Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:36]=[CH:37][C:38]=1[OH:39])[O:7][CH2:8][CH2:9][N:10](CC1C=CC=CC=1)[CH2:11][CH:12]([OH:28])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[CH:17][CH:16]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([CH:36]=[CH:37][C:38]=1[OH:39])[O:7][CH2:8][CH2:9][NH:10][CH2:11][CH:12]([OH:28])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[CH:17][CH:16]=1)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(CCOCC3CC3)cc2)ccc1O
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(OCCNCC(O)COc2ccc(CCOCC3CC3)cc2)ccc1O

Procedure:
A solution of 30 g of crude 1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-benzylamino]-3-[4-[2-(cyclopropylmethoxy)ethyl]-phenoxy]-2-propanol in 600 ml of methanol is hydrogenated, with the addition of 4 g of a Pd/C catalyst (5%), under normal conditions until 1 mol-equivalent of hydrogen has been absorbed. By the addition of dioxane and by heating, the product which has already crystallied out is taken into solution; the catalyst is filtered off and the filtrate is concentrated by evaporation. Recrystallisation from isopropanol and then from methanol yields pure 1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-3-[4-[2-(cyclopropylmethoxy)-ethyl]-phenoxy]-2-propanol, m.p. 149°-150°.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:36])([F:38])[F:37])[C:27]=3[Cl:26])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Product: FC(F)(F)c1cccc(CNc2cccc(-c3c(Cc4ccccc4)nnc4c(Cl)cccc34)c2)c1Cl

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and 2-chloro-3-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ESI) m/z 538.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1
Reactant: O=Cc1ccc(F)cc1
Product: O=S(=O)(/C=C/c1ccc(F)cc1)Cc1ccc(Cl)cc1
Yield: 72 %

Procedure:
A solution of 4-chlorobenzyl sulfonylacetic acid (0.01 mol) and 4-fluorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 72% yield.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[N:27]=1.[OH-].[Na+].Cl>O1CCCC1.O>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1
Reactant: COC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)n1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a solution of methyl 2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate (1.17 g, 2.79 mmol) in tetrahydrofuran (20 mL) was added a solution of sodium hydroxide (0.45 g, 11.1 mmol) in water (5 mL). The mixture was stirred at reflux for 16 h. After cooling down to ambient temperature, the mixture was acidified with concentrated hydrochloric acid (2 mL). The reaction mixture was concentrated in vacuo to remove most of tetrahydrofuran and extracted with ethyl acetate (3×25 mL). The combined organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with diethyl ether and ethyl acetate to afford 2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid (0.65 g, 58%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 13.07 (br, 1H), 8.74 (s, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.17 (d, J=6.6 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.66 (s, 1H), 6.34 (s, 1H), 6.04 (s, 2H), 5.20-5.08 (m, 2H), 4.73 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.1, 162.2, 159.9, 155.7, 148.8, 146.4, 142.2, 142.1, 133.8, 132.2, 129.4, 124.1, 123.9, 120.3, 109.7, 103.8, 101.9, 93.7, 80.0, 57.8, 31.2; MS (ES+) m/z 407.1 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([CH3:34])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:36]([CH3:35])(=[O:38])=[O:37])[N:18]=[C:17]([CH3:34])[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCN
Reactant: CS(=O)(=O)Cl
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCNS(C)(=O)=O

Procedure:
According to the procedure described in Example 4a) 103 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide was reacted with methanesulfonylchloride to give 105 mg 4-tert.-butyl-N-[6-(2-(methanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide. LC-MS: tR=5.12 min, [M+1]+=565.58, [M−1]−=563.69.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:25]=[C:24]([CH2:26][CH3:27])[O:23][C:15]=3[C:16]([O:19][CH:20]([F:22])[F:21])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[CH3:28][C:29]1[C:33]([NH2:34])=[C:32]([CH3:35])[O:31][N:30]=1>>[CH3:28][C:29]1[C:33]([NH:34][C:11]([C:13]2[C:14]3[CH:25]=[C:24]([CH2:26][CH3:27])[O:23][C:15]=3[C:16]([O:19][CH:20]([F:21])[F:22])=[N:17][CH:18]=2)=[O:12])=[C:32]([CH3:35])[O:31][N:30]=1
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC(F)F)c2o1
Reactant: Cc1noc(C)c1N
Product: CCc1cc2c(C(=O)Nc3c(C)noc3C)cnc(OC(F)F)c2o1
Yield: 9.7 %

Procedure:
This Example was conducted following the procedure of Example 1, but starting from 7-difluoromethoxy-2-ethylfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (200 mg) and 3,5-dimethylisoxazol-4-ylamine (118 mg). Purification by column chromatography on silica eluting with 30% ethyl acetate in hexane followed by trituration in diethyl ether afforded the title compound as an off-white solid (18 mg).
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:55][C:56]([F:66])([F:65])[CH2:57][CH2:58][C:59]1N=C(N)[S:61][N:60]=1>ClCCl>[F:55][C:56]([F:66])([F:65])[CH2:57][CH2:58][C:59]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])[S:61][N:60]=1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: Nc1nc(CCC(F)(F)F)ns1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1nc(CCC(F)(F)F)ns1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 68 mg, 0.21 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg, 0.23 mmol) and 1-hydroxybenzotriazole (30 mg, 0.22 mmol). The resulting solution was stirred for 5 min before 3-(3,3,3-trifluoro-propyl)-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.25 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water gradient) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [3-(3,3,3-trifluoro-propyl)-[1,2,4]thiadiazol-5-yl]-amide (52 mg, 49%) as a light yellow solid: HR-ES-MS m/z calculated for C21H22ClF3N4O3S [M+H]+ 503.1126, observed 503.1127; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.48 (br. s., 1H), 1.55-1.77 (m, 1H), 1.77-1.97 (m, 1H), 2.66-2.90 (m, 2H), 3.05 (t, J=6.9 Hz, 2H), 4.30 (d, J=18.4 Hz, 1H), 4.51 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 4.93-5.07 (m, 1H), 7.37 (td, J=8.0, 1.5 Hz, 1H), 7.47 (td, J=8.0, 1.5 Hz, 1H), 7.54 (dd, J=8.0, 1.2 Hz, 1H), 7.66 (dd, J=8.0, 1.2 Hz, 1H), 13.38 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[O:8][C:9]2[CH:15]=[C:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1.C1COCC1.[OH-].[Na+]>Cl>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[O:8][C:9]2[CH:15]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: COC(=O)Cc1ccc2nc(-c3cccn3C)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cccc1-c1nc2ccc(CC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.9 %

Procedure:
To methyl (2-(1-methyl-2-pyrrolyl)-6-benzoxazolyl)acetate (228 mg, 0.84 mmol) were added THF (8.5 ml) and 0.25N NaOH (5.10 ml, 1.27 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was poured in 1N HCl (10 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give (2-(1-methyl-2-pyrrolyl)-6-benzoxazolyl)acetic acid (144 mg, 67%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](=[O:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.O1[CH:19]=[CH:18][C:17](=[O:20])[CH:16]=[CH:15]1.Cl.N>O>[O:20]=[C:17]1[CH:18]=[CH:19][N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][C:11](=[O:13])[NH:10][N:9]=3)=[CH:6][CH:7]=2)[CH:15]=[CH:16]1
Reactant: O=c1ccocc1
Reactant: Nc1ccc(-c2n[nH]c(=O)o2)cc1
Agent: Cl
Agent: N
Solvent: O
Product: O=c1ccn(-c2ccc(-c3n[nH]c(=O)o3)cc2)cc1

Procedure:
A mixture of 5-(4-aminophenyl)-1,3,4-oxadiazol-2(3H)-one (0.41 g), 4H-pyran-4-one (0.24 g), and hydrochloric acid (2N, 1.15 ml) in water (25 ml) was stirred under reflux for 3 hours to afford a yellow solid. This solid was added to hot water with stirring and the resulting suspension was made alkaline (pH 8) with aqueous ammonia and was then filtered. The collected solid was dissolved in aqueous potassium carbonate and the resulting solution was neutralised with dilute acetic acid to afford an emulsion from which after centrifugation was obtained the title compound, 0.47 g, m.p. 220° C. (decomp), contaminated with potassium acetate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH2:22]([O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O)[CH2:23][CH:24]([CH3:26])[CH3:25].[O-]CC.[Na+]>C(O)C>[CH2:22]([O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1/[CH:30]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=1)[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCCC(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C(F)(F)F)cc2)c1OCCC(C)C
Yield: 46.4 %

Procedure:
The title compound was synthesized by condensation of Intermediate 5 (400 mg, 1.289 mmol) with 2-isopentyloxy-3-methoxybenzaldehyde (400 mg, 1.812 mmol) in presence of sodium ethoxide (163 mg, 2.418 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to give 308 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.92 (d, J=6.3 Hz, 6H), 1.42 (q, J=6.3 Hz, 2H), 1.80-1.90 (m, 1H), 3.77 (s, 3H), 3.84 (t, J=6.3 Hz, 2H), 6.90-7.00 (m, 4H), 7.51 (d, J=4.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 2H), 7.83 (d, J=7.8 Hz, 2H), 8.01 (d, J=4.8 Hz, 1H), 8.09 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 515.52 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:18]=[C:17]([CH:19]=O)[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[O:23][CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:18]=[C:17](/[CH:19]=[CH:26]/[C:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[O:27])[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[O:23][CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)c(-c2cccn2C(=O)OC(C)(C)C)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OC)c(-c2cccn2C(=O)OC(C)(C)C)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 6 %

Procedure:
The title compound was prepared by condensing 2-(5-formyl-2,4-dimethoxy-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester (Ex-57A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 205–207° C., 6% yield. 1H-NMR (DMSO-d6) δ 8.19 (d, J=5 Hz, 2H), 8.00–8.10 (m, 3H), 7.87 (s, 1H), 7.80 (d, J=16 Hz, 1H), 7.27–7.28 (m, 1H), 6.71 (s, 1H), 6.22–6.23 (m, 1H), 6.14–6.16 (m, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 1.29 (s, 9H). MS m/z=476 ([M−H]+). HMRS (EI) calcd. for C27H27NO7: 477.1788; found: 477.1793.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.Cl.[F:70][C:71]1([F:76])[CH2:75][CH2:74][NH:73][CH2:72]1.N#N>>[F:70][C:71]1([F:76])[CH2:75][CH2:74][N:73]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=2)[CH2:72]1
Reactant: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)nc1
Reactant: FC1(F)CCNC1
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: Cl
Agent: N#N
Product: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CCC(F)(F)C5)cc4)c3c2)nc1
Temperature: 50 °C
Yield: 40.8 %

Procedure:
To a sealable vial was added racemic cis-2-{1-(4-bromobenzyl)-6-[(5-methylpyridin-2-yl)methoxy]-1H-benzimidazol-2-yl}cyclohexanecarboxylic acid (320 mg, 0.56 mmol) RuPhos precatalyst (45 mg, 0.060 mmol), RuPhos (28.5 mg, 0.060 mmol) and 3,3-difluoropyrrolidine hydrochloride (172 mg, 1.20 mmol) and N2 sparged THF (6.0 mL) followed by LiHMDS (3.0 mL, 1.0 M in THF). The resulting reddish mixture was heated to 50° Celsius for 2 h. The reaction mixture was cooled to RT and treated with HCl (3 mL, 0.5 N) and MeOH until homogeneous. The mixture was purified using reverse phase HPLC to afford the title compound (128 mg, 38%). MS (ESI): mass calcd. for C32H34F2N4O3, 560.26; m/z found, 561.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 7.64 (dd, J=8.0, 1.6, 1H), 7.54 (d, J=8.9, 1H), 7.43 (d, J=8.0, 1H), 7.03-6.92 (m, 4H), 6.54 (d, J=8.7, 2H), 5.42 (d, J=16.5, 1H), 5.33 (d, J=16.5, 1H), 5.10 (s, 2H), 3.62 (t, J=13.3, 2H), 3.58-3.52 (m, 1H), 3.47 (t, J=7.2, 2H), 2.92-2.82 (m, 1H), 2.48 (m, 2H), 2.38-2.27 (m, 4H), 2.07-1.95 (m, 1H), 1.88-1.69 (m, 4H), 1.56-1.37 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[C:6]=2[N:19]=1.IC.[CH3:22]N(C)C(=O)C.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[C:6]=2[N:19]=1
Reactant: CC(=O)N(C)C
Reactant: CC1CCCC1N1CCC(=O)Nc2cnc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC1CCCC1N1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.14 g (0.0005 mole) of (rac)-2-chloro-9-(2-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-57), 0.047 mL (0.00075 mole) of iodomethane and 1 mL of N,N-dimethylacetamide at 0 degrees, was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.130 g of (rac)-2-chloro-5-methyl-9-(2-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-57) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:45])[CH:3]([NH:12][C:13]1[CH:14]=[C:15]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([S:28](CCC(OC)=O)(=[O:30])=[O:29])[CH:26]=3)[N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:20]=2)[CH:16]=[N:17][CH:18]=1)[C:4](=[O:11])[NH:5][CH2:6][C:7]([F:10])([F:9])[F:8].C1CCN2C(=[N:50]CCC2)CC1.NOS(O)(=O)=O.C([O-])(=O)C.[Na+]>CS(C)=O.O>[CH3:1][CH:2]([CH3:45])[CH:3]([NH:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([S:28](=[O:30])(=[O:29])[NH2:50])[CH:26]=3)[N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:20]=2)[CH:14]=1)[C:4]([NH:5][CH2:6][C:7]([F:10])([F:9])[F:8])=[O:11]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)CCS(=O)(=O)c1cnc2c(c1)c(-c1cncc(NC(C(=O)NCC(F)(F)F)C(C)C)c1)cn2COCC[Si](C)(C)C
Agent: CC(=O)[O-]
Agent: NOS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(S(N)(=O)=O)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
To a mixture of methyl 3-(3-(5-(3-methyl-1-oxo-1-(2,2,2-trifluoroethylamino)butan-2-ylamino)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)propanoate 4-1d (300 mg, 0.447 mmol) in DMSO (1.2 ml) was added DBU (0.135 ml, 0.893 mmol) and the reaction allowed to stir for 15 min. A solution of hydroxylamine-o-sulfonic acid (253 mg, 2.233 mmol) and sodium acetate (147 mg, 1.786 mmol) in water (0.8 mL) was added. The cloudy oily mixture was allowed to stir at RT for ½ hrs and then an additional charge of sodium acetate (147 mg, 1.786 mmol) and hydroxylamine-o-sulfonic acid (253 mg, 2.233 mmol) added and the mixture warmed to 40° C. for 2 hrs. The reaction was diluted with water (30 mL) and product extracted with ethyl acetate (50 ml), dried over sodium sulfate, filtered and concentrated to an oil. The oil was dissolved in DCM and chromatographed on silica (25 gm, using 2-10% methanol/DCM to give the desired product 4-1e as a white solid (240 mg). LRMS (ESI) m/z 601.2 [(M+H)+; calcd for C25H35F3N6O4SSi: 601.2].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[C:12]([N+:16]([O-])=O)[CH2:13][CH2:14][CH3:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]([NH2:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=Cc1ccc2ccccc2c1)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(N)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7.70 g (31.9 mmol) of 1-(2-naphthyl)-2-nitro-1-pentene in tetrahydrofuran (THF) (30 ml) was added dropwise to a suspension of 2.42 g (63.8 mmol) of lithium aluminum hydride (LiAlR4) in THF (40 ml) over 1 hr under ice cooling and the mixture was stirred overnight at room temperature. After excessive LiAlH4 was decomposed with distilled water under ice cooling the mixture was filtered and the filtrate was concentrated. Thereafter, ether (100 ml) was added to the concentrate and was extracted three times with 0.5 N hydrochloric acid (50 ml). The obtained water phase was alkalized with 28% aqueous ammonia and was extracted three times with ether (100 ml). The obtained organic phase was dried over anhydrous sodium sulfate, concentrated and purified by flash column chromatography. A mixture of chloroform/methanol (10:1) was used for eluting solvent, 1-(2-naphthyl)-2-aminopentane was obtained to yield 5.36 g (79%) as light yellow oil.
Reaction SMILES: ClC1C=C(SC2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)NC=2CCC(N)=O)C=C(Cl)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.C(O)C1C=CC=CC=1.N1C=CC=CC=1>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([O:45][CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[CH:13][CH:14]=2)=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1cccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c12
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: OCc1ccccc1
Product: Cc1cccc2[nH]c(C(=O)OCc3ccccc3)c(Sc3ccc(Cl)cc3)c12
Yield: 20 %

Procedure:
Following the method used to prepare 24a, the use of 1a (0.21 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with benzyl alcohol (33 μL, 0.32 mmol) in the presence of pyridine (54 μL, 0.68 mmol) provided 17 mg (20%) of product 17 as a pale yellow foam. 1H NMR (300 MHz, DMSO-d6) δ 2.59 (s, 3H), 5.36 (s, 2H), 6.89 (d, J=7 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 7.22 (d, J=8 Hz, 2H), 7.24-7.27 (m, 2H), 7.31-7.39 (m, 5H), 7.43 (d, J=8 Hz, 1H), 12.45 (s, 1H). LC-MS (CI): m/z 408.1 [(M+H)+ C23H18ClNO2S requires 407.6]. Purity (100%). Calcd for C23H18ClNO2S: C, 67.72; H, 4.45; N, 3.43; S, 7.86; Cl, 8.69. Found: C, 67.48; H, 4.43; N, 3.42; S, 7.85; Cl, 8.98.
Reaction SMILES: Cl.Cl.CNC1CCN(CC2C=CC=CC=2)CC1.C(N(CC)CC)C.C(N=C=O)CC.[CH2:31]([NH:34][C:35](=[O:51])[N:36]([CH3:50])[CH:37]1[CH2:42][CH2:41][N:40](CC2C=CC=CC=2)[CH2:39][CH2:38]1)[CH2:32][CH3:33]>C(Cl)(Cl)Cl>[CH2:31]([NH:34][C:35](=[O:51])[N:36]([CH3:50])[CH:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]1)[CH2:32][CH3:33]
Reactant: CCCNC(=O)N(C)C1CCN(Cc2ccccc2)CC1
Agent: CCCN=C=O
Agent: CNC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)N(C)C1CCNCC1
Reaction time: 8 h

Procedure:
4-(N-methylamino)-1-benzylpiperidine dihydrochloride (41.4 g) (prepared as in German Offenlegungsschrift No. 2341376), triethylamine (30.2 g) and n-propylisocyanate (12.7 g) in chloroform (200 ml) were mixed together then allowed to stand overnight. The resulting solution was then washed with water (3×100 ml), and, after separation, the chloroform layer was dried and evaporated to leave an oil which on crystallization from petrol (b.p. 60°-80°) gave, 3-n-propyl-1-methyl-1-(1-benzyl-4-piperidyl)urea (42.0 g), m.p. 84°-86°.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:21]=2)[CH:16]=[N:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:20]2[CH:21]=[C:22]3[C:17]([CH:16]=[N:15][N:14]3[CH3:13])=[CH:18][CH:19]=2)[S:25]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3cnn(C)c3c2)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3cnn(C)c3c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-methyl-1H-indazol-6-yl)methyl)sulfamoyl)benzoate (step-1 of Example 17).