Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:11]=[C:10]([C:18]3[CH:19]=[C:20]([C:23]([OH:25])=O)[S:21][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CC[N:28]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[Br:1][C:2]1[C:3]2[N:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[N:11]=[C:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:28])=[O:25])[S:21][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)c2c1c(-c1csc(C(=O)O)c1)nn2C1CCCC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Br)c2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Yield: 88.2 %

Procedure:
A solution of 4-(7-bromo-1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (100 mg), HOBt ammonium salt (227 mg) and EDCI hydrochloride (180 mg) in DMF (15 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol) to give the title compound (88 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:26]=[CH:25][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[CH:15][CH:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:28]1([CH2:37][CH2:38][O:39][CH3:40])[C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30][C:29]1=[O:36]>>[CH3:40][O:39][CH2:38][CH2:37][C:28]1([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:11]=[CH:12][N:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)[N:9]=4)=[CH:26][CH:25]=3)=[CH:19][CH:20]=2)[C:29](=[O:36])[NH:30][C:31](=[O:35])[NH:32][C:33]1=[O:34]
Reactant: Oc1ccc(Oc2ccc(-c3ccn(-c4cccc(F)c4)n3)cc2)cc1
Reactant: COCCC1(Br)C(=O)NC(=O)NC1=O
Product: COCCC1(Oc2ccc(Oc3ccc(-c4ccn(-c5cccc(F)c5)n4)cc3)cc2)C(=O)NC(=O)NC1=O

Procedure:
By the same procedure as Example 1, Part C, 4-{4-[1-(3-fluorophenyl)-1H-pyrazol-3-yl]-phenoxy}phenol and 5-bromo-5-(2-methoxyethyl)-pyrimidine-2,4,6-trione (from Preparation 3B) were converted to the title compound. MS m/z: ESI+531.2 (M+H)+, ESI 529.4 (M−H)−.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.C[O-:13].[Na+]>CC#N.CO>[O:13]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[O:3]1
Reactant: C[O-]
Reactant: CCOC(=O)c1cnc(Cl)o1
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: O=C(O)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-chlorooxazole-5-carboxylate (1.816 g, 10.34 mmol) was solubilised in MeCN (20 ml) and MeOH (20 ml). Sodium methoxide (9 ml, 25% solution in MeOH, 41.4 mmol) was added and the reaction mixture was heated at reflux overnight. The solvent was removed under reduced pressure and the crude product was dissolved in MeOH (20 ml) and 2M NaOH(aq) (20 ml) and stirred at RT overnight. The resulting mixture was acidified with 1M HCl and evaporated under reduced pressure. The residue was triturated with a minimal volume of 5M HCl and filtered. The solid was slurried with ice chips (approx. 10 ml), filtered, washed with water and dried under high vacuum to afford the title compound;
Reaction SMILES: [C:1]([NH:8][C:9]([NH2:11])=[S:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.C([O-])(O)=O.[Na+]>CC(C)=O>[C:1]([NH:8][C:9]1[S:10][CH:16]=[C:14]([CH2:13][Cl:12])[N:11]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.2 %

Procedure:
To a solution of N-Boc-thiourea (3.0 g, 17 mmol) in acetone (75 mL) was added 1,3-dichloroacetone (2.4 g, 18.7 mmol) at once. The mixture was stirred at room temperature for 72 h. The reaction mixture was treated with 3 g of NaHCO3 and stirred for 15 min. The solids were removed by filtration and the filtrate was concentrated in vacuo. Column chromatography (EtOAc/Heptanes 4/1) afforded N-Boc-4-(chloromethyl)thiazol-2-amine (2.9 g, 11.6 mmol, 68%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17](=[N:21]O)C(O)=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(OC(=O)C)(=O)C>[C:1]1([C:7]2[C:15]([CH2:16][C:17]#[N:21])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(Cc1c(-c2ccccc2)nn2ccccc12)=NO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#CCc1c(-c2ccccc2)nn2ccccc12
Yield: 63.3 %

Procedure:
A solution of 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-hydroxyiminopropionic acid (0.20 g) in acetic anhydride (1 ml) was stirred for an hour at 80° C. After cooling, to the mixture was added water (10 ml). The resulting precipitates were collected by filtration to give 2-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acetonitrile (0.10 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:7][CH2:6][C:5]([CH2:22][OH:23])([CH2:8][N:9]2[CH:13]=[C:12]([CH2:14][O:15][CH2:16][O:17][CH3:18])[N:11]=[C:10]2[N+:19]([O-:21])=[O:20])[CH2:4][O:3]1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.[Cl-].[NH4+]>C(N(CC)CC)C>[CH3:1][C:2]1([CH3:24])[O:3][CH2:4][C:5]([CH2:8][N:9]2[CH:13]=[C:12]([CH2:14][O:15][CH2:16][O:17][CH3:18])[N:11]=[C:10]2[N+:19]([O-:21])=[O:20])([CH2:22][O:23][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:6][O:7]1
Reactant: COCOCc1cn(CC2(CO)COC(C)(C)OC2)c([N+](=O)[O-])n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: COCOCc1cn(CC2(COS(=O)(=O)c3ccc(C)cc3)COC(C)(C)OC2)c([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
23 mg (0.11 mmol equivalents) of 2,2-dimethyl-5-hydroxymethyl-5-[(4-methoxymethoxymethyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane was dissolved in 1.0 mL of triethylamine, 1 mg (0.01 mmol equivalents) of N,N-dimethylaminopyridine and 23 mg (0.12 mmol equivalents) of p-toluenesulfonyl chloride were added thereto, and the mixture was stirred at room temperature (25° C.) for 16 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were dried with anhydrous magnesium sulfate, and then concentrated under vacuum. The obtained crude product was purified by flash silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=1/3) to give 16 mg (0.03 mmol equivalents) of 2,2-dimethyl-5-[(4-methoxymethoxymethyl-2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][CH:8]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:21](O)=[O:22])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[Cl:53][CH2:54][CH2:55][NH:56][CH2:57][CH2:58][Cl:59].C(N(CC)CC)C>C(#N)C>[Cl:53][CH2:54][CH2:55][N:56]([CH2:57][CH2:58][Cl:59])[C:21]([C:20]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:18]([CH:8]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH:19]=1)=[O:22]
Reactant: ClCCNCCCl
Reactant: Cc1ccc(C(=O)O)cc1C(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C(=O)N(CCCl)CCCl)cc1C(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
Adapting a literature known protocol (U.S. Pat. No. 3,235,594), to a reaction mixture of 3-[3-tert-butoxy-1-[(tert-butoxycarbonylamino)methyl]-3-oxo-propyl]-4-methyl-benzoic acid (8e) (787 mg, 2.0 mmol), N-hydroxysuccinimide (NHS, HOSu) (235 mg, 2.2 mmol) in anhydrous acetonitrile (MeCN) (10 mL) is added solid dicyclohexylcarbodiimide (DCC) (433 mg, 2.1 mmol) in small portions at about room temperature. The reaction mixture is stirred for about 12 hours and the precipitated dicyclohexylurea side product is filtered off using a Biichner funnel. The filtrate is treated with commercial di-(2-chloroethyl)amine hydrochloride (2-chloro-N-(2-chloroethyl)ethanamine hydrochloride; HN(CH2—CH2—Cl)2.HCl) (393 mg, 2.2 mmol) followed by neat triethylamine (Et3N, TEA) (321 μL, 233 mg, 2.3 mmol). The reaction mixture is stirred for about 12 hours at room temperature. The reaction is followed by TLC and/or LC/MS to completion. The volatile solvents are removed under reduced pressure using a rotary evaporator. The residue is diluted with 1.0M hydrochloric acid (HCl). The aqueous phase is extracted with ethyl acetate (EtOAc) and the combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and evaporated to dryness. Purification by silica gel column chromatography using EtOAc and hexane mixtures furnishes the target compound (8f).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][Cl:12].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+].O>C(O)(=O)C>[Cl:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:16][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: ClCCCc1ccccc1CCl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCc1ccccc1CCCCl

Procedure:
70 g (345 mmols) of 3-(2-Chloromethylphenyl)-propyl chloride (JACS 75, 2053 (1953) and 50 g (0.61 mmol) of sodium acetate were heated to the boiling point while stirring in 250 ml of glacial acetic acid. It resulted from the thin layer chromatography that the reaction was finished after 41/2 hours. After cooling about 700 ml of water were added and the product was extracted with benzene. The organic phase was washed with water, dried and distilled off after evaporation of the solvent. Boiling point0.1 : 101° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].Cl.O.[N:46]1([CH2:52][CH:53]=O)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C([BH3-])#N>CO>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@@H:23]2[CH2:27][CH2:26][N:25]([CH2:53][CH2:52][N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@@H]2CCNC2)cn1
Reactant: O=CCN1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@@H]2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
A vial was charged with (R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate (Example 233, 700 mg, 1.14 mmol) and morpholin-4-yl-acetaldehyde monohydrate hydrochloride (250 mg, 1.37 mmol) in methanol (10 mL). MP-cyanoborohydride (730 mg, 1.71 mmol) beads were added and the resulting mixture was allowed to stir at room temperature overnight. The reaction mixture was filtered and the beads were washed with more methanol. The filtrate was concentrated under reduced pressure and purified by Analogix SF15-24 g in dichloromethane/methanol system to give a light yellow solid (320 mg, 38.6%).
Reaction SMILES: [Cl:1][C:2]([Cl:15])([Cl:14])[CH:3]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4]1.[OH-].[Na+].I[CH3:19]>C(O)C>[CH3:19][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]1[C:2]([Cl:1])([Cl:14])[Cl:15]
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccccc21
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)c2ccccc2OC1C(Cl)(Cl)Cl
Reaction time: 0.25 h

Procedure:
3,4-Dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (prepared as described in Example 3--5 g.) was suspended in ethanol (100 ml.), 63 ml. of a solution of sodium hydroxide (1.0 g.) in ethanol (83 ml.) was added, and the mixture was stirred for 15 minutes to obtain a clear solution. Iodomethane (5 ml.) was added, and the solution was boiled under reflux for 30 minutes. The solvents were evaporated, and the residue was dissolved in a mixture of toluene and ethyl acetate (7:3 by volume) and chromatographed on silica, eluting with the same solvent mixture. The first 100 ml. of eluate was collected, the solvent was evaporated and the residue crystallised on trituration with petroleum ether (b.p. 60°-80° C.) to give 3,4-dihydro-3-methyl-2-trichloromethylbenzo[e]-[1,3]-oxazin-4-one, m.p. 82°-84° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:42][C:43]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][C@H:50]([NH:54][C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])[C:51](O)=[O:52])=[O:44])=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])([O:14][C:51](=[O:52])[CH:50]([NH:54][C:55]([O:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)=[O:56])[CH2:49][CH2:48][CH2:47][CH2:46][NH:45][C:43]([O:42][CH2:41][C:38]2[CH:37]=[CH:36][CH:35]=[CH:40][CH:39]=2)=[O:44])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1

Procedure:
A suspension of 96 mg of 4-{4-[5-(5S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (MW: 481.52, 0.2 mmol), 195 mg of Z-Lys (Z)—OH (MW: 414.46, 0.4 mmol) and 49 mg of 4-dimethylaminopyridine (MW: 122.17, 0.4 mmol) in 2 ml dichloromethane was treated under stirring at room temperature with 115 mg N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid hydrochloride (MW: 191.70, 0.6 mmol). The reaction mixture was stirred over night. The mixture was diluted with 20 ml ethyl acetate and the organic layer washed successively with 10 ml N aqueous hydrochloric acid, 20 ml water and 20 ml brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated to dryness. The residue was purified by chromatography on silica, using a 9/1 dichloromethane/methanol mixture as eluent to leave a colorless sticky oil. Yield: 150 mg, 88%. MS: 878.8 (M+H)+, Method ESI+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[NH:8][C:7]=2[CH:15]=1.Cl[CH2:17][CH2:18][CH2:19][O:20][CH3:21].[F-].[K+].[I-].[K+]>C(#N)C>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]=2[CH:15]=1
Reactant: CC1(C)Oc2ccc(CO)cc2NC1=O
Reactant: COCCCCl
Agent: [F-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(CO)cc21

Procedure:
A suspension of 2.270 g of 6-hydroxymethyl-2,2-dimethyl-4H-benz[1,4]oxazin-3-one in 180 ml of acetonitrile is admixed with 2.410 ml of 1-chloro-3-methoxypropane, 9.844 g of potassium fluoride on alumina and 0.036 g of potassium Iodide. The reaction mixture is heated to reflux over 30 hours and filtered through Hyflo, and the filtrate is concentrated. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (3:1 EtOAc-heptane); Rt=3.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[O:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][CH2:20][O:21][CH3:22].C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:19][CH2:20][O:21][CH3:22])[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc(C=O)cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 3-methoxy-4-hydroxybenzaldehyde (8.0 g) in DMF (60 mL) was added K2CO3 (8.0 g) and 1-chloro-2-methoxyethane (5.1 g). The resulting mixture was stirred at 80° C. overnight. After reaction finished, ethyl acetate (200 mL) was added, and washed with 2 N aqueous HCl solution, brine, dried over Na2SO4, filtered, concentrated. The residue was washed with petrol ether to give 3-methoxy-4-(2-methoxyethoxy)benzaldehyde (10 g) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ: 9.86 (s, 1H); 7.45-7.41 (m, 2H); 7.01 (d, J=8.0, 1H); 4.27-4.25 (m, 2H); 3.93 (s, 3H); 3.85-3.82 (m, 2H); 3.46 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:27][S:28]([CH2:31][CH2:32][CH2:33]Cl)(=[O:30])=[O:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:27][S:28]([CH2:31][CH2:32][CH2:33][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)(=[O:30])=[O:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)CCCCl)cc1)c1ccccc1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)CCCN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1x and piperidine (15 eq)in tetrahydrofuran at reflux. 1z was then precipitated from a mixture of ethyl acetate and 1N HCl as the HCl salt. Yield (60%); 1H NMR (d6-DMSO) δ 11.90 (br s, 1H), 7.47 (d, J=15.7 Hz, 1H), 7.40-7.09 (m, 12H), 6.87 (d, J=7.7 Hz, 2H), 6.53 (d, J=15.7 Hz, 1H), 3.08 (br, 2H), 2.95 (br, 1H), 2.81 (br, 2H), 2.37 (q, J=7.3 Hz, 2H), 2.08 (br, 2H), 1.71 (br, 6H), 1.62 (br, 1H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 541 (M−H−).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH3:4].CN1CCOCC1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH2:2][C@@H:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH3:4])(=[O:28])=[O:27]
Reactant: C[C@@H](CO)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@@H](COS(C)(=O)=O)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
To a solution of (S)—N-(1-hydroxypropan-2-yl)-2-nitrobenzenesulfonamide (6.20 kg, 23.8 mol) in methylene chloride (32 L) was added 4-methylmorpholine (3.13 kg, 30.9 mol) at an internal temperature of 10° C. or below. The resulting reaction mixture was cooled to 0° C., and added a solution of methanesulfonyl chloride (3.27 kg, 28.5 mol) in methylene chloride (2 L) at an internal temperature of −5° C. to 0° C. Subsequently, the reaction mixture was stirred at room temperature for 20 hours. After confirming the disappearance of the starting materials by TLC, purified water was added to the reaction mixture. The resulting organic layer was partitioned, washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure to give the target product as a yellow solid (7.30 kg, yield 90.70).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[CH3:35]>>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:31])=[CH:28][C:27]=1[CH3:35]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: COc1ccc(C(=O)O)cc1C
Product: COc1ccc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)cc1C

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Methoxy-3-methyl-benzoic acid.
Reaction SMILES: O.[OH-].[Na+].[C:4]([C:6]1([CH2:12][C:13]([O:15]CC)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)#[N:5]>CO>[C:4]([C:6]1([CH2:12][C:13]([OH:15])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)#[N:5]
Reactant: CCOC(=O)CC1(C#N)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#CC1(CC(=O)O)CCCCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suitable reactor is charged 120 L of water, 32 kg of 50% aqueous sodium hydroxide solution, 21 L of methanol, and 70 kg of ethyl 1-cyanocyclohexaneacetate. This mixture is stirred at 50° C. for 1 hour, after which 40 to 60 L of solvent is removed by vacuum distillation while maintaining a temperature of below 50° C. After cooling to 20° to 25° C., the reaction mixture is filtered through a 0.45 micron Pall filter. The filtered solution is then diluted with 70 L of water and extracted with 20 L of methylene chloride, followed by a second extraction with 15 L of methylene chloride. The aqueous solution is charged to a pH of 8 with 37% hydrochloric acid solution. About 6 to 8 kg of 37% hydrochloric acid solution is required. The solution is then extracted two times with 20 L each of methylene chloride. After the final extraction, the aqueous solution is stirred under full vacuum at 20° to 30° C. for 30 minutes minimum, then cooled to 3° to 10° C. While maintaining this temperature, 37% hydrochloric acid solution is charged to a pH of 3. About 32 to 36 kg of 37% hydrochloric acid solution is required. After the addition is complete, the product slurry is stirred at 3° to 10° C. for 30 minutes. The product is then collected on a centrifuge and washed with 300 to 400 L of water which is prechilled to 5° C. or less. The product is spun as dry as possible on the centrifuge and is then removed from the centrifuge and stored as a wet cake in a cold room at 5° C. or less. After vacuum drying at 40° C. for 24 hours 1-cyanocyclohexaneacetic acid is obtained; mp 103°-105° C.