Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:21]([OH:23])=[O:22])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:20]=[CH:19][C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]=2[N+:11]([O-:13])=[O:12])[CH:5]=1.[CH:31]1([CH2:37][C@H:38]([NH-:50])[C@@H:39]([OH:49])[CH2:40][CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.COCCOC.[ClH:57]>>[NH2:1][C@H:2]([C:21]([OH:23])=[O:22])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:20]=[CH:19][C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]=2[N+:11]([O-:13])=[O:12])[CH:5]=1.[ClH:57].[CH:31]1([CH2:37][C@H:38]([NH-:50])[C@@H:39]([OH:49])[CH2:40][CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)C(=O)O
Agent: Cl
Agent: [NH-][C@@H](CC1CCCCC1)[C@@H](O)CCCc1ccccn1
Solvent: COCCOC
Product: N[C@@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)C(=O)O

Procedure:
230 mg of Boc-His(DNP)-1(S)-cyclohexylmethyl-2(S)-hydroxy-5-(2-pyridyl)-pentylamide are stirred in 5 ml of saturated DME/HCl for 90 minutes and subsequently concentrated. 220 mg of the title compound are obtained as a resin.
Reaction SMILES: [I-].[K+].[SH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]2.Cl[C:17]1[S:18][C:19]([C:22]2([OH:30])[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)=[CH:20][N:21]=1>>[OH:30][C:22]1([C:19]2[S:18][C:17]([S:3][C:4]3[CH:5]=[C:6]4[C:11](=[CH:12][CH:13]=3)[N:10]([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]4)=[N:21][CH:20]=2)[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]1
Reactant: CC1(C)CC(O)(c2cnc(Cl)s2)CCO1
Reactant: CN1C(=O)CCc2cc(S)ccc21
Agent: [I-]
Agent: [K+]
Product: CN1C(=O)CCc2cc(Sc3ncc(C4(O)CCOC(C)(C)C4)s3)ccc21
Yield: 92 %

Procedure:
Using an analogous procedure to that described in Example 26 except that a catalytic amount (0.01 g) of potassium iodide was added to the reaction mixture, 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with 4-(2-chlorothiazol-5-yl)-4-hydroxy2,2-dimethyltetrahydropyran to give 4-hydroxy-2,2-dimethyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thiazol-5-yl]tetrahydropyran in 92% yield as a foam;
Reaction SMILES: [N:1]([CH:4]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]([O:7]CC)=[O:6])=[C:2]=[O:3].[CH3:15][N:16]([CH3:18])[NH2:17].C(Cl)Cl>C(O)(=O)C>[CH3:15][N:16]([CH3:18])[NH:17][C:2]([NH:1][CH:4]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]([OH:7])=[O:6])=[O:3]
Reactant: CN(C)N
Reactant: CCOC(=O)C(N=C=O)c1cccs1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)NC(=O)NC(C(=O)O)c1cccs1
Reaction time: 0.5 h

Procedure:
A solution of 4.2 g. (0.02 mole) of DL-α-isocyanato-2-thiopheneacetic acid, ethyl ester and 1.2 g. (0.02 mole) of N,N-dimethylhydrazine in 80 ml. of methylene chloride is stirred overnight. The solution is concentrated and to the syrupy residue are added 10 ml. of 2N sodium hydroxide solution. After stirring for 30 minutes, a clear yellow solution results. By the addition of acetic acid, 3.9 g. of α-dimethylhydrazinocarbonylamino-2-thiopheneacetic acid are obtained, m.p. 208°-210°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH3:16][C@@H:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:25](=[O:26])[NH:24][C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])=[CH:6][CH:7]=1
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)N[C@H](C)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol (0.120 g, 0.45 mmol) and (R)-(+)-α-methylbenzyl isocyanate (0.17 mL, 1.2 mmol) were combined in toluene and stirred overnight at 90° C. The mixture was diluted with CH2Cl2 and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15](O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.I.S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)CCC(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(-c2ccc(F)cc2)cc1

Procedure:
1.50 gm (0.005 mol) of the sodium salt of 4-(4'-fluoro-4-biphenylyl)-4-hydroxy-butyric acid were refluxed in 15 ml of glacial acetic acid and 25 ml of hydroiodic acid (d=2.00) for 10 hours, and then the reaction mixture was poured into a solution of 5 gm of sodium bisulfite in 400 ml of water. The colorless precipitate was collected and recrystallized from cyclohexane, yielding 4-(4'-fluoro-4-biphenylyl)-butyric acid, m.p. 119°-120° C. Melting point of the cyclohexylamine salt: 177° C. (precipitated from ethyl acetate). Yield: 1.3 gm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[CH:15][CH:16]=2)[N:11]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:33].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.C(Cl)Cl>[Cl:33][C:18]1[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[CH:15][CH:16]=2)[N:11]=[C:10]([C:3]2[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:19]=1
Reactant: COc1cccc(F)c1-c1nc2cc(C)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CN(C)c1ccccc1
Product: COc1cccc(F)c1-c1nc(Cl)c2ccc(C)cc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
Under an N2 atmosphere, 2-(2-fluoro-6-methoxyphenyl)-7-methylquinazolin-4(3H)-one (20 g, 70.35 mmol) was suspended in benzene (300 mL), followed by the addition of N,N-dimethylaniline (26.8 mL, 211.05 mmol), then POCl3 (13.11 mL, 140.7 mmol). The reaction was heated at reflux, and completion of product formation was observed after 1.5 h. After cooling to room temperature, the mixture was slowly poured over 1 liter of ice. The solution was then diluted with CH2Cl2, and the pH was adjusted to 7 using a saturated aqueous NaHCO3 solution. The layers were partitioned, separated and extracted with CH2Cl2. All organic layers were combined, dried over Na2SO4, filtered, and concentrated to a dark oil. The crude material was purified by silica gel chromatography using 75% CH2Cl2/25% hexanes to obtain 4-chloro-2-(2-fluoro-6-methoxyphenyl)-7-methylquinazoline as a yellow solid (18.82 g, 88%). LC/MS: m/z 302.9 (M+H)+ at 3.28 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J=8.6, 1.5 Hz, 1H), 7.42-7.40 (m, 1H), 6.86-6.84 (m, 2H), 3.81 (s, 3H), 2.64 (s, 3H) ppm.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=2)=[N:6]1)[CH3:4].[C:20]([C:23]1[O:27][N:26]=[C:25]([C:28](O)=[O:29])[CH:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:20]([C:23]1[O:27][N:26]=[C:25]([C:28]([NH:1][CH2:2][C@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:29])[CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)no1
Reactant: C[C@H](CN)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3cc(F)c(C#N)c(F)c3)n2)no1

Procedure:
The title compound was synthesized from (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.955 g, 3.64 mmol), 5-acetylisoxazole-3-carboxylic acid (0.565 g, 3.64 mmol), HOBt (0.738 g, 5.46 mmol), DIPEA (1.9 mL, 10.92 mmol) and EDCI (1.05 g, 5.46 mmol) using DMF (10 mL) as solvent using the method of Example 34(d). The product was purified with CombiFlash to afford 60 mg of pure product. 1H NMR (400 MHz; CDCl3): δ 1.63 (d, 3H), 2.64 (s, 3H), 3.82 (m, 1H), 3.95 (m, 1H), 4.64 (m, 1H), 6.61 (d, 1H), 7.29 (s, 1H), 7.52 (m, 3H), 7.62 (m, 1H).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)C[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1.N[CH2:48]C1(N(CC2C=CC=CC=2)CC2C=CC=CC=2)COC1>>[NH2:8][C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][C:36]([CH3:48])=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:10][O:11][CH2:12]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Product: Cc1ccc2c(c1)S(=O)(=O)CCN(c1cc(NCC3(N)COC3)c3ccccc3n1)C2

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloroquinolin-2-yl)-8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloroquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 7.91 (d, J=8.34 Hz, 1 H), 7.84 (d, J=7.58 Hz, 1 H), 7.72-7.60 (m, 1 H), 7.49-7.35 (m, 3 H), 7.09 (ddd, J=8.21, 5.18, 3.03 Hz, 1 H), 6.52 (t, J=5.43 Hz, 1 H), 6.22 (s, 1 H), 5.06 (brs, 2 H), 4.45 (d, J=6.06 Hz, 3 H), 4.38 (d, J=6.06 Hz, 3 H), 3.61 (t, J=4.80 Hz, 2 H), 3.56 (d, J=5.31 Hz, 2 H), 2.31 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([F:10])=[C:4]([Cl:11])[N:3]=1.P(Br)(Br)[Br:13].C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:13][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:11])=[C:5]([F:10])[CH:6]=1
Reactant: OCc1cc(F)c(Cl)nc1Cl
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Fc1cc(CBr)c(Cl)nc1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To a stirred mixture of alcohol 1A (3.52 g, 17.9 mmol) in CHCl3 (100 mL) under argon was added 1M PBr3 in CH2Cl2 (18.0 mL, 18.0 mmol). The reaction mixture was heated to reflux for 15 minutes, cooled to room temperature, then poured into a mixture of ice and saturated NaHCO3 solution (200 mL). The pH was adjusted to basic by addition of solid NaHCO3. The aqueous layer was extracted with EtOAc. The combined EtOAc extracts were washed with brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 1B (4.11 g, 88%). HPLC Rt=2.78 min. (Column: YMC ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.[CH:28]12[CH2:35][CH2:34][CH:31]([CH:32]=[CH:33]1)[CH2:30][CH:29]2[S:36]([CH2:39][C:40]1[C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:50][CH3:51])[C:43](Br)=[CH:42][CH:41]=1)(=[O:38])=[O:37]>>[CH:28]12[CH2:35][CH2:34][CH:31]([CH:32]=[CH:33]1)[CH2:30][CH:29]2[S:36]([CH2:39][C:40]1[C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:50][CH3:51])[C:43]([C:23]2[CH:27]=[CH:26][O:25][CH:24]=2)=[CH:42][CH:41]=1)(=[O:38])=[O:37]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)C2CC3C=CC2CC3)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)C2CC3C=CC2CC3)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 6-(bicyclo[2.2.2]oct-5-ene-2-ylsulphonylmethyl)-3-bromo-2-methoxybenzoate.
Reaction SMILES: FC1C(O[C:9](=[O:20])[NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([CH2:18][CH3:19])[CH:12]=2)=C(F)C(F)=C(F)C=1F.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([N:34]([CH2:45][CH2:46][CH3:47])[S:35]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:30][CH2:29]1>>[CH2:18]([C:13]1[CH:12]=[C:11]([NH:10][C:9](=[O:20])[NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([N:34]([CH2:45][CH2:46][CH3:47])[S:35]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)(=[O:36])=[O:37])[CH2:30][CH2:29]2)[CH:16]=[C:15]([CH3:17])[N:14]=1)[CH3:19]
Reactant: CCc1cc(NC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc(C)n1
Reactant: CCCN(C1CCN(CCN)CC1)S(=O)(=O)c1ccc(F)cc1
Product: CCCN(C1CCN(CCNC(=O)Nc2cc(C)nc(CC)c2)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (2-ethyl-6-methyl-pyridin-4-yl)-carbamic acid pentafluorophenyl ester (Example C13., 0.2M, 3 mL, 0.6 mmol) is added a solution of N-[1-(2-amino-ethyl)-piperidin-4-yl]-4-fluoro-N-propyl-benzenesulfonamide (Example B6., 182 mg, 0.53 mmol). The mixture is stirred at r.t. for 15 h. The mixture is evaporated and the residue purified by HPLC to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][C@H:25]2[CH2:30][CH2:29][CH2:28][O:27][CH2:26]2)[CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][C:19]=3[O:24][C@H:25]3[CH2:30][CH2:29][CH2:28][O:27][CH2:26]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: Nc1ccc(F)cc1O[C@H]1CCCOC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCOC3)c2c1C

Procedure:
Prepared analogously to example 1.1 from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (S)-4-fluoro-2-(tetrahydro-2H-pyran-3yloxy)aniline (Intermediate XIII).
Reaction SMILES: [CH3:1][O:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=1[Cl:15].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl.O>[CH3:1][O:2][N:3]([CH2:4][CH2:5][CH2:6][C:7]1[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=1[Cl:13])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONCCCc1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(CCCc1c(Cl)cc(Cl)cc1Cl)C(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a stirred solution of O-methyl-N-[3-(2,4,6-trichloro-phenyl)-propyl]-hydroxylamine (0.35 g, 1.3 mmol) prepared as described in example P24c in dichloromethane (5 ml), triethylamine (0.55 ml, 3.9 mmol) and a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride acid in dichloromethane (2 ml) was added slowly at a temperature of 0° C. After complete addition of the acid chloride the mixture was stirred at ambient temperature for the next 3 hours. When the TLC confirmed the completion of the reaction, the reaction mass was diluted with water and extracted with dichloromethane (3×60 ml). The combined dichloromethane layer was washed with 2N HCl followed by saturated NaHCO3 solution, water and finally brine. The organic layer was then dried over anhydrous sodium sulphate and concentrated under reduced pressure. The resulting crude mass was purified over column chromatography (silica gel 60-120 mesh, 26% ethylacetate in hexane) to afford 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[3-(2,4,6-trichloro-phenyl)-propyl]-amide (0.5 g, 91%) as white crystalline solid. m.p-95-96° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:6][CH:7]=1.O.NN.[OH-].[K+].N#N.Cl>C(O)COCCO.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CCC(=O)CCCCCC(=O)O)c1
Agent: Cl
Agent: N#N
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: Cc1cccc(CCCCCCCCC(=O)O)c1
Temperature: 70 °C
Yield: 61 %

Procedure:
To a stirred solution of 66 gm 9(3-methylphenyl)-7-ketononanoic acid in 35 ml diethylene glycol was added 4.3 ml hydrazine hydrate. The reaction mixture was heated at 120° for 5 hrs, cooled to 70° C., connected to a water aspirator, and re-heated to 120°-30° for 31/2 hrs. The mixture was then cooled to 70°, 6.5 g KOH was added, and the reaction mixture was heated to 160°-200° (temperature varied with N2 evolution) for 11 hr, then cooled to room temperature. The solidified reaction mass was dissolved in 150 ml hot water, acidified with conc. HCl, three times extracted with CHCl3 and the organic phases were combined. They were washed three times with water, once with saturated NaCl solution, dried over MgSO4, filtered, treated with charcoal, filtered through diatomaceous earth, and the solvent was removed in vacuo to give a brown oil which was vacuum distilled. Yield 61%. The main fraction boiled at 170°-80° at 0.1 mm and later solidified to a product of m.p. 39°-40°. Elemental analysis: calculated C 77.37, H 9.74. Found: C 77.25, H 9.98.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=O)[CH2:15][CH3:16])[C:9](=[O:18])[CH2:8]2)=[CH:5][C:4]([CH3:19])=[N:3]1.[Cl:20]/[CH:21]=[CH:22]/[CH2:23][O:24][NH2:25]>CO>[Cl:20][CH:21]=[CH:22][CH2:23][O:24]/[N:25]=[C:14](/[CH:10]1[C:11](=[O:13])[CH2:12][CH:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:19])[CH:5]=2)[CH2:8][C:9]1=[O:18])\[CH2:15][CH3:16]
Reactant: CCC(=O)C1C(=O)CC(c2cc(C)nn2C)CC1=O
Reactant: NOC/C=C/Cl
Solvent: CO
Product: CC/C(=N\OCC=CCl)C1C(=O)CC(c2cc(C)nn2C)CC1=O

Procedure:
To 10 ml of a solution of 5.60 g (21.3 mmols) of 5-(1,3-dimethyl-1H-pyrazol-5-yl)-2-propionylcyclohexane-1,3-dione in methanol was added 57 ml (21.7 mmols) of 0.38 mol ethanolic solution of (E)-3-chloro-2-propenyloxyamine. The mixture was reacted for 10 hours with stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 6.84 g of the product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1.[ClH:22].[NH2:23][CH:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[ClH:22].[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:23][CH:24]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25]4)=[CH:7][CH:8]=3)=[N:13][O:14][C:15]=2[CH:20]=1
Reactant: Fc1ccc2c(-c3ccc(OCCCBr)cc3)noc2c1
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCCNC4Cc5ccccc5C4)cc3)noc2c1

Procedure:
The title compound is prepared from a mixture of 3-[4-(3-bromo-propoxy)-phenyl]-6-fluoro-benzo[d]isoxazole, 2-aminoindan hydrochloride, potassium carbonate, potassium iodide and 4% aqueous acetonitrile essentially as described above in Example 13 except that 3.2 equivalents of potassium carbonate is used. Purity by LC/MS=93%, [M+H]+=403.
Reaction SMILES: [NH:1]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)[C:2]([NH2:4])=[S:3].Br[CH2:17][C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)=O>C1COCC1.C(OCC)C>[CH2:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([NH:1][C:2]2[S:3][CH:17]=[C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[N:4]=2)[CH2:6][CH2:7]1)=[O:12])[CH3:15]
Reactant: CCOC(=O)N1CCC(NC(N)=S)CC1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2nc(-c3ccc(C(=O)O)cc3)cs2)CC1
Temperature: 25 °C
Yield: 70161.2 %

Procedure:
A solution of ethyl 4-thioureidopiperidine-1-carboxylate (3.8 g, 0.0164 mol.) and 4-(2-bromoacetyl)benzoic acid (4 g, 0.0164 mmol) in THF (100 mL) was heated at 70° C. for 2 hours, cooled to room temperature and then diluted with diethyl ether. A resulting solid was collected by filtration and washed with diethyl ether to provide 4-[2-(1-ethoxycarbonylpiperidin-4-ylamino)thiazol-4-yl]benzoic acid (4.32 g, 70% yield) as an off white solid. HNMR (dmso-d6): 7.93 (4H, m), 7.27 (1H, s), 4.05 (2H, q), 3.82 (3H, m), 3.04 (2H, m), 2.02 (2H, m), 1.41 (2H, m), 1.18 (3H, t). LC/MS: M+1: 376.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH3:12])[O:5][N:4]=1)[CH3:2].C([Li])CCC.CCCCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH2:12][CH:24]([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(C)c1C(=O)NC
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1noc(CC(O)c2ccccc2)c1C(=O)NC
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 58.5 g. (0.348 mole) of 3-ethyl-N,5-dimethyl-isoxazole-4-carboxamide and 1 liter of tetrahydrofuran is cooled to -65° C. and 478 ml. of 1.6 M n-butyllithium in hexane (0.765 mole) is added dropwise maintaining the temperature between -60° and -70° C. After the addition is complete, the suspension is stirred for 11/2 hours at -60° to -70° C., and then 37.2 g. (0.350 mole) of benzaldehyde in 375 ml. tetrahydrofuran is added dropwise maintaining the temperature between -60° and -70° C. After addition is complete, the mixture is stirred for 11/2 hours at -60° to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with ether and filtered to give 3-ethyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide, m.p. 135° to 137° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:36])[C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[N:22]=2)[NH:17][CH:16]=1)=[O:14])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:36][C:9]1([C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCN4C(=O)OC(C)(C)C)c3n2)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCN4)c3n2)cc(OC)c1OC
Reaction time: 48 h
Yield: 63.1 %

Procedure:
To a solution of 2-methyl-2-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (18 mg, 0.04 mmol) in anhydrous dichloromethane (3.0 ml) was added trifluoroacetic acid (1.0 ml, 13.5 mmol) dropwise. The reaction mixture was stirred for two days. The reaction mixture was partitioned between EtOAc/saturated aqueous Na2CO3. The organic layers were collected, dried over MgSO4, filtered, and concentrated. The residue was purified by preparative thin layer chromatography using 0.5:9.5:90 concentrated aqueous NH4OH: MeOH: dichloromethane as eluant to provide 10 mg (70%) of (2-methyl-pyrrolidin-2-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as a light yellow solid. M+H=397.