Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[C:17]([C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27]([O:29][CH3:30])=[O:28])[N:16]=2)=[O:14])=[CH:11][C:10]=1[O:36][CH3:37]>N1C=CC=CC=1.ClCCl>[CH3:37][O:36][C:10]1[CH:11]=[C:12]([CH:34]=[CH:35][C:9]=1[NH:8][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[C:13]([C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[C:17]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([O:29][CH3:30])=[O:28])[N:16]=1)=[O:14]
Reactant: COC(=O)c1cccc(-c2nc(C(=O)c3ccc(N)c(OC)c3)n3ccccc23)c1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(C(=O)c2nc(-c3cccc(C(=O)OC)c3)c3ccccn23)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.17 ml (1.5 mmol) of 1-propanesulfonyl chloride is added to 0.5 g (1.24 mmol) of methyl 3-[3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridin-1-yl]benzoate obtained in example 111 in 6 ml of pyridine. The reaction medium is stirred at ambient temperature for 18 h and then concentrated under reduced pressure. The residue obtained is taken up in dichloromethane. The organic phase obtained is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel, elution being carried out with dichloromethane. 0.34 g of a yellow oil is collected. MS+: 508; 1H NMR (d6-DMSO): 0.96-1.01 (3H, t), 1.74-1.81 (2H, m), 3.16-3.19 (2H, m), 3.92 (3H, s), 4.00 (3H, s), 7.33-7.73 (2H, m), 7.38-7.51 (1H, m), 7.53-7.96 (2H, m), 8.03-8.30 (2H, m), 8.33-9.85 (2H, m), 8.38 (1H, s), 8.63 (1H, s), 9.25 (1H, m)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[O:24])=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:14]2[N:15]([C:39]3[CH:38]=[CH:37][N:36]=[C:35]([Cl:34])[CH:40]=3)[C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]2)=[O:24])=[CH:18][CH:17]=3)=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Product: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2ccnc(Cl)c2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 5, from 4-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-piperazine-1-carboxylic acid ethyl ester (example 43) and 2-chloropyridine-4-boronic acid to give the desired product as a light-yellow foam (60%). MS (ISP): 567.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]([C:27]1[N:31](COCC[Si](C)(C)C)[C:30]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:29]=2[N:28]=1)(O)[C:4]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].FC(F)(F)C(C1N(COCC[Si](C)(C)C)C2C=C(C#N)C=CC=2N=1)(O)C1C(SC)=CC(C)=C2C=1C=[CH:54][N:55]2S(C1C=CC(C)=CC=1)(=O)=O.Cl.S(Cl)(Cl)=O.CN>CN(C=O)C>[F:47][C:2]([F:46])([F:1])[C:3]([C:27]1[NH:31][C:30]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:29]=2[N:28]=1)([C:4]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[NH:55][CH3:54]
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CNC(c1nc2cc(C#N)ccc2[nH]1)(c1c(SC)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Temperature: 60 °C

Procedure:
To a mixture of (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 14-A) (0.37 g, 0.528 mmol) was added HCl (1.25M in MeOH, 4.22 mL, 5.28 mmol) and the mixture was stirred at 60° C. After 40 minutes the mixture was cooled to room temperature and concentrated. The residue was dissolved in CHCl3 (10.56 mL), and thionyl chloride (0.385 mL, 5.28 mmol) and a few drops of DMF were added and the mixture was heated at 70° C. After 2 hours the reaction was cooled to room temperature and concentrated. The residue was dissolved in methylamine (33% in EtOH, 6.57 mL, 52.8 mmol) and stirred at room temperature. After 5 minutes the reaction was concentrated and purified directly by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 584.2 (M+H).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[C:38]2=[CH:39][N:40]=[N:41][C:42](=O)[C:37]2=[N:36][CH2:35]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)[Cl:56]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Cl:56][C:42]1[N:41]=[N:40][CH:39]=[C:38]2[N:34]([C@@H:11]3[O:12][C@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:14]([O:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C@H:10]3[O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:35]=[N:36][C:37]=12
Reactant: O=C1N=NC=C2C1=NCN2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: ClP(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)c1ccccc1
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nncc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
A solution containing the compound from Step B (1.32 g, 2.27 mmol), the N,N-diethylaniline (365 μL), tetrabutylammonium chloride (1.2 g), freshly distilled phosphorus chloride (1.3 μL) and anhydrous acetonitrile (17 mL) was stirred at 90° C. for 1 hour. The reaction mixture was poured over cracked ice/water. The aqueous layer was extracted with dichloromethane (3×60 mL). The organic layer was washed with sodium hydrogenocarbonate 5%, water and was evaporated to dryness. The crude product was purified on silica gel using n-hexane/ethyl acetate (3/1) as eluant to give the title compound (404 mg) as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(C(=O)c2ccc(O)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(Cc2ccc(O)cc2)c1

Procedure:
Methyl 3-(4-hydroxybenzoyl)benzoate (0.1 mol) in absolute ethanol (500 ml) is shaken under 50 psi of hydrogen in the presence of 10% palladium on carbon (2 g). After consumption of the starting material the suspension isfiltered and evaporated to give methyl 3-(4-hydroxybenzyl)benzoate
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][CH2:11][C:10]2[N:9]=[C:8]([CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:7]=[CH:6][C:5]1=2)=[N+]=[N-].CCOC(C)=O.CO>CCOC(C)=O.CO.[Pd]>[Si:17]([O:16][CH2:15][CH2:14][C:8]1[N:7]=[CH:6][C:5]2[CH:4]([NH2:1])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1)([C:30]([CH3:33])([CH3:31])[CH3:32])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2N)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A suspension of 80 mg of Pd/C (10% w/w) in a solution of 5-azido-2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazoline (800 mg, 1.75 mmol) in 30 mL of EtOAc was stirred under H2 atmosphere overnight. The reaction mixture was then directly submitted to flash chomatograph (SiO2, EtOAc to EtOAc/MeOH=100:15 to EtOAc/2M NH3 in MeOH=2:1) to give the desired product as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14](C(=O)C=O)[NH2:15])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.[C:21]([OH:25])(=[O:24])[CH:22]=O.Cl>C(#N)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][N:15]=[CH:22][C:21]([OH:25])=[O:24])(=[O:12])=[O:13])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N(N)C(=O)C=O)cc1
Reactant: O=CC(=O)O
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)NN=CC(=O)O)cc1

Procedure:
The subject compound is prepared using the general method of Example 1 except that 4.58 g (20 mmol) of glyoxylic acid p-acetamidobenzenesulfonylhydrazide was reacted with 2.4 g (26 mmol) of glyoxylic acid monohydrate in the presence of 1/2 cc conc. HCl and 200 cc acetonitrile. The desired product was obtained in a yield of 5.4 g, m.p. 136° (dec.).
Reaction SMILES: C([O:3][C:4](=[O:10])[CH:5](Cl)[C:6]([CH3:8])=O)C.[CH:11]([NH2:13])=[O:12].[OH-].[Na+]>CCOC(C)=O>[CH3:8][C:6]1[N:13]=[CH:11][O:12][C:5]=1[C:4]([OH:3])=[O:10]
Reactant: NC=O
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ncoc1C(=O)O
Temperature: 120 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
Ethyl-2-chloroacetoacetate (1 wt; 1 eq., 1000 g) was aged with formamide (0.68 vol; ca. 2.8 eq.) and the resulting solution was heated to 120° C. After 5 hours the mixture was allowed to cool to room temperature and allowed to age under nitrogen over night. The mixture was treated with NaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at room temperature for 4 hours. Ethyl acetate (6 vol) was added and the phases allowed to separate. The organic layer was discarded while the aqueous was acidified with conc. (32%) aqueous HCl to pH 2 (ca. 2.0 vol). A precipitate started to form. The suspension was treated with AcOEt (8 vol) and vigorously stirred until the bulk of the precipitate had dissolved. The aqueous phase was further extracted with AcOEt twice (6 vol each) and the combined organic layers distilled to low volume (again a suspension was observed at low volume). Fresh AcOEt (8 vol) was added and the mixture evaporated to dryness. The collected solid was placed in the oven at 40° C. over night under reduced pressure to give 4-methyl-1,3-oxazole-5-carboxylic acid (498 g, 64.5%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:24]([OH:26])[CH3:25])=[N:14][N:15]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:24]([O:26][CH3:29])[CH3:25])=[N:14][N:15]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-(6-(Benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-indazol-3-yl) ethanol (10 mg) which can be prepared according to the method described in Reference example 24, etc. was dissolved in dehydrated DMF (0.12 mL; manufactured by Kanto Chemical Co., Inc.), added with sodium hydride-comprising 400 oil (2.0 mg; manufactured by Kanto Chemical Co., Inc.), followed by stirring at room temperature for 5 minutes. To the reaction solution, methyl iodide (4.87 μL; manufactured by Tokyo Chemical Industry, Co., Ltd.) was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, which was then extracted twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-F”; n-hexane:ethyl acetate=5:1) to obtain the title compound (10.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](O)=[O:15])=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C(=O)C2C=CC=CC=2N=N1.[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[O:15])=[CH:9][C:8]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CC(=O)O)cc1-c1ccccc1
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CC(=O)Nc2ccccn2)cc1-c1ccccc1

Procedure:
To a solution of the resultant acid from Example 62B (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (1.5 equivalents) followed by 2-aminopyridine (1.0 equivalent) and 1-(3-dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with 1N HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH:12]1([C:18]2[NH:19][CH:20]=[C:21]([CH3:23])[N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(#N)C>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:19]2[CH:20]=[C:21]([CH3:23])[N:22]=[C:18]2[CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:3]=1
Reactant: Cc1c[nH]c(C2CCCCC2)n1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cn(-c2cc(Cl)ccc2[N+](=O)[O-])c(C2CCCCC2)n1

Procedure:
3.75 g 4-Chloro-2-fluoro-nitrobenzene, 3.4 g 2-Cyclohexyl-4-methyl-imidazole, 50 ml acetonitrile and 5 ml triethylamine were heated 6 hours at 60° C. The solvent was distilled off followed by extraction with 100 ml ethylacetate and 2 times 50 ml water. The organic layer was distilled off and the residue chromatographed on silica gel with 5% MeOH/CH2Cl2.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.[CH3:12][O-:13].[Na+]>CC#N.CO>[CH3:12][O:13][C:2]1[O:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cnc(Cl)o1
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1ncc(C(=O)O)o1
Yield: 69.9 %

Procedure:
To a solution of ethyl 2-chlorooxazole-5-carboxylate (510 mg, 2.90 mmol) in anhdryous MeCN (10 mL) and anhydrous MeOH (10 mL) is added NaOMe (628 mg, 11.62 mmol). The crude is stirred at reflux for 2 hrs. To this crude is added additional MeOH. The crude is refluxed for another 4 hrs. The crude is concentrated and is redissolved in MeOH (10 mL). To this crude is added 1 N NaOH (10 ml). The crude is stirred at room temperature for 3 hrs. The crude is quenched with concentrated HCl, PH adjusted to 7 via PH paper indicator. The crude is concentrated and diluted in water. The aq. layer is acidified with concentrated HCl and diluted in EtOAc. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated to give 2-methoxyoxazole-5-carboxylic acid (290 mg). HPLC retention time=0.58 minutes (condition D); MS (m+1)=144.0.
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:17]#[N:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:19])=O.C(O)(=O)C>S(=O)(=O)(O)O.O>[O:19]=[C:6]1[CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:17]#[N:18])[CH2:10][CH2:5]1
Reactant: COC(=O)C1CC(C#N)(c2ccccc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(c2ccccc2)CCC(=O)CC1

Procedure:
5-cyano-2-oxo-5-phenyl cyclohexane carboxylic acid methyl ester (16.1 g, 63 mmol) was dissolved in 10% sulphuric acid (218 mL) and conc. acetic acid (502 mL) and stirred for 21 h at 100° C. For work up the batch was carefully diluted with water (400 mL) with ice cooling, extracted with ethyl acetate (3×100 mL), the organic phase washed thoroughly with water (6×100 mL), saturated NaHCO3 solution (10×100 mL) and saturated NaCl solution (1×100 mL). After drying with Na2SO4 the solvent was distilled off in a vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([C:47]#[N:48])[CH2:44][N:43]6C(=O)C(NC(OC)=O)C6C=CC=CC=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(NC(C1C=CC=CC=1)C(O)=O)=O.[CH3:79][N:80]([CH:82]([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)[C:83]([OH:85])=O)[CH3:81]>>[CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([C:47]#[N:48])[CH2:44][N:43]6[C:83](=[O:85])[CH:82]([N:80]([CH3:79])[CH3:81])[C:86]6[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Reactant: CN(C)C(C(=O)O)c1ccccc1
Agent: COC(=O)NC(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)C(c6ccccc6)N(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C

Procedure:
Synthesized similar to [1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester replacing the methoxycarbonylamino-phenyl-acetic acid with dimethylamino-phenyl-acetic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:6]1(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30]1>CN(C=O)C.O>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:33][CH2:34]2)[S:6]1(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=S1(=O)N(CCCBr)c2ccccc2N1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CCCN2c3ccccc3N(c3ccccc3F)S2(=O)=O)CC1
Temperature: 70 °C
Yield: 57.2 %

Procedure:
1-(3-bromopropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.61 g, 1.56 mmol) was dissolved in 5 mL of DMF along with 430 mg (3.1 mmol) of potassium carbonate and 0.32 g (1.56 mol) of tert-butyl piperidin-4-ylcarbamate. The solution was heated to 70° C. for 16 hours then poured in water. The solution was extracted 2× with ethyl acetate and the water layer discarded. The combined organic phase was washed 3 times with brine, then dried (MgSO4) and concentrated. The residue was subjected to Biotage chromatography (10-50% ethyl acetate-hexane) to afford 0.45 g (55%) of tert-butyl (1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-yl)carbamate. MS (ES) m/z 505.1; HPLC purity 97.9% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Bicarb Buff.Ph=9.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])[CH2:12][CH3:13].S(Cl)(Cl)=O.S(=O)=O.Cl>ClC1C=CC=CC=1>[CH2:11]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH2:12][CH3:13]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCCOc1cccc(N)c1
Agent: Cl
Agent: O=S=O
Solvent: O=S(Cl)Cl
Solvent: Clc1ccccc1
Product: CCCOc1cccc(NC(=O)c2ccccc2C)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A 13.6 g (0.1 mol) portion of o-methylbenzoic acid and 15.1 g (0.1 mol) of m-n-propoxy-aniline were dissolved in 100 ml of chlorobenzene. An 11.9 g (0.1 mol) amount of thionylchloride was added dropwise to the prepared solution at 40°-50°C, and the mixture was stirred at 90°-95°C for 4 hours, whereby sulfur dioxide and hydrogen chloride were continuously generated. After the reaction, the reaction mixture was poured into ice water and extracted with a mixture of benzene and hexane. The product was recrystallized from the mixed solvent to obtain 23.6 g (88%) of white needles having a melting point of 92°-94°C.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](O)=O.[C:14]([OH:33])(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=C\CCCCCCCC>>[C:14]([OH:33])(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:13])=[O:12]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=C(O)CCCCCCCC(=O)O
Product: O=C(O)CCCCCCCC=CCCCCCCCC(=O)O

Procedure:
Another preferred embodiment of the invention is based on the preparation of azelaic acid by biooxidation of oleic acid to form 9-octadecenedioic acid followed by oxidation of the 9-octadecenedioic acid to azelaic acid. While any grade of oleic acid can be used as the substrate, a typical technical grade oleic acid consists of the following carboxylic acids: 0.42% C12; 2.7% C14; 0.86% C14:1; 6.3% C16; 4.6% C16:1; 0.93% C17; 2.8% C18; 71.8% C18:1; 8.3% C18:2; 0.58% C18:3. The oleic acid can also be a high grade oleic acid obtained from a fatty oil of a Helianthus annuus (sunflower seed oil) species described, for example, in U.S. Pat. No. 4,627,192, the entire contents of which are incorporated herein by reference. Such oils are very rich in oleic acid and contain at least 80% by weight of oleic.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[CH:32]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([N:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)[CH:32]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CC1(C)OB(c2ccnc(N3CCNCC3)c2)OC1(C)C
Product: COc1cc(CCc2cnc3[nH]c(-c4ccnc(N5CCNCC5)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedure analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine (from Aldrich). LCMS calculated for C25H29N6O2 (M+H)+: m/z=445.2. Found 445.2.