product is prepared from 9.28 g. (40 mmoles) of 1,3-dimethoxy-2-naphthoic acid and 10.15 g. (80 mmoles) of oxalyl chloride by the process of Step 3 of Example 1.
Reaction SMILES: [CH:1]12[C:7]([CH3:9])([CH3:8])[CH:6]1[CH2:5][CH:4]=[C:3]([CH3:10])[CH2:2]2.C([O-])([O-])=O.[Ca+2].[Br:16]N1C(=O)CCC1=O.[OH2:24]>O1CCOCC1>[Br:16][C@@H:4]1[CH2:5][C@@H:6]2[C@@H:1]([C:7]2([CH3:9])[CH3:8])[CH2:2][C@@:3]1([CH3:10])[OH:24]
Reactant: O
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=CCC2C(C1)C2(C)C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: CC1(C)[C@@H]2C[C@@H](Br)[C@](C)(O)C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (+)-3-carene (82 g, 0.6 mol) and CaCO3 (80 g, 0.8 mol) in water (300 mL) and dioxane (600 mL) is added N-bromosuccinimide (142 g, 0.8 mol). The mixture is stirred at rt for 1 h, diluted with water (1500 mL) and extracted with diethyl ether (500 mL). The organic extract is washed with water (3×1000 mL) and 5% aq. Na2S2O3 (2×500 mL), and dried over Na2SO4. The solvent is removed under reduced pressure and the crude product is purified by column chromatography on silica gel eluting with hexane/EA 4:1 to yield (1S,3R,4R,6R)-4-bromo-3,7,7-trimethyl-bicyclo[4.1.0]heptan-3-ol (48.3 g) as a beige solid. 1H NMR (CDCl3): δ 4.05 (dd, J=7.6, 10.6 Hz, 1H), 2.48-2.36 (m, 2H), 2.20 (dd, J=10.0, 14.7 Hz, 1H), 1.42-1.38 (m, 1H), 1.36 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.90-0.80 (m, 1H), 0.72-0.66 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10]C)=[O:8].[OH-].[Na+].C(Cl)(Cl)=[O:16].C1(C)C=CC=CC=1>CO>[CH3:12][C:5]1[C:6]2[C:7](=[O:8])[O:9][C:10](=[O:16])[NH:1][C:2]=2[S:3][CH:4]=1
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1csc2[nH]c(=O)oc(=O)c12
Yield: 59 %

Procedure:
A mixture of ethyl 2-amino-4-methylthiophene-3-carboxylate (5 g, 0.03 mol) in methanol (25 ml) and aq. 2M sodium hydroxide (20.24 ml, 0.04 mol) was heated under reflux for 4 h. After cooling the solvents were evaporated, the residue dissolved in water (30 ml) and a 20% solution of phosgene in toluene (24 ml, 0.05 mol) added dropwise with ice cooling. After a further 30 min the solid which had precipitated was filtered, washed with water then ether, and dried to give the title compound 2.93 g (59%). 1H NMR (d6-DMSO) δ 2.31 (3H, s), 6.78 (1H, s), 12.50 (1H, br. s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][CH2:13][C:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]([O:12][CH2:13][C:14]2([CH2:17][OH:18])[CH2:16][CH2:15]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Reactant: OCC1(CO)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(I)ccc1OCC1(CO)CC1
Temperature: 50 °C
Yield: 70.4 %

Procedure:
A solution of 1-fluoro-4-iodo-2-nitrobenzene (2.50 g, 9.4 mmol) in DMF (30 mL) was treated with 1-(hydroxymethyl)cyclopropylmethanol (1.91 g, 19 mmol) and K2CO3 (2.6 g, 19 mmol) and the mixture was heated at 50° C. for 8 hours. TLC indicated complete consumption of the arylfluoride. The mixture was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. Purification by flash column chromatography (EtOAc in heptanes) gave the titled compound as a light yellow solid (2.31 g, 71% yield). 1H NMR (400 MHz, DMSO) δ 8.15 (d, J=2.2 Hz, 1H), 7.92 (dd, J=8.8, 2.2 Hz, 1H), 7.17 (d, J=8.9 Hz, 1H), 4.60 (t, J=5.6 Hz, 1H), 4.05 (s, 2H), 3.36 (d, J=5.6 Hz, 2H), 0.50 (s, 4H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([S:19][CH2:20][C:21]([OH:23])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:24][C@@H:25]1[C:32](=[O:33])[N:31]2[C@@H:26]1[S:27][CH2:28][C:29](/[CH:37]=[C:38]1/[C:39](=[O:47])[N:40]([CH2:43][CH:44]3[CH2:46][CH2:45]3)[CH2:41][CH2:42]/1)=[C:30]2[C:34]([OH:36])=[O:35]>CN(C)C=O>[CH:44]1([CH2:43][N:40]2[CH2:41][CH2:42]/[C:38](=[CH:37]\[C:29]3[CH2:28][S:27][C@H:26]4[N:31]([C:32](=[O:33])[C@H:25]4[NH:24][C:21](=[O:23])[CH2:20][S:19][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:30]=3[C:34]([OH:36])=[O:35])/[C:39]2=[O:47])[CH2:46][CH2:45]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12
Reactant: O=C(O)CSc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(CSc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12

Procedure:
With 167.0 mg (1.03 mmol) 1,1′-carbonyldiimidazole, 173.0 mg (1.03 mmol) 2-(phenylthio)acetic acid and 300.0 mg (0.86 mmol) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 6 ml N,N-dimethylformamide.