Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7](O)[C@H:5]([OH:6])[C@H:3]1O.[C:13]([O:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][C@H:17]1[O:19][C@H:7]([CH2:5][O:6][C:11](=[O:12])[CH3:9])[C@@H:9]([O:10][C:2](=[O:1])[CH3:3])[C@H:11]([O:12][C:5](=[O:6])[CH3:7])[C@H:18]1[O:10][C:2](=[O:1])[CH3:3])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 88 %

Procedure:
Analogously to what is described for the synthesis of title compound 70a, the reaction of 100 g (555.0 mmol) of α-D-glucopyranose with a mixture that consists of 1000 ml of absolute pyridine and 1000 ml of acetic acid anhydride after working-up and recrystallization from 95% aqueous ethanol yields 190.6 g (88.0%) of the above-mentioned title compound as a colorless and crystalline compound. By 1H-NMR-spectroscopic study of the thus obtained title compound, it was possible to determine the a to β ratio of two possible anomers at ≧98:2. The title compound accordingly is the exclusively α-configured anomer.
Reaction SMILES: C(S[C:4]1[N:5]=[C:6]([OH:13])[C:7]2[S:12][CH:11]=[CH:10][C:8]=2[N:9]=1)C.[NH2:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1>C(OCC)C>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:4]1[N:5]=[C:6]([OH:13])[C:7]2[S:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: Cc1ccccc1N
Reactant: CCSc1nc(O)c2sccc2n1
Solvent: CCOCC
Product: Cc1ccccc1Nc1nc(O)c2sccc2n1

Procedure:
2-Ethylmercapto-4-hydroxythieno[3,2-d]pyrimidine 10 g, 0.047I mol) and o-toluidine (30 g, 0.0279 mol) were heated in an oil bath at 210° for 20 hours. The reaction mixture was poured into diethyl ether and the solid obtained was collected by filtration and dried. The mother liquor was extracted with 2N sodium hydroxide (3×100 ml). The aqueous extracts were combined, acidified with glacial acetic acid and extracted with chloroform (3×100 ml). The chloroform extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a solid. Recrystallization from methanol gave a pure sample, (5.32 g), m.p. 243°-245°.
Reaction SMILES: [C@H:1]([OH:10])([C:7]([OH:9])=[O:8])[C@H:2]([OH:6])[C:3]([OH:5])=[O:4].N[C@@H](C(O)=O)C(S)(C)C>>[C:7]([OH:9])(=[O:8])[C@@H:1]([C@H:2]([C:3]([OH:5])=[O:4])[OH:6])[OH:10]
Reactant: O=C(O)[C@@H](O)[C@@H](O)C(=O)O
Agent: CC(C)(S)[C@@H](N)C(=O)O
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
Via chiral HPLC the absolute amounts of D-, L-, and meso-tartaric acid were determined (Column used: Chirex 3126 (D)-penicillamine (ligand exchange)) (see Table 4).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:54][C:55]1[N:59]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[N:58]=[CH:57][C:56]=1[C:66](O)=[O:67]>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:66]([C:56]1[CH:57]=[N:58][N:59]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:55]=1[CH3:54])=[O:67]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 11.74 %

Procedure:
DIPEA (189 mg, 0.256 mL, 1.48 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method described above) (208 mg, 0.59 mmol) in DMF (2 mL). HOBT (80 mg, 0.59 mmol) and EDCI (114 mg, 0.59 mmol) were then added at room temperature. After 2 minutes, 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (100 mg, 0.49 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 29 mg (11.74% yield) 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 94.32%. 1H NMR (DMSO-d6): δ 8.24 (bs, 1H), 8.14 (s, 1H), 7.88-7.74 (m, 2H), 7.7-7.6 (m, 1H), 7.6-7.4 (m, 6H), 4.2-4.4 (d, 2H), 3.9-3.6 (m, 4H), 3.5-3.4 (m, 2H), 3.2-3.0 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:66][CH2:67][CH2:68][CH2:69][CH2:70]O>O1CCCC1.O>[Cl:66][CH2:67][CH2:68][CH2:69][CH2:70][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:31])([CH3:32])[C:21]=2[CH:20]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: OCCCCCl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCl)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
10 g (23 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are dissolved in 400 ml of tetrahydrofuran. 9.2 g (35 mmol) of triphenylphosphine and 6.9 ml (35 mmol) of diisopropyl azodicarboxylate are added and the reaction medium is stirred at room temperature for 30 minutes. 2.8 ml (28 mmol) of 4-chlorobutanol are then added, and the medium is kept stirring for 12 hours, and then poured into 500 ml of water and extracted with ethyl acetate. The residue obtained is purified by chromatography on silica gel (eluent: 80/20 heptane/ethyl acetate). 8.9 g of ethyl 4′-(4-chlorobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a colorless oil (yield=73%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.[C:17]([C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[C:28]([CH:29]=O)=[CH:27][N:26]=[CH:25]2)=[CH:21][C:20]=1[F:33])#[N:18].[BH3-]C#N.[Na+].CC(O)=O>CO>[F:33][C:20]1[CH:21]=[C:22]([CH2:23][N:24]2[C:28]([CH2:29][NH:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=3)=[CH:27][N:26]=[CH:25]2)[CH:31]=[CH:32][C:19]=1[C:17]#[N:18]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: NCc1ccccc1-c1cccc(O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(Cn2cncc2CNCc2ccccc2-c2cccc(O)c2)cc1F
Reaction time: 72 h

Procedure:
2-Aminomethyl-3′-hydroxybiphenyl hydrochloride from Step H (129 mg, 0.548 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde from Example 3, Step G (132 mg, 0.576 mmol) were stirred in MeOH (2 mL) for 30 min, then NaCNBH3 (38 mg, 0.60 mmol) was added. The reaction mixture was adjusted to pH 5 with AcOH, as judged from wetted pH paper, and stirring was continued at ambient temperature for 3 days. The reaction was quenched with 10% aq. citric acid and stirred for 20 min. Sat. aq. NaHCO3 (10 mL) was added and the mixture was extracted with CH2Cl2 (4×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The titled product was crystallized from CH2Cl2-hexane and the first crop of white needles used for the next reaction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>C(OCCO)C>[CH:17]1([NH:22][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCC1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Solvent: CCOCCO
Product: COc1cc2c(NC3CCCC3)c(C#N)cnc2cc1F
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
A mixture of 4-chloro-7-fluoro-6-methoxy-3-quinolinecarbonitrile (400 mg, 1.69 mmol) and cyclopentylamine (307 mg, 3.72 mmol) in 11 mL of 2-ethoxyethanol is heated at 100° C. for 1.5 hours then cooled to room temperature. The reaction mixture is concentrated in vacuo and aqueous sodium bicarbonate is added to the residue. After stirring for 20 minutes, the solids are collected by filtration. Purification by preparative thin layer chromatography, eluting with 5% methanol in dichloromethane, followed by trituration with diethyl ether and hexane, provides 359 mg of 4-cyclopentylamino-7-fluoro-6-methoxy-3-quinolinecarbonitrile, mp 162-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][OH:18])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[N:56]1[C:60](=[O:61])[C:59]2=[CH:62][CH:63]=[CH:64][CH:65]=[C:58]2[C:57]1=[O:66]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][N:56]4[C:60](=[O:61])[C:59]5[C:58](=[CH:65][CH:64]=[CH:63][CH:62]=5)[C:57]4=[O:66])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCON1C(=O)c2ccccc2C1=O
Yield: 71.9 %

Procedure:
A modification of the method described in Part A of Example 1 was followed using 3-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol (4.60 g, 13.2 mmol), triphenylphosphine (4.17 g, 15.9 mmol), diisopropyl azodicarboxylate (3.13 mL, 15.9 mmol), and N-hydroxyphthalimide (2.59 g, 15.9 mmol). After the solvent was removed under reduced pressure, the residue was dissolved in chloroform (200 mL), washed sequentially with saturated aqueous sodium bicarbonate (2×30 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was triturated twice with ethyl acetate to provide 4.68 g of 2-[3-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg]Cl>>[CH2:4]1[CH2:5][CH2:6][CH2:7][CH:2]([C:1]([Cl:9])=[O:8])[CH2:3]1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Mg]Cl
Product: O=C(Cl)C1CCCCC1

Procedure:
Compound of formula (XI) where all R5 s are H and R7 and R8 are methyl was prepared by reacting 4-PgO benzoic acid chloride, prepared as in the above paragraph, in a Grignard reaction with CH3MgCl in a procedure similar that employed in Example I for producing (1-methyl-1-hydroxy) ethyl-3-cyclohexene from 3-cyclohexane carboxylic acid chloride.
Reaction SMILES: [Cl:1][Si](C)(C)C.[CH3:6][N:7]([CH3:34])[C:8]1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:16])[CH2:10][CH2:9]1.CCOCC>CC(CC)=O>[ClH:1].[CH3:34][N:7]([CH3:6])[C:8]1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2cccc(F)c2)CCC(CC(=O)NCCCc2ccccc2)CC1
Solvent: CCOCC
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (0.132 ml, 1.04 mmol) was added to a solution of the more polar diastereoisomer of 2-[4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]-N-(3-phenylpropyl)-acetamide (274 mg, 0.69 mmol) in ethyl methyl ketone (20 ml) and the mixture was stirred at RT for 1 h. Ether (20 ml) was added to the reaction mixture and the mixture was stirred at RT for 1 h. The hydrochloride was obtained as a colourless solid in a yield of 82% (245.5 mg) with an m.p. of 205-207° C. (Example 54).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:13])=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:50][C:51]1[CH:52]=[CH:53][C:54]2[N:58]=[C:57]([C@@H:59]([NH2:61])[CH3:60])[NH:56][C:55]=2[CH:62]=1.ClCl>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:13])=[O:12])[C:5]([NH:61][C@H:59]([C:57]1[NH:56][C:55]2[CH:62]=[C:51]([Cl:50])[CH:52]=[CH:53][C:54]=2[N:58]=1)[CH3:60])=[O:7]
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCC2)c(Cl)c1
Reactant: C[C@H](N)c1nc2ccc(Cl)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc(S(=O)(=O)N2CCCC2)c(Cl)c1)c1nc2ccc(Cl)cc2[nH]1
Yield: 50 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(pyrrolidin-1-ylsulfonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(6-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylformamide. Yield: 50%; Rf value: 0.57 (silica gel; ethyl acetate); C20H20Cl2N4O3S (467.38); mass spectrum: (M+H)+=467/469/471 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH2:22][CH2:21]3)=[O:19])=[CH:7][N:8]2[CH2:11][CH2:12]CS(N)(=O)=O)=[CH:4][CH:3]=1.[H-].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH2:22][CH2:21]3)=[O:19])=[CH:7][N:8]2[CH2:11][CH2:12][N:20]([CH3:21])[C:18](=[O:19])[CH3:6])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)CCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)N(C)CCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl-methanesulfonamide (preparation described herein), was treated with NaH (1.05 eq), MeI (1.05 eq) in dry DMF under argon at RT for 2 h to give after purification by prep. HPLC the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[NH2:32]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:26]3[O:27][N:32]=[C:31]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[N:30]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccnc3)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 37.7 mg (0.275 mmol) of N′-hydroxypyridine-3-carboximidamide were reacted according to the General Method 1. Yield: 26.0 mg (21% of theory).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH3:17])=[N:14]2)=[CH:9][CH:8]=1)[CH3:5].[Se](=O)=[O:19]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][C@H:4]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH:17]=[O:19])=[N:14]2)=[CH:9][CH:8]=1)[CH3:5]
Reactant: O=[Se]=O
Reactant: COC[C@@H](C)Oc1ccc2ccc(C)nc2c1
Solvent: O
Solvent: C1COCCO1
Product: COC[C@@H](C)Oc1ccc2ccc(C=O)nc2c1
Yield: 46.7 %

Procedure:
To a solution of (R)-7-(1-methoxypropan-2-yloxy)-2-methylquinoline (0.22 g, 0.96 mmol) in dioxane (7 mL) and water (0.07 mL) was added selenium dioxide (0.13 g, 1.2 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title compound (0.11 g, 46%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:38])[CH2:16][N:17]([CH2:35][CH2:36]O)[C:18]([C:20]2[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:22][C:23]([N:26]([CH3:28])[CH3:27])=[N:24][CH:25]=2)=[O:19])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:27][N:26]([CH3:28])[C:23]1[N:22]=[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:20]([C:18]([N:17]2[CH2:35][CH2:36][O:38][CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)[CH2:16]2)=[O:19])=[CH:25][N:24]=1
Reactant: CN(C)c1ncc(C(=O)N(CCO)CC(O)c2cccc(OCc3ccccc3)c2)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(C)c1ncc(C(=O)N2CCOC(c3cccc(O)c3)C2)c(-c2ccccc2)n1
Temperature: 100 °C
Yield: 14.6 %

Procedure:
To 2-dimethylamino-4-phenylpyrimidin-5-carboxylic acid [2-(3-benzyloxyphenyl)-2-hydroxyethyl]-(2-hydroxyethyl)amide (0.20 g, 0.39 mmol) 48% hydrogen bromide solution (4 ml) is added. The mixture is heated at 100° C. for 1 hour, cooled to room temperature, poured onto water and neutralized (pH 7) with sodium carbonate solution. The precipitate is filtered oft washed with water and dried. The crude product is chromatographed on silicagel using chloroform and chloroform-ethyl acetate 9:1 mixture as eluent. 0.023 g light-yellow title compound is obtained, m.p.: 140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:22][OH:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:30].[Na+].OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:30])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:22][OH:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)CC4)cc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)CC4)cc3)cc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 30.5 %

Procedure:
To a mixture of 6-chloro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carbaldehyde (80 mg, 0.24 mmol) in acetonitrile (3 mL) and tert-butanol (3 mL) was added 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (420 mg, 4.80 mmol) and sodium phosphate monobasic (650 mg, 4.80 mmol) in water (3 mL) dropwise via addition funnel. The reaction mixture was warmed to room temperature and stirred for 20 hours. The solvent was removed in vacuo to give a residue, which was purified by prep-HPLC (Column: Boston Symmetrix ODS-H 150*30 mm*5 μm Mobile phase: from 36% MeCN in water (0.1% TFA) to 36% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min) to give 6-chloro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carboxylic acid (25 mg, 32% yield) as a white solid. MS (ES+) 364.0 (M+Na)+. 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1 H), 11.96 (s, 1 H), 8.07 (d, 1 H), 7.92 (s, 1 H), 7.62 (s, 1 H), 7.38-7.32 (m, 4 H), 4.73-4.71 (m, 1 H), 3.58-3.57 (m, 2 H), 0.88-0.77 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[S:13][CH:14]=[CH:15][C:7]1=2)=[O:5].C([O-])(O)=O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[S:13][CH:14]=[CH:15][C:7]1=2)=[O:5]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCCc2sccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCCCc3sccc32)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A mixture of 5.0 g of 4-(2-chloro-4-nitrobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine, 16.8 g of stannous chloride dihydrate in 184 ml of ethanol is heated at 80° C. under argon for 1 hour. The solution is cooled in an ice bath and made basic by the slow careful addition of 1M NaHCO3 (ca. 380 ml). The mixture is stirred for 1 hour at room temperature and extracted with 400 ml of ethyl acetate. The aqueous layer is extracted with an additional 250 ml of ethyl acetate. The extracts are combined and washed with 300 ml of brine, dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated under vacuum to give a white solid which is recrystallized from ethyl acetate to give 4.23 g of off-white crystals, m.p. 176°-179° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][C:10](=[O:13])[CH:9]([C:14]([O:16][CH3:17])=[O:15])[S:8][C:7]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Cl:23][CH2:22][CH2:21][CH2:20][C:9]1([C:14]([O:16][CH3:17])=[O:15])[S:8][C:7]2[CH:18]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:12][CH2:11][C:10]1=[O:13]
Reactant: ClCCCBr
Reactant: COC(=O)C1Sc2cc(OC)ccc2OCC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: COC(=O)C1(CCCCl)Sc2cc(OC)ccc2OCC1=O

Procedure:
A mixture of 30 g of methyl 7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate, 50 g of 1-bromo-3-chloropropane, 46 g of anhydrous potassium carbonate, 10 g of potassium iodide, 1.0 g of tetrabutyl ammonium iodide and 300 ml of acetonitrile is heated under reflux for 4 hours. After the mixture is cooled, the inorganic substance is filtered off, and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, and the solution is washed with water and dried. The solvent is evaporated off under reduced pressure, and the residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate:methylene chloride=10:1:10). Recrystallization from ethanol yields colorless prisms of methyl 4-(3-chloropropyl)-7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate. Yield of 17 g. m.p. of 64°-65° C.
Reaction SMILES: [K].C(OCC)(=O)C([O-])=O.[CH3:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[N:21]=[CH:22]OC>CN(C)C=O>[CH3:17][C:16]1[CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=[C:12]2[C:11]=1[CH:10]=[CH:22][NH:21]2
Reactant: COC=Nc1cc([N+](=O)[O-])cc(C)c1C
Agent: CCOC(=O)C(=O)[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc2[nH]ccc12
Temperature: 40 °C

Procedure:
A solution of 31 g of potassium ethoxylate, 51 ml of ethyl oxalate and 0.25 l of dimethylformamide is added to a solution of methyl N-(2,3-dimethyl-5-nitrophenyl)formimidate (52 g) in 0.37 l of dimethylformamide. The temperature of the mixture is raised to 40° C. for 3 hours. The precipitate is filtered off and washed with water. The precipitate is taken up in hot isopropyl ether and then filtration is carried out.