Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[N:4]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH:12]=[CH:15][N:16]([CH3:18])[CH3:17])[N:4]=1
Reactant: COC(OC)N(C)C
Reactant: COc1ccc([N+](=O)[O-])c(C)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])c(C=CN(C)C)n1
Temperature: 120 °C
Yield: 99.6 %

Procedure:
To 2-methoxy-5-nitro-6-methylpyridine (29.39 g, 175 mmol) dissolved in 300 mL of N,N-dimethylformamide was added dimethylformamide dimethylacetal (120 mL, 896 mmol) and triethylamine (1 mL). The bright red reaction mixture was heated at 120° C. for 2 hours, then concentrated in vacuo to provide 38.90 g of the title compound as a red solid, which was used in Preparation 13 without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:15]=1.Cl[C:33]([C:35]1[CH:36]=[C:37]([CH:49]=[CH:50][CH:51]=1)[CH2:38][S:39][CH2:40][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:34]>ClCCl>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:33]([C:35]3[CH:36]=[C:37]([CH:49]=[CH:50][CH:51]=3)[CH2:38][S:39][CH2:40][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])=[O:34])=[C:3]([C:14]3[CH:15]=[C:16]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=4)[N:17]=[CH:18][N:19]=3)[CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A solution of 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine (122 mg) in 1.0 mL of dichloromethane was treated with 54 mg of tert-butyl 3-((3-(chlorocarbonyl)benzyl)thio)propanoate. The mixture was stirred overnight. The solvent was evaporated and the residue was purified by silica gel chromatography to give 120 mg of product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cn2cc(Cl)ccc2n1
Temperature: 60 °C
Yield: 72.3 %

Procedure:
A solution of 2-amino-5-chloropyridine (2.0 g, 16 mmol) [Matrix Scientific, 021118] in acetone (39 mL) was treated with ethyl bromopyruvate (2.2 mL, 16 mmol) and heated at 60° C. for 45 min. The reaction mixture was cooled to 20° C. and the suspension was filtered. The solid that was collected was washed with a small amount of cold acetone and dried in vacuo. The solid was diluted with ethanol (12 mL) and water (19 mL), heated at 65° C., and treated with sodium bicarbonate (1.6 g, 19 mmol) portionwise. The reaction mixture was cooled to 20° C. and the suspension was filtered. The solid that was collected was washed with water (4×80 mL) and dried in vacuo to give the desired product (2.6 g, 74%). LCMS for C10H10ClN2O2 (M+H)+: m/z=225.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:11]=1)[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2.[OH-].[Na+:29]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:11]=1)[O:8][CH:7]([C:21]([F:23])([F:24])[F:22])[C:6]([C:25]([O-:27])=[O:26])=[CH:5]2.[Na+:29]
Reactant: O=C(O)C1=Cc2cc(Cl)cc(C#Cc3ccccc3F)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])C1=Cc2cc(Cl)cc(C#Cc3ccccc3F)c2OC1C(F)(F)F

Procedure:
A solution of 84.3 mg (0.213 mmole) of 6-chloro-8-[(2-fluorophenyl)ethynyl]-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 2.0 mL of ethanol was treated with 2.108 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide a quantitative yield of a yellow solid: 1H NMR (CD3OD/400 MHz) 5.97 (q, 1H, J=7.2 Hz), 7.14-7.20 (m, 2H), 7.28-7.30 (m, 1H), 7.36-7.42 (m, 3H), 7.51-7.54 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:27]#[C:26][CH2:25][OH:28])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)C(F)(F)F
Product: OCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl ester and 2-propyn-1-ol were converted to yield 3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol as yellow solid, MS: 299 (M, 1 Cl).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=3)=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(O)CC3)nc2)n1
Reactant: Oc1cc(Cl)ccc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(Cl)ccc4Cl)CC3)nc2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 3 (step 4) from ethyl {5-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate, 2,5-dichlorophenol, triphenylphosphine and di-tert-butyl azodicarboxylate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8](C(O)=O)[C:7]2=[O:15]>C1(OC2C=CC=CC=2)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=[O:15]
Reactant: O=C(O)c1c[nH]c2c(I)cccc2c1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc[nH]c2c(I)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
8-Iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (15.69 g, 49.8 mmol) was suspended in phenylether (40 mL) and the mixture heated to boiling. After 30 min, reaction was completed by LCMS. The crude was transferred to a bequer and cooled to room temperature. Hexanes (500 mL) were added and the mixture was stirred for 10 min. The solid was retrieved by filtration, thoroughly washed with hexanes and purified by HPLC to afford 8-iodo-1H-quinolin-4-one as a brownish solid (4.4 g, 23%). 1H NMR (DMSO-d6, 400 MHz) δ 6.14 (d, 1H), 7.09 (t, 1H), 7.88 (d, 1H), 8.08 (dd, 1H), 8.16 (dd, 1H). Exact mass calculated for C9H6INO 270.95, found 271.8 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[C:4]([CH3:18])=[C:3]([CH3:19])[C:2]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: Cc1c(Cl)nn2cc(-c3ccc(F)cc3)nc2c1C
Reactant: C1CNCCN1
Solvent: O
Product: Cc1c(N2CCNCC2)nn2cc(-c3ccc(F)cc3)nc2c1C
Temperature: 150 °C
Yield: 69.6 %

Procedure:
A mixture of 1.4 g (5.08 mmol) of 6-chloro-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazine and 8.7 g (100 mmol) of piperazine is heated at 150° C. for 3 hours in a reactor. The medium is then poured into water and the precipitate formed is isolated by filtration. The product is then recrystallized from a mixture of diisopropyl ether and isopropanol to give 1.15 g of a white powder.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH2:13][CH2:14][CH3:15])=[CH:7][N:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH2:13][CH2:14][CH3:15])=[CH:7][N:6]=1
Reactant: CCCOc1cnc(CN=[N+]=[N-])cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCOc1cnc(CN)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-azidomethyl-5-propoxy-pyridin-4-ol (9.70 g, 46.6 mole), is then suspended in 120 mL of tetrahydrofuran and treated with triphenylphosphine (12.22 g, 46.6 mmole) after stirring for 10 mins at ambient temperature water is added (12.6 mL, 15 equivalents) and the reaction mixture is stirred at ambient temperature overnight. The solids gradually dissolved followed by the formation of a precipitate. The resulting solid is filtered, washed with fresh 10:1 tetrahydrofuran:water and dried to give, 5.92 g, (69%), mp 159-60° C.; MS (ES+): m/z 183.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[N:8][C:9]([N:16]([CH2:24][CH3:25])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C>C(O)C>[CH2:24]([N:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[N:8]=[C:7]([CH3:26])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)[C:10]=1[N+:13]([O-:15])=[O:14])[CH3:25]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(C)nc(N(CC)Cc2ccccc2)c([N+](=O)[O-])c1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(N(CC)Cc2ccccc2)c([N+](=O)[O-])c1N1CCN(C)CC1

Procedure:
37.8 g. of 4-chloro-6-[ethyl(phenylmethyl)amino]-2-methyl-5-nitro-3-pyridinecarboxylic acid ethyl ester (0.1 Mol.), 12 g. of N-methylpiperazine (0.12 Mol.) and 15 g. of triethylamine (0.15 Mol.) are refluxed in 200 ml. of ethanol for three hours. After this time, the solvent is distilled off, the residue is dissolved in 100 ml. of water, made alkaline with potassium hydroxide and extracted three times with 100 ml. portions of ethyl acetate. The extract is dried with calcium chloride, the solvent distilled off and the residual 6-[ethyl(phenylmethyl)amino]-2methyl-4-(4-methyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid, ethyl ester is used without further purification, yield of crude product: 40 g. (90%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[C:8]([CH3:14])[C:7]=2[C:15]=1[O:16][CH3:17])#[N:2].[CH3:18][O:19][C:20](=[O:42])[C@@H:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>[Cl-].[Na+].O.CN(C=O)C>[CH3:18][O:19][C:20](=[O:42])[C@@H:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:11]([C:9]3[O:10][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[C:15]([O:16][CH3:17])[C:7]=4[C:8]=3[CH3:14])=[O:13])=[CH:39][CH:40]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23]
Reactant: COc1c(C#N)ccc2oc(C(=O)O)c(C)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(C#N)c(OC)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.2 %

Procedure:
To 110 mg (0.48 mmol) of 5-cyano-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 207 mg (1.2 eq) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester, BOP (252 mg, 1.2 eq), N,N-diisopropylethylamine (74 mg,1.2 eq) and 4 mL of DMF. The mixture was stirred at room temperature for 48 h. Brine was added and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2N HCl and water. Concentration of the organics in vacuo gave crude product, which was purified by column chromatography on silica gel to give 89 mg (32% yield) of (S)-2-{4′-[(5-cyano-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN=C=NCCCN(C)C.[CH2:24]([C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[N:30][CH:31]=1)[CH3:25].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH2:24]([C:26]1[C:27]([C:32]([NH:1][C:2]2[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=2)=[O:33])=[N:28][CH:29]=[N:30][CH:31]=1)[CH3:25]
Reactant: CCc1cncnc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)cnc1O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCc1cncnc1C(=O)Nc1cc(C(F)(F)F)cnc1O
Temperature: 80 °C
Reaction time: 10 h

Procedure:
To a mixture of 3-amino-5-trifluoromethylpyridin-2-ol (0.27 g), WSC (0.58 g), and pyridine (10 ml), 5-ethyl-pyrimidine-4-carboxylic acid was added under ice-cooling, and the reaction mixture was stirred at 80° C. for 10 hours. After standing to cool the reaction mixture to room temperature, to the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.26 g of 5-ethyl-N-(2-hydroxy-5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxamide.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]([C@@H:28]([CH2:46][C@H:47]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([O:60][CH2:61][CH2:62][CH2:63][O:64][CH3:65])[CH:53]=1)[CH:48]([CH3:50])[CH3:49])[C@@H:29]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:30][C@@H:31]([CH:35]([CH3:37])[CH3:36])[C:32](O)=[O:33])=[N+:26]=[N-:27].[NH2:66][CH2:67][CH2:68][N:69]1[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]1.CCN(CC)CC>CC#N.CCOC(C)=O>[N:69]1([CH2:68][CH2:67][NH:66][C:32](=[O:33])[C@H:31]([CH:35]([CH3:37])[CH3:36])[CH2:30][C@H:29]([O:38][Si:39]([C:42]([CH3:45])([CH3:43])[CH3:44])([CH3:40])[CH3:41])[C@@H:28]([N:25]=[N+:26]=[N-:27])[CH2:46][C@H:47]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([O:60][CH2:61][CH2:62][CH2:63][O:64][CH3:65])[CH:53]=2)[CH:48]([CH3:49])[CH3:50])[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](N=[N+]=[N-])[C@H](C[C@H](C(=O)O)C(C)C)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Reactant: NCCN1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C[C@@H](C[C@H](N=[N+]=[N-])[C@H](C[C@H](C(=O)NCCN2CCCCC2)C(C)C)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
HBTU (1.20 g, 3.0 mmol) was added to a solution of (2S,4S,5S,7S)-5-azido-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1.50 g, 2.5 mmol) in CH3CN (50 mL). Then 2-aminoethylpiperidine (324 mg, 2.5 mmol) and NEt3 (3.9 mL) were added and the resulting solution was stirred at RT for 2.5 hours. For workup, EtOAc was added and the organic phase was washed with 1 N HCl, saturated NaHCO3 solution and brine. Drying of the organic phase (Na2SO4) and evaporation of the solvent affords the crude product which is purified by flash column chromatography [CH2Cl2:MeOH (95:5)] to give the desired product as a colorless oil. MS (LC-MS): 705.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 6.82 minutes.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17](=[O:30])[NH:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:15]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:37].[Li+].[OH-]>COCCOC.O>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][NH:18][C:17]([C:16]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:38])=[O:2])=[C:7]([CH3:37])[CH:8]=2)=[N:13][O:14][C:15]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30]
Reactant: COC(=O)COc1ccc(-c2noc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2noc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (4-{4-[2-(2,4-dichloro-phenoxy)-ethyl-carbamoyl]-5-phenyl-isoxazol-3-yl}-2-methyl-phenoxy)-acetic acid methyl ester is dissolved in DME (1 mL). A solution of 1 M LiOH in H2O (0.2 mL) and is added and the mixture is stirred overnight at room temperature. The mixture is concentrated, then acidified with 1 M HCl, extracted with EtOAc (10 mL), dried over MgSO4, filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound I30 as a white solid: 1H-NMR (400 MHz, CD3CN) δ=7.56 (d, J=1.6, 1H), 7.49 (dd, J=8.4, 2.4 Hz, 1H), 7.45 (m, 5H), 7.39 (d, J=2.4 Hz, 1H), 7.27 (dd, J=8.8, 2.8 Hz, 1H), 7.20 (t, J=5.6 Hz, NH), 6.96 (d, J=8.8 Hz, 1H), 6.73 (d, J=8.8 Hz, 1H), 4.64 (s, 2H), 4.08 (t, J=5.2 Hz, 2H), 3.70 (q, J=5.3 Hz, 2H), 2.23 (s, 3H). MS calculated for C27H23Cl2N2O6 (M+H+) 541.0, found 541.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=2.[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31](O)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31]([O:1][CH2:2][CH2:3][C:4]4[NH:5][C:6]5[C:11]([CH:12]=4)=[CH:10][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=5)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][N:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)noc12
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3[nH]2)ccc2c(-c3ccccc3)noc12

Procedure:
Using the procedures in Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and 3-phenyl-7-propyl-6-hydroxybenz[4,5]isoxazole as a colorless gum.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:20])[CH2:4][CH:5]1[CH2:9][S:8][C:7]2=[C:10]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH:11]([CH3:13])[CH2:12][N:6]12.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3](=[O:20])[CH2:4][CH:5]1[CH2:9][S:8][C:7]2=[C:10]([C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[O:15])[C:11]([CH3:13])=[CH:12][N:6]12
Reactant: CNC(=O)CC1CSC2=C(C(=O)OC(C)C)C(C)CN21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)CC1CSc2c(C(=O)OC(C)C)c(C)cn21
Yield: 49.1 %

Procedure:
4.1 g of N-methyl-(7-isopropoxycarbonyl-6-methyl-2,3,5,6- tetrahydropyrrolo[2,1-b]-thiazol-3-yl)acetamide was dissolved in 150 ml of chloroform and 3.9 g of 2,3-dicyano-5,6-dichloro-parabenzoquinone was added thereto under ice-cooling and stirring. The mixture was stirred at room temperature for 1 hour. After removing the insoluble matters, the chloroform layer was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate and distilling off the solvent, the obtained residue was purified by silica gel column chromatography. Thus 2.0 g of the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:36]=[CH:35][C:13]3[N:14]([C:17]4[CH:18]=[C:19]([NH:31]C(=O)C)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])[CH:22]=4)[CH:15]=[N:16][C:12]=3[CH:11]=2)[CH:7]=[N:6]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:36]=[CH:35][C:13]3[N:14]([C:17]4[CH:18]=[C:19]([NH2:31])[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])[CH:22]=4)[CH:15]=[N:16][C:12]=3[CH:11]=2)[CH:7]=[N:6]1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(CCN(C)C)c4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-c3ccc(F)cc3F)c2)cn1
Temperature: 100 °C
Yield: 58 %

Procedure:
To a solution of the compound of Example 8 (1.5 g, 3.0 mmol) in ethanol (30 ml) was added aqueous solution of NaOH (1.5 g, 37.5 mmol, 12.5 eq.) and the mixture was heated at 100° C. for 4 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 58% yield (0.8 g).
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].[CH:9]1([NH:17][C:18]([NH2:20])=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([NH:17][C:18]2[S:19][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3](=[O:4])[N:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC(=S)NC1CCCCCCC1
Reactant: CC(C)C(Br)C(=O)O
Product: CC(C)C1SC(NC2CCCCCCC2)=NC1=O

Procedure:
Synthesis was performed from 2-bromo-3-methylbutyric acid and N-cyclooctylthiourea according to Method C1.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:10][CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:27][OH:28]>>[CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:10][CH:9]=2)=[N:27][OH:28])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Agent: Cl
Product: ON=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1

Procedure:
In analogy to the procedure of Example IV, the title compound is prepared from 20 g (60.3 mmol) of the compound from Example VIII and 6.3 g (90.7 mmol) of hydroxylamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])C.C(O)=O>O>[CH:27]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])=[O:29]
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: O
Solvent: c1ccccc1
Product: O=CNNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 1 h

Procedure:
To a suspension of 2.88 parts of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide with 100 parts by volume of dry benzene is added about 1 part offormic acetic anhydride, prepared from 10.2 parts of acetic anhydride and 4.6 parts of formic acid. The reaction mixture is stirred until no evidence of starting material is detected, at which time 100 parts of water is added with vigorous stirring. Stirring is continued for about 1 hour, at the end of which time the mixture is filtered and the resulting product is dried to afford 1-formyl-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine, melting at about 177°-181°.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C([Li:15])CCC>CCCCCC>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Li:15])[CH2:2][CH3:3]
Reactant: CCCc1ccc(I)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li]c1ccccc1CCC

Procedure:
Air in a dried four-necked flask was replaced with nitrogen, and 10 ml of n-hexane and 2.86 g (0.0116 mol) of p-n-propyliodobenzene were introduced. Then, 10 ml of a hexane solution of n-butyl lithium (0.0116 mol) was gradually added thereto under stirring to obtain a hexane solution of n-propylphenyl lithium.