Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:9][C:10]([C:12]1[S:42][C:15]2[N:16](C(OC(C)(C)C)=O)[N:17]=[C:18]([NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][CH:22]=3)[C:14]=2[CH:13]=1)=[O:11]>CO>[CH3:7][N:8]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:9][C:10]([C:12]1[S:42][C:15]2[NH:16][N:17]=[C:18]([NH:19][C:20](=[O:34])[C:21]3[CH:22]=[CH:23][C:24]([CH2:27][N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[CH:25][CH:26]=3)[C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCOCC4)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCOCC4)cc3)n[nH]c2s1)c1ccccc1
Yield: 52.9 %

Procedure:
21 mg (154 μmol) of potassium carbonate are added to a solution of 0.09 g (154 μmol) of tert-butyl 5-(N′-methyl-N′-phenylhydrazinocarbonyl)-3-(4-morpholin-4-ylmethylbenzoylamino)thieno[2,3-c]pyrazole-1-carboxylate in 5 mL of methanol in a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 180° C. for 3 minutes. The reaction mixture is then concentrated to dryness under vacuum (0.6 kPa) at a temperature in the region of 30° C. The residue is purified by chromatography on a cartridge of 25 g of silica gel (0.015-0.040 mm), eluting with a dichloromethane/methanol mixture (99/1 by volume, then 98/2 and finally 97/3) at a flow rate of 10 mL/min. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (1.0 kPa) at a temperature in the region of 30° C. The residue is taken up in 10 mL of diisopropyl ether, triturated and then reconcentrated to dryness. The solid obtained is dried in an oven under vacuum (0.01 kPa) at a temperature in the region of 60° C. 40 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-morpholin-4-ylmethylbenzamide are thus obtained in the form of an off-white solid melting at 242° C. MS-EI: 490(+)=M(+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)O)=[C:8]([CH2:21][OH:22])[CH:7]=1)=[O:5])[CH3:2].O.CCOC(C)=O>OP(O)(O)=O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH:12]2[C:9]3[C:8](=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[CH2:21][O:22]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccc(C(O)c2ccc(F)cc2)c(CO)c1
Agent: O=P(O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 80 °C

Procedure:
Crude (4-ethoxycarbonyl-2-hydroxymethylphenyl)(4-fluorophenyl)methanol (30 g) is dissolved in H3PO4 (60%, 250 ml) and the solution is heated to 80° C. for 1.5 hours. Water (300 ml) and EtOAc (100 ml) is added and the phases are separated. The aqueous phase is further extracted with EtOAc (100 ml). The organic phases are joined and the solvents are removed in vacuo. The yield of the remaining somewhat impure oil is 30 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[N:10]([CH3:16])[CH2:9]2)=[CH:4][C:3]=1[C:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.[C:24]([C:26]1[N:27]=[C:28]([C:39](O)=[O:40])[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=1)#[N:25].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N>>[C:17]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][N:10]([CH3:16])[C:11](=[O:15])[N:12]([CH3:14])[CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:39]([C:28]2[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=[C:26]([C:24]#[N:25])[N:27]=2)=[O:40])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: CN1CC(c2ccc(N)c(C3=CCCCCC3)c2)CN(C)C1=O
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: CN1CC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCCC3)c2)CN(C)C1=O
Yield: 96 %

Procedure:
5-(4-Amino-3-cyclohept-1-enyl-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one (as prepared in the previous step, 47.5 mg, 0.151 mmol) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d), 27.2 mg, 0.0890 mmol) as described in Example 1, step (1) to obtain the title compound (82 mg, 96%) after purification on silica (20-100% EtOAc-hexane): Mass spectrum (ESI, m/z): Calcd. for C30H42N6O3Si, 563.3 (M+H). found 563.1.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:25]3[C:20](=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][CH:24]=3)[N:19]([CH:30]([CH3:32])[CH3:31])[N:18]=2)=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C.C1CCCCC=1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([C:17]2[C:25]3[C:20](=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][CH:24]=3)[N:19]([CH:30]([CH3:32])[CH3:31])[N:18]=2)=[O:16])=[CH:13][CH:14]=1
Reactant: CC(C)n1nc(C(=O)c2ccc(OCc3ccccc3)cc2)c2cccc(C(F)(F)F)c21
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(C)n1nc(C(=O)c2ccc(O)cc2)c2cccc(C(F)(F)F)c21
Temperature: 70 °C
Yield: 98.2 %

Procedure:
A mixture of [4-(benzyloxy)phenyl][1-isopropyl-7-(trifluoromethyl)-1H-indazol-3-yl]methanone (0.17 g, 0.38 mmol) and 10% palladium on carbon (0.10 g) in 10 mL ethanol/cyclohexene (3:1, v/v) was heated at 70° C. for 0.5 hours. The catalyst was filtered (celite) and the filtrate concentrated in vacuo to give crude product. The residue was crystallized from Et2O/hexane to give 0.130 g of product as a white solid
Reaction SMILES: C(OC(=O)[NH:7][N:8]1[CH2:11][CH:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9]1)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[C:16]([Si:13]([CH3:15])([CH3:14])[O:12][CH:10]1[CH2:9][N:8]([NH2:7])[CH2:11]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NN1CC(O[Si](C)(C)C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OC1CN(N)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[3-(t-Butyl-dimethyl-silanyloxy)-azetidin-1-yl]-carbamic acid t-butyl ester (100 mg, 331 mmol) was at 0° C. combined with trifluoroacetic acid (2 mL) to give a colorless solution. The reaction mixture was stirred for 2 h at 0° C. and subsequently concentrated in vacuo to give the title compound as colorless oil, which was used without further purification in the next step.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C@@H:11]([CH3:29])[CH2:10]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:8]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:28])[C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C@@H:11]([CH3:29])[CH2:10]2)[C:6](=[O:7])[CH2:5][OH:4])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)COC(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CO)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
2-{(4-Chlorophenyl)[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-oxoethyl acetate (496 mg, 0.98 mmol, 1 eq.) was dissolved in methanol (12 ml). A solution of potassium carbonate (1.08 g, 7.84 mmol, 8 eq.) in water (5 ml) was added and reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated and the residue dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride/methanol: 98/2) to afford N-(4-chlorophenyl)-2-hydroxy-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (380 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1)[CH2:34][CH2:35][CH3:36]>ClCCl>[CH2:33]([O:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:46])=[CH:40][CH:39]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCOc1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of 1-butoxy-4-isocyanato-benzene (49.0 mg, 0.26 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol 3-yl]-piperidine-1-carboxylic acid (4-butoxy-phenyl)-amide as a white solid. (Yield 0.05 g, 41.7%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].C[N:31]1C(=O)CCC1>>[CH:1]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[C:26]([NH2:31])=[N:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3nccnc3Cl)c3ccc(C#N)cc23)C1
Reactant: CN1CCCC1=O
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3nccnc3N)c3ccc(C#N)cc23)C1
Temperature: 0 °C
Yield: 18 %

Procedure:
Dissolve (S)-[4-(3-chloro-pyrazin-2-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester (8.89 g, 21.7 mmol) in NMP (36 mL) and distribute the mixture evenly between three 10-20 mL microwave reactor vials. Cool each reaction vessel to 0° C. and sparge with anhydrous NH3 for 15 min. Seal each vessel and heat to 200° C. for 1 h in a microwave reactor. Combine the reaction mixtures together in water (500 mL) and sonicate for 20 min. Filter off a tan solid, then dissolve the solid in EtOAc (500 mL). Dry the organics (MgSO4), filter, and concentrate to a volume of 10 mL. Dilute the organics with MeOH (20 mL) and CH2Cl2 (10 mL) and absorb onto silica gel in vacuo. Purify on silica gel (340 g) using 1-10% (2 M NH3/MeOH)/(1:1 CH2Cl2/hexanes) to afford 1.50 g (18%) of the title compound as a yellow solid. MS (m/z) 391 (M+1), 389 (M−1). Pool and concentrate fractions containing impure product (1.2 g), and re-purify on silica gel (80 g) using 3-8% (2 M NH3/MeOH)/(1:1 CH2Cl2/hexanes) to afford a second crop (503 mg, 6%) of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.C[C:25]1[C:30]([NH:31]S(C)(=O)=O)=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:2]5[CH:11]=[CH:29][C:28]([C:27]6[NH:31][CH:30]=[CH:25][N:26]=6)=[CH:4][CH:3]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(-c5ncc[nH]5)cc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide (Stage 77.1.1) to give the title compound as a white solid. (HPLC: tR 2.15 min (Method A); M+H=436 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 12.58 (s, br, 1H), 8.96 (s, 1H), 8.20-8.15 (m, 1H), 8.14-8.07 (m, 1H), 8.05-7.94 (m, 3H), 7.63-7.53 (m, 3H), 7.31-7.07 (m, br, 2H), 3.95 (s, 3H), 3.57 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [C:1]1(O)[C:5](=[O:6])[C:3](=O)[C:2]=1[OH:7].[OH:9][CH2:10][CH2:11][NH:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1>CC(C)=O>[OH:9][CH2:10][CH2:11][N:12]([C+:1]1[C:2]([O-:7])=[C:3]([N:12]([CH:13]2[CH2:14][C:15]([CH3:22])([CH3:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH2:18]2)[CH2:11][CH2:10][OH:9])[C+:5]1[O-:6])[CH:13]1[CH2:14][C:15]([CH3:22])([CH3:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH2:18]1
Reactant: O=c1c(O)c(O)c1=O
Reactant: CC1(C)CC(NCCO)CC(C)(C)N1
Solvent: CC(C)=O
Product: CC1(C)CC(N(CCO)c2c([O-])[c+](N(CCO)C3CC(C)(C)NC(C)(C)C3)[c+]2[O-])CC(C)(C)N1
Yield: 66.8 %

Procedure:
5.7 g of quadratic acid (0.05 mole) and 50.1 g of 97.7% strength 4-(2-hydroxyethyl)amino-2,2,6,6-tetramethylpiperidine (0.244 mole) were heated for five hours to 200° C. After cooling, the reaction product was boiled with 150 cc of acetone and, after another cooling step, vacuum-filtered and washed with acetone, thus obtaining 16.0 g. Yield: 66.8% of theory, mp 309°-311° C. Extinction (g/l.cm) at 336 nm: 97.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[CH2:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19][CH2:20][C:21]#[CH:22]>CCCCCCC.CCOC(C)=O>[C:23]1([CH2:18][CH2:19][CH2:20][C:21]#[C:22][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Reactant: C#CCCCc1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C(#Cc1cccnc1)CCCc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid pyridin-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (80 mg, 72%); 1H NMR δ (CDCl3): 8.62-8.63 (m, 1H), 8.48-8.46 (m, 1H), 7.68-7.64 (m, 1H), 7.21-7.17 (m, 6H), 2.76 (t, J=7.11 Hz, 2H), 2.4 (t, J=7.10 Hz, 2H), 1.91 (p, J=7.12 Hz, 2H); LCMS m/z: 221.
Reaction SMILES: ClS(C1C=C(C=CC=1F)C(O)=O)(=O)=O.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1.[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([S:32](NCC)(=[O:34])=[O:33])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([S:32]([NH:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:34])=[O:33])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: NC1CCCC1
Reactant: CCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Agent: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Product: O=C(O)c1cc(S(=O)(=O)NC2CCCC2)c(F)cc1Cl

Procedure:
1.01 g (3.7 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 1.08 mL (10.9 mmol) cyclopentylamine following the general procedure in for 2-chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid. Crude product was used in subsequent step without further purification
Reaction SMILES: O=C1O[C:5]([CH2:11][CH2:12][C:13]([O:15]C(C)(C)C)=O)([C:7]([F:10])([F:9])[F:8])[N:4]=C1C(C)C.Cl.[NH2:24]N.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[F:8][C:7]([F:10])([F:9])[C:5]1[CH2:11][CH2:12][C:13](=[O:15])[NH:24][N:4]=1
Reactant: NN
Reactant: CC(C)C1=NC(CCC(=O)OC(C)(C)C)(C(F)(F)F)OC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(C(F)(F)F)=NN1

Procedure:
8.44 g (26.1 mmol) of tert-butyl 3-[5-oxo-4-(propan-2-yl)-2-(trifluoromethyl)-2,5-dihydro-1,3-oxazol-2-yl]propanoate [CAS Reg. No. 87341-14-8] and 13.44 g (130.5 mmol) of hydrazine hydrochloride were stirred in 100 ml of glacial acetic acid at 118° C. for 2 hours. The reaction solution was then evaporated to dryness under reduced pressure. The residue obtained was taken up in 100 ml of water and made basic using potassium carbonate. The basic solution was subsequently extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified chromatographically on silica gel (mobile phase dichloromethane/methanol 50:1→10:1). This gave 2.65 g (15.95 mmol, 61% of theory) of the title compound.
Reaction SMILES: [Cl-].[NH2:2][NH2:3].C(O[CH:7]=[CH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])C>CCO>[F:11][C:10]([F:13])([F:12])[C:9]1[CH:8]=[CH:7][NH:3][N:2]=1
Reactant: NN
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: [Cl-]
Solvent: CCO
Product: FC(F)(F)c1cc[nH]n1
Yield: 86 %

Procedure:
To a stirred solution of hydrazine monochloride (6.62 g, 1.6 eq.) in EtOH (300 mL) was added dropwise compound 231 (10.16 g, 1 eq.) in EtOH (200 mL). The reaction mixture was refluxed for 6 hrs and evaporated to dryness. Water and EtOAc were added to the residue. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 233a as a brown solid in 86% yield. 1H NMR (CDCl3, 376 MHz) δ (ppm) 6.66 (d, J=2.30 Hz, 1H), 7.72 (d, J=2.30 Hz, 1H); 19F NMR (CDCl3, MHz) δ (ppm) 61.41 (s, 3F).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](O)(=O)[CH:11]([CH3:13])[OH:12].C(Cl)Cl>C1(C)C(C)=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:10]([CH:11]([OH:12])[CH3:13])[O:9][C:3]=2[CH:4]=1
Reactant: CC(O)C(=O)O
Reactant: Nc1ccc(F)cc1O
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CC(O)c1nc2ccc(F)cc2o1
Yield: 61.2 %

Procedure:
A suspension of 2-amino-5-fluorophenol (5.50 g, 43.3 mmol) and 85-92% lactic acid (6 g) in xylene was refluxed overnight while removing off water by-produced as a result of the reaction. After replacing the solvent with methylene chloride, the resultant mixture was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, dried over magnesium sulfate, and then concentrated. The resulting residue was subjected to recrystallization from a mixture of diisopropyl ether and hexane to afford 6-fluoro-2-(1-hydroxyethyl)benzoxazole (4.80 g, yield: 61%).
Reaction SMILES: C([NH:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(OC(C)(C)C)=O.C(Cl)Cl>CN(C)C=O>[NH2:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 0.17 h

Procedure:
While maintaining the nitrogen gas atmosphere, 3 fold molar excess of Boc-L-Tryptophan (Peninsula, supra.) dissolved in dimethylformamide and adjusted to 15 ml. with the addition of methylene chloride is added to the product of Step (F) above and the resulting mixture shaken. After about 10 minutes, 3 fold molar excess of N,N-dicyclohexylcarbodiimide is added and the resulting mixture is shaken for 4.5 to 5 hours at room temperature. At the end of this period, the reaction mixture is filtered and the residue washed with dimethylformamide. The washed residue is dried.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][O:4][C:5]([N:7]1[CH2:13][C@H:12]([NH:14]C(OC(C)(C)C)=O)[C:11](=[O:22])[NH:10][C:9]2[CH:23]=[CH:24][CH:25]=[CH:26][C:8]1=2)=[O:6].[ClH:29]>O1CCOCC1>[ClH:29].[F:28][C:2]([F:1])([F:27])[CH2:3][O:4][C:5]([N:7]1[CH2:13][C@H:12]([NH2:14])[C:11](=[O:22])[NH:10][C:9]2[CH:23]=[CH:24][CH:25]=[CH:26][C:8]1=2)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCC(F)(F)F)c2ccccc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CN(C(=O)OCC(F)(F)F)c2ccccc2NC1=O

Procedure:
In an analogous manner to that described in Example 1d), the treatment of the (S)-3-tert-butoxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-carboxylic acid 2,2,2-trifluoro-ethyl ester with hydrochlorid acid (37%) in dioxane yielded (98% of theory) the title compound as an off-white solid; MS (m/e): 304 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2](CC(O)=O)[OH:3].[C:10]([O-:13])(=[O:12])[CH3:11].[Na+:14]>C(O)(=O)C>[C:10]([OH:13])(=[O:12])[CH2:11][O:3][CH2:2][C:1]([O-:9])=[O:8].[Na+:14]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C([O-])COCC(=O)O

Procedure:
In reaction ii, sodium bisulfate is reacted with sodium acetate to produce sodium sulfate and solid acetic acid. In reaction iii., malic acid is reacted with sodium acetate to produce sodium hydrogen diglycolate and solid acetic acid. In reaction iv., fumaric acid is reacted with sodium acetate to produce sodium hydrogen fumarate and solid acetic acid. In reaction v., tartaric acid is reacted with sodium acetate to produce sodium hydrogen tartrate and solid acetic acid. In reaction vi., adipic acid is reacted with sodium acetate to produce sodium hydrogen adipate and solid acetic acid. In reaction vii, sulfamic acid is reacted with sodium acetate to produce sulpher sodium nitrate and solid acetic acid.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:17][CH2:18][S:19][C:3]1=2>Cl>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:17][CH2:18][S:19][C:3]1=2
Reactant: CCOC(=O)c1ccc2nc3c(c(=O)n2c1)SCC3
Agent: Cl
Product: O=C(O)c1ccc2nc3c(c(=O)n2c1)SCC3

Procedure:
A suspension of ethyl 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylate (5.0 g, 0.018 mol) in 2 N hydrochloric acid (60 ml) is refluxed for 3 hours. The reaction mixture is cooled in an ice-bath. The precipitate is filtered, washed with water, with acetone and dried to give the product (3.5 g.), mp 325° C. (dec).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1([C:15](OCC)=[O:16])[CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:15][OH:16])[CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(CCOCc2ccccc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1(CCOCc2ccccc2)CCC1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 2.0 g (7.63 mmol) of ethyl 1-[2-(benzyloxy)ethyl]cyclobutanecarboxylate in 20 mL of diethyl ether at 0° C. was added a 1.0 M solution of 15.9 mL (15.9 mmol) of lithium aluminum hydride in tetrahydrofuran and the contents stirred for 2 h. The reaction was quenched with 20 ml of 20% sodium hydroxide solution. After filtration, the organic phase was isolated, dried with magnesium sulfate, and concentrated under vacuum to afford 1.6 g (95%) of {1-[2-(benzyloxy)ethyl]cyclobutyl}methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.41-7.30 (m, 5H), 4.54 (s, 2H), 3.55 (t, J=6 Hz, 2H), 2.03-1.83 (m, 8H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc3c(C(F)(F)F)cccc23)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: FC(F)(F)c1cccc2c(C3CCNCC3)noc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 4-(7-trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (8.00 g, 21.6 mmol), HCl (100 mL of a 1 M ether solution, 100 mmol), and methanol (50 mL) was stirred at room temperature under nitrogen overnight. The reaction was concentrated and the solid triturated with methanol/ether to afford 5.84 g (88%) of the desired product as a white powder, mp: 242-243° C.