Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>N1C=CC=CC=1.CO>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:20][C:18]2[O:19][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)=[CH:14][CH:13]=3)=[N:16][N:17]=2)=[O:28])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Agent: Br
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(=O)Nc2nnc(-c3ccc(Oc4cccnc4)cc3)o2)cc1C(F)(F)F
Reaction time: 3 h
Yield: 16.2 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 4-methoxy-3-trifluoromethylbenzoyl chloride (179.0 mg, 0.75 mmol) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (37.0 mg). Yield 16.2%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:20]([CH3:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH:28]=O.[OH-].[Na+].Cl>CO.O.C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:20]([CH:22]=[CH:28][C:27]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=1)=[O:21]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C=CC(=O)c2cc(Oc3ccccc3)c(NS(C)(=O)=O)cc2O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
In 25 ml of methanol were suspended 2.0 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone and 1.03 g of 3,4-dimethoxybenzaldehyde. Thereto was added 5 ml of 50% aqueous sodium hydroxide. The mixture was stirred for 3 hours at room temperature. The reaction mixture was introduced into a mixture of 20 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 2.0 with 4N hydrochloric acid. The resulting crystal was collected by filtration, washed with water and ethyl acetate in this order, and recrystallized from acetic acid to obtain 2.2 g (yield: 75.6%) of 2-(3,4-dimethoxyphenyl)vinyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone.
Reaction SMILES: [F:1][C:2]1([Cl:9])[CH2:4][C:3]1([CH3:8])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[F:1][C:2]1([Cl:9])[CH2:4][C:3]1([CH3:8])[C:5]([O:7][CH2:15][CH3:16])=[O:6]
Reactant: CC1(C(=O)O)CC1(F)Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(C)CC1(F)Cl
Yield: 79 %

Procedure:
44 ml of ethanol are added at room temperature and with stirring to 43 g (0.28 mol) of 2-fluoro-2-chloro-1-methyl-cyclopropanecarboxylic acid. After the addition of sulphuric acid, the reaction mixture is refluxed for 16 hours. Excess ethanol is subsequently distilled off and the residue is dried and distilled under reduced pressure. In this manner, 40 g (79% of theory) of ethyl 2-fluoro-2-chloro-1-methyl-cyclopropane-carboxylate are obtained in the form of a liquid of boiling point 62°-63° C./17 mbar.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:20][CH:19]=2)[N:3]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: Clc1cncc(Cl)n1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Clc1cncc(Oc2ccc(-c3ccccc3)cc2)n1
Yield: 99 %

Procedure:
Using Method DD (reaction time: 20 hours) with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 4-phenyl-phenol (268 mg, 1.49 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:2), the title compound was obtained (376 mg). Yield: 99%. 1H NMR (250 MHz, DMSO-d6) δ 7.40-7.60 (m, 5H, Harom), 7.76 (d, 2H, Harom 3+5, J=7.1 Hz), 7.82 (d, 2H, Harom 2+6, J=8.7 Hz), 8.59 (s, 1H, HPz 5), 8.65 (s, 1H, HPz 3). m/z: 283.1 [(M+H)+, calcd for C16H11ClN2O 282.1].−
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O>[CH:1]1([O:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[N+:24]([O-:26])=[O:25])[C:17]([O:19][CH3:20])=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Reaction time: 4 h
Yield: 102.2 %

Procedure:
Cyclopentyl bromide (38.7 g, 0.26 mol) is added slowly (over 1 hour) to a stirred suspension of potassium carbonate (41.4 g, 0.3 mol) in N,N-dimethylformamide (200 mL) containing methyl 3-hydroxy-4-nitrobenzoate (39.4 g, 0.2 mol) at 65° C. and then the stirring is continued for 4 hours. The mixture is allowed to cool and then filtered. The filtrate is diluted with water (700 mL) containing sodium chloride (50 g) and then extracted with toluene (3×200 mL). The combined organic extract is washed with 1N sodium hydroxide solution (1×200 mL) and then water (2×200 mL) and then evaporated under reduced pressure to give methyl 3-cyclopentyloxy-4-nitrobenzoate (54.2 g, 100%) as a pale green solid which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: Cc1ccc(CCBr)cc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(C)cc3)CC1)O2
Yield: 89.7 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (253 mg, 0.749 mmol, Intermediate 1, hydrochloride salt) was alkylated using 1-(2-bromo-ethyl)-4-methyl-benzene (0.23 ml, 1.5 mmol) as described in Example 56, Step A, giving (E)-3-{1′-[2-(4-methyl-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (282 mg) as a light brown solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: NCC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A solution of 1-benzyl-4-carbamoylpiperidine (2.5 g) in tetrahydrofuran (10 ml) was added dropwise to 1N solution of diborane-tetrahydrofuran complex in tetrahydrofuran (34.3 ml) at 0° C. and then the mixture was refluxed for 3 hours. After cooling to room temperature, 6N hydrochloric acid (10 ml) was added thereto. The mixture was stirred overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate and made basic with 5N sodium hydroxide. The separated organic layer was washed with water and brine and dried over magnesium sulfate, and evaporated in vacuo to give (1-benzylpiperidin-4-yl)methylamine (1.4 g) as an oil.
Reaction SMILES: [N:1]1([C:7]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH:11]([NH2:12])[C:7]2([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)[CH2:10][CH2:9][CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC1(N2CCSCC2)CCC1
Reactant: [Li]c1ccccc1
Product: NC(c1ccccc1)C1(N2CCSCC2)CCC1

Procedure:
The title compound, yellow oil, MS: m/e=263.1 [(M+B)+], was prepared in accordance with the general method of intermediate B from 1-thiomorpholin-4-yl-cyclobutanecarbonitrile (intermediate X) and phenyllithium.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=2)[C:13]([OH:15])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:27]([O:29][C:30](=[O:39])[CH2:31][S:32][C:33]1[S:37][C:36]([NH2:38])=[N:35][CH:34]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:39])[CH2:31][S:32][C:33]1[S:37][C:36]([NH:38][C:13](=[O:15])[C:12]2[CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=[C:10]([O:9][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:26][CH:25]=3)[CH:11]=2)=[N:35][CH:34]=1)[CH3:28]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-(4-methanesulfonyl-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.Cl.N[C@@H](CCN1CC(OC2C=CC([F:48])=CC=2)C1)CO>>[F:48][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(F)cc2)C1
Reactant: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)n(C)n1
Agent: Cl
Product: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(F)cc3)C2)n(C)n1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 88 except using (S)-2-amino-4-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[O:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[NH:2]=[C:1]([N:43]1[CH2:42][CH2:41][N:40]([CH2:39][CH:35]2[CH2:36][CH2:37][CH2:38][O:34]2)[CH2:45][CH2:44]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: C1COC(CN2CCNCC2)C1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCN(CC2CCCO2)CC1
Yield: 48 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalent of 1-(tetrahydro-2-furylmethyl)piperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C)CCN
Product: CN(C)CCNc1ccc(N)cn1
Yield: 50.1 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with N1,N1-dimethylethane-1,2-diamine (308 mg, 3.5 mmol) followed by reduction to afford the desired product (280 mg, 50%) as a purple solid: ESI MS m/z 181 [C9H16N4+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[Br:19]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:19][C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH2:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:13][C:14]=1[F:18]
Reactant: COc1ncc(CNc2cccc(F)n2)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ncc(CNc2ccc(Br)c(F)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
To (5-fluoro-6-methoxy-pyridin-3-ylmethyl)-(6-fluoro-pyridin-2-yl)-amine (58, 3.21 g, 12.8 mmol) in 100 mL of acetonitrile, N-bromosuccinimide (2.30 g, 12.9 mmol) in 30 mL of acetonitrile was added slowly at room temperature. The reaction was stirred at room temperature for 4 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (59, 3.60 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([N:12]2[C@@H:19]3[C@@H:14]([CH2:15][CH2:16][NH:17][CH2:18]3)[CH2:13]2)[CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]2[N:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[C:38]=1[C:39](O)=[O:40].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]2[N:47]=[CH:48][CH:49]=[CH:50][N:51]=2)[C:38]=1[C:39]([N:17]1[CH2:16][CH2:15][C@@H:14]2[C@@H:19]([N:12]([C:4]3[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[N:5]=3)[CH2:13]2)[CH2:18]1)=[O:40]
Reactant: O=C(O)c1c(F)cccc1-c1ncccn1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(C(F)(F)F)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-c4ncccn4)C[C@@H]32)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[8-(6-methyl-2-trifluoromethyl-pyrimidin-4-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 9) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-(pyrimidin-2-yl)benzoic acid (Intermediate 48) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. For C23H20F4N6O, 472.45; m/z found 473.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[CH3:15].O.[NH2:17][NH2:18]>Cl.C(O)C>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[CH3:15].[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH2:8][CH2:9][C:10](=[O:11])[NH:17][N:18]=2)=[CH:4][C:3]=1[CH3:15]
Reactant: NN
Agent: Cc1cc(C(=O)CCC(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C2=NNC(=O)CC2)ccc1N

Procedure:
There are obtained from 70 g of N-acetyl-1,2-toluidine, with 47 g of succinic anhydride and 234 g of aluminum chloride in 2000 ml of tetrachlorethane, by the customary method, 50 g of 3-(3-methyl-4-acetamido-benzoyl)-propionic acid, m.p. 150°-160° C., as crude product. From this are obtained, by hydrolysis in 18% hydrochloric acid, 28 g of crude 3-(4-amino-3-methyl-benzoyl)-propionic acid. And from 6 g of 3-(4-amino-3-methyl-benzoyl)-propionic acid are obtained, with 1.7 ml of hydrazine hydrate in 70 ml of ethanol, in a manner analogous to that in Example 1, 2.6 g of 6-(4-amino-3-methyl-phenyl)-4,5-dihydro-3(2H)-pyridazinone having a melting point of 215°-225° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14]C)[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1>Br.CC(O)=O.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[OH:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2c(O)c(F)c(F)cc2c1=O
Temperature: 0 °C

Procedure:
A solution of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (13.02 g) in HBr in AcOH (33%; 100 ml) was stirred at 100° C. for 1 day. The reaction mixture was cooled to 0° C. and diluted with water (400 ml). The resulting crystals were collected by filtration, affording, after drying, 12.4 g of a colourless material.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH:39]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][CH2:44][CH:39]([OH:38])[CH2:40]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OC1CCCNC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCCC(O)C1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 3-hydroxypiperidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H41Cl2N4O3 [(M+H)+] 623.255, observed 623.2547.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][C:39]5[N:44]6[CH:45]=[CH:46][N:47]=[C:43]6[CH:42]=[CH:41][CH:40]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([C:39]5[N:44]6[CH:45]=[CH:46][N:47]=[C:43]6[CH:42]=[CH:41][CH:40]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Sc4cccc5nccn45)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)c4cccc5nccn45)cc2)CCN3CC(C)C)cc1
Temperature: -20 °C
Reaction time: 5 h
Yield: 25.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(imidazo[1,2-a]pyridin-5-ylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (1.0 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.56 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 5 hours at −20° C., sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 1:1→3:1), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(imidazo[1,2-a]pyridin-5-ylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 169) (259 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([O:25][Si](C(C)(C)C)(C)C)=[C:20]([CH3:33])[CH:19]=2)([OH:17])[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])([C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:33])[CH:19]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)cc(C)c1O
Yield: 107.6 %

Procedure:
Dissolve 1-benzyl-3-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-3-hydroxy-1,3-dihydro-indol-2-one (152 mg, 0.3 mmol) in THF (5 mL) and treat with 1.0M in THF tetrabutylammonium fluoride (0.36 mL, 0.36 mmol) for 6 h. Pour into ethyl acetate (25 mL) and wash with water (3×25 mL) and brine (25 mL). Dry (MgSO4), filter and concentrate in vacuo to give a summy residue. Purify by flash chromatography (gradient of 5% EtOAc/hexanes to 50% EtOAc/hexanes) to give 116 mg (98%) of the title compound as a white solid. MS (ES): m/z=376 (M+1−H2O); 1H NMR(DMSO-d6); δ8.26 (s, 1H), 7.54 (dd, J=1.7, 1.4 Hz, J=7.7, 7.4 Hz, 1H), 7.38-7.15 (m, 5H), 7.05 (t, J=7.4 Hz, 1H), 6.85 (m, 3H), 6.65 (s, 1H), 4.96 (q, 2H), 2.12 (s, 6H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][O:21][CH:20]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([C:32]3[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:39])[OH:31])=[CH:26][CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC.[NH4+].[OH-]>C(Cl)Cl>[CH2:11]([N:18]1[CH2:23][CH2:22][O:21][CH:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([C:32]3[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:39])=[O:31])=[CH:26][CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(C)c1C(O)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cccc(C)c1C(=O)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a solution of oxalyl chloride (0.46 mL, 5.4 mmol) in CH2Cl2 (20 mL), was added dropwise DMSO (0.94 mL, 13.2 mmol), at −78° C. Subsequently, a solution of [4-(4-benzyl-morpholin-2-yl)-phenyl]-(2,6-dimethyl-phenyl)-methanol (1.6 g, 4.1 mmol) in CH2Cl2 (30 mL) was added, dropwise, at −78° C. After the addition was complete the mixture was stirred for 30 min., at −78° C., and then Et3N (2.9 mL, 20.8 mmol) was added. After complete addition the mixture was allowed to warm to room temperature, overnight. Next, a 2M aqueous NH4OH solution (30 mL) was added, and the mixture extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford [4-(4-benzyl-morpholin-2-yl)-phenyl]-(2,6-dimethyl-phenyl)-methanone (1.5 g), which was used as such in the next step.