Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([OH:13])=[CH:8][CH:9]=2)[CH2:4]1.[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]([OH:23])[C:20](O)=[O:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[Cl-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[OH:13][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH2:12][CH:3]([NH:2][C:20](=[O:21])[CH:19]([C:18]3[CH:24]=[CH:25][C:15]([Cl:14])=[CH:16][CH:17]=3)[OH:23])[CH2:4]2)=[CH:9][CH:8]=1
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Reactant: NC1CCc2ccc(O)cc2C1
Agent: Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCc2ccc(O)cc2C1)C(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
To a mixture of 3.2 g of 2-amino-7-hydroxytetralin hydrobromide (PREPARATION Ic), 2.4 g of 4-chloromandelic acid and 5.2 g of benzotriazolyl-N-oxytris-(dimethylamino) phosphonium hexafluorophosphate in 50 ml of methylene chloride, there is added 3.6 ml of triethylamine. The solution obtained is left under stirring at room temperature for 3 hours, then a saturated sodium chloride solution is added and the mixture is stirred for 30 minutes. The organic phase that separates is evaporated to dryness and an oil is obtained that is dissolved in 200 ml of ethyl acetate. The solution thus obtained is washed twice with 40 ml of a 2N hydrochloric acid, twice with a saturated sodium bicarbonate solution and, then, with a saturated sodium chloride solution. The solution is dried over sodium sulfate, filtered and evaporated to dryness. The oil so obtained is chromatogrpahed (elution with a 1/1 mixture of ethyl acetate/cyclohexane) and all of the fractions are collected. An amount of 2.7 g (63%) of N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-4-chloromandelamide is obtained as a diastereoisomeric mixture; m.p. about 170° C. (large interval of melting), pure enough for a further reaction. In this mixture, the (RS,SR) and (RR,SS) diastereoisomers are well detectable by chromatography; they are easily separable and obtainable in pure form.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@@H:28]3[CH2:32][C@H:31]([OH:33])[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34]I.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:26]=[C:25]([O:27][C@@H:28]3[CH2:32][C@H:31]([O:33][CH3:34])[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C=C[C@@H](O)C3)c3ccccc3n2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO[C@@H]1C=C[C@H](Oc2nc(N3CCN(C(=O)OCc4ccccc4)CC3)nc3ccccc23)C1
Yield: 91 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,4S)-(4-hydroxycyclopent-2-en-1-yl)oxy]quinazoline [cf. Example 35(3)] (6.31 g) and methyl iodide (4.00 g) in dimethylformamide (52 ml) is added 60% sodium hydride (in oil) (678 mg) with stirring under ice-cooling, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate, and washed with water 5 times. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=500:1, v/v) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,4S)-(4-methoxycyclopent-2-en-1-yl)oxy]quinazoline (5.92 g) as oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.C[O-].[Na+].S(OC)(O[CH3:21])(=O)=O>CS(C)=O>[CH3:21][O:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1ccc(O)c2ncccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C=O)c2cccnc12
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
To a solution of 0.76 g (4.39 mmol) of 8-hydroxyquinoline-5-carboxaldehyde (G. R. Clemo and R. Howe, J. Chem. Soc., 1955, 3552) in 5 mL of dimethyl sulfoxide was added 0.24 g (4.4 mmol) of sodium methoxide, while keeping the mixture under nitrogen. After stirring for 5 min, 0.56 g (4.4 mmol) of dimethyl sulfate was added. The reaction was stirred for 1 hr and the solvent removed under vacuum. The residue was partitioned between dichloromethane (100 mL) and 0.5N sodium hydroxide (50 mL); the organic layer was washed with water (100 mL), dried over anhydrous magnesium sulfate, and concentrated to give 0.61 g (74%) of 8-methoxyquinoline-5-carboxaldehyde, mp 121°-122° after recrystallization from ethanol-hexane (2:25). Anal. Calcd for C11H9NO2 : C, 70.58; H, 4.85; N, 7.48. Found: C, 70.55; H, 4.91; N, 7.44.
Reaction SMILES: [CH3:1][N:2]([CH2:4]Cl)[CH3:3].CN(CCCCl)C.C([N:21]1[C:26](=[O:27])[C:25]2[CH:28]=[N:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[CH:32][C:31]=3[C:24]=2[N:23]2[N:41]=[C:42]([CH3:44])[CH:43]=[C:22]12)(=O)C1C=CC=CC=1>>[CH3:1][N:2]([CH2:4][N:21]1[C:26](=[O:27])[C:25]2[CH:28]=[N:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[CH:32][C:31]=3[C:24]=2[N:23]2[N:41]=[C:42]([CH3:44])[CH:43]=[C:22]12)[CH3:3]
Reactant: CN(C)CCl
Reactant: Cc1cc2n(C(=O)c3ccccc3)c(=O)c3cnc4c(cnn4-c4ccccc4)c3n2n1
Agent: CN(C)CCCCl
Product: Cc1cc2n(CN(C)C)c(=O)c3cnc4c(cnn4-c4ccccc4)c3n2n1

Procedure:
By substituting dimethylaminomethyl chloride for the dimethylaminopropyl chloride in the procedure of Example 4 and utilizing 2-methyl-8-phenyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one product of Example 15 instead of 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one, 4-dimethylaminomethyl-2-methyl-8-phenyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:38])=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[F:37])[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[F:38][C:22]([CH2:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1)=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:28]=2[F:37])[CH2:25][CH2:26]1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(C(F)(F)F)cc2F)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 27.1 %

Procedure:
The method of Example 25 was updated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.26 g), tetrahydrofuran (2 ml) and magnesium (22 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(2-fluoro-4-trifluoromethylphenyl)cyclopropane (Example 21) (0.1 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: phenyl; solvent: methanol; flow rate: 2 ml/min) to afford 1-(2-fluoro-3-(4-fluoro-3-phenoxyphenyl)prop-1-enyl)-1-(2-fluoro-4-trifluoromethylphenyl)cyclopropane (38 mg, 27%).
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][N:7]=[C:6]2[N:14](S(C3C=CC=CC=3)(=O)=O)[CH:15]=[CH:16][C:5]=12.S([O-])(O)(=O)=O.[K+]>C1COCC1>[Cl:3][C:4]1[C:9]([C:10]([F:12])([F:13])[F:11])=[CH:8][N:7]=[C:6]2[NH:14][CH:15]=[CH:16][C:5]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(C(F)(F)F)cnc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cnc2[nH]ccc2c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.2 %

Procedure:
A solution of 2M LiOH (19.1 mL, 38.2 mmol) was added to a solution of 4-chloro-1-(phenylsulfonyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (4.59 g, 12.7 mmol) in THF (20 mL), and the reaction was stirred at room temperature for 20 hours. The mixture was neutralized to a pH of about 8 with saturated potassium hydrogen sulfate and extracted with ethyl acetate (50 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to provide 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (2.5 g, 91% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.54 (br s, 1H), 8.59 (s, 1H), 7.82 (d, 1H), 6.71 (d, 1H); LCMS (APCI+) m/z 220.9 (M+H)+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15](=[O:18])[CH2:16][CH3:17].C(Cl)(Cl)Cl.O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:14][C:15](=[O:18])[CH2:16][CH3:17])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: CCC(=O)CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C

Procedure:
To a stirred suspension of potassium phthalimide (5.0 g, 0.027 mmole) in 25ml of dimethylformamide is added, dropwise, 3.80 g (0.025 mmole) of 1-bromobutanone. The mixture is heated for 10 hours at 80° C under nitrogen and then 150 ml of chloroform is added. The resulting mixture is poured into 30 ml of water and the organic layer is separated and washed with 10 ml of 0.2N sodium hydroxide. The resulting chloroform and dimethylformamide solution is dried over anhydrous sodium sulfate, and evaporated in vacuo to give 1-phthalimidobutanone.
Reaction SMILES: C([O:9][C@H:10]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:22][C:13]2[C:14]3[CH:15]=[N:16][NH:17][C:18]=3[C:19]([Cl:21])=[CH:20][C:12]=2[CH2:11]1)(=O)C1C=CC=CC=1.C1COCC1.[OH-].[Li+].O>>[Cl:21][C:19]1[C:18]2[NH:17][N:16]=[CH:15][C:14]=2[C:13]2[CH2:22][N:23]([CH2:26][C:27]([F:28])([F:30])[F:29])[C:24](=[O:25])[C@H:10]([OH:9])[CH2:11][C:12]=2[CH:20]=1
Reactant: O=C(O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1[C@H](O)Cc2cc(Cl)c3[nH]ncc3c2CN1CC(F)(F)F
Reaction time: 3 h
Yield: 53 %

Procedure:
(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl benzoate (7.00 g, 16.0 mmol) in THF (60.00 ml, 732 mmol) was added lithium hydroxide (0.766 g, 32.0 mmol) followed by water (6.0 ml, 333 mmol). After 3 h, the solvent was removed and the crude product was diluted with dichloromethane and neutralized with 1.0 M HCl. The organic phase was dried and the crude product was purified by flash chromatography using 70% EtOAc in hexane to give (R)-4-chloro-7-hydroxy-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3 H)-one in 53% yield. 1HNMR (500 MHz, CDCl3): in δ 8.12 (s, 1H), 7.16 (s, 1H), 5.18-5.14 (m, 2H), 4.55 (d, J=17 Hz, 1H), 4.30-4.28 (m, 1H), 4.27-4.24 (m, 1H), 3.86 (m, 1H), 3.46 (dd, J=5 Hz, J=1.5 Hz, 1H), 3.09 (dd, J=5 Hz, J=1.5 Hz, 1H), 1.52 (s, 9H), MS (ESI) 334 (M+H); Rf=1.49.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.O.NN.[C:21](=O)([O-])O.[Na+]>CO>[CH3:2][CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:21])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: O=C([O-])O
Agent: NN
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(C)C)cc1

Procedure:
A mixture of 4-isopropylbenzoic acid (10 g) and sulfuric acid (5 mL) in methanol (50 mL) was heated under reflux overnight, hydrazine monohydrate (3.66 g) was added, and the mixture was heated under reflux overnight. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (10.32 g) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7]N(C)CN(C)C1.[C:10]([S:18]CN)([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:11].[ClH:21]>C(#N)C>[ClH:21].[CH3:1][NH:2][CH2:7][S:18][C:10]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:11]
Reactant: CN1CN(C)CN(C)C1
Reactant: CC(C)(C)CC(C)(C)SCN
Agent: Cl
Solvent: CC#N
Product: CNCSC(C)(C)CC(C)(C)C

Procedure:
300 ml. of acetonitrile, 12.9 g. (0.1 mole) of 1,3,5-trimethylhexahydro-s-triazine; 43.8 g. (0.3 mole) of tert.-octylthiomethylamine and 12 g. of hydrogen chloride gas are reacted together in the manner of Example I. A yield of 43.7 g. (64.6% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12]/[N:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[S:11])=[CH:5][CH:4]=1.I[CH3:39]>CCO>[CH3:1][N:2]([CH3:37])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][N:13]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:36])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[SH:11][CH3:39])=[CH:5][CH:4]=1
Reactant: CI
Reactant: CN(C)c1ccc(NC(=S)N/N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)cc1
Solvent: CCO
Product: C[SH]=C(NN=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)Nc1ccc(N(C)C)cc1
Temperature: 80 °C
Yield: 60.3 %

Procedure:
A solution containing (E)-N-(4-(dimethylamino)phenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (150 mg, 0.285 mmol) and iodomethane (0.054 mL, 0.856 mmol) in EtOH (5 mL) was heated at 80° C. for 3 h before the solvent was removed under reduced pressure. The residue was purified via normal phase flash chromatography (gradient elution with hexanes/EtOAc) to afford the title compound as an orange foam (93 milligrams (mg), 60%): 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.48 (s, 1H), 8.22 (d, J=8.24 Hz, 2H), 8.17 (s, 1H), 7.89 (d, J=8.24 Hz, 2H), 7.80 (d, J=8.28 Hz, 2H), 7.41 (d, J=8.28 Hz, 2H), 7.19 (d, J=8.24 Hz, 2H), 6.71 (d, J=8.24 Hz, 2H), 2.99 (s, 6H), 2.42 (s, 3H); EIMS m/z 540 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[C:22]([C:26]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:20][CH3:21])=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: CSc1cc(Oc2ccnc3ncc(=O)[nH]c23)ccc1N
Product: CSc1cc(Oc2ccnc3ncc(=O)[nH]c23)ccc1NC(=O)Nc1cc(C(C)(C)C)nn1-c1ccccc1
Yield: 59 %

Procedure:
Method F2 was used with 8-(4-amino-3-(methylthio)phenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound (54 mg, 59%) was obtained as a pale brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH3:16][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:13]=[C:6]([C:7](=[O:8])[CH3:16])[C:5]([O:14][CH3:15])=[N:4][CH:3]=1
Reactant: C[Mg+]
Reactant: COc1ncc(Br)cc1C(=O)N(C)OC
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ncc(Br)cc1C(C)=O
Temperature: 20 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of 5-bromo-N,2-dimethoxy-N-methylnicotinamide (5.0 g, 18.18 mmol) in THF (50 mL), MeMgBr (10 mL, 30.0 mmol) was added dropwise at −78° C. The reaction mixture was stirred at 20° C. overnight. Then the reaction mixture was added to NH4Cl solution. The mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using column chromatography (eluted with petroleum ether:EtOAc=10:1) to provide 1-(5-bromo-2-methoxypyridin-3-yl)ethanone (3.0 g, yield: 71%). 1H-NMR (CDCl3, 400 MHz) δ 8.33 (d, J=2.4 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 4.03 (s, 3H), 2.63 (s, 3H). MS (M+H)+: 230/232
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)(=O)C.CN(C)[CH:19]=[C:20]([C:26]1[N:27]=[N:28][N:29]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:30]=1)[C:21](OCC)=[O:22]>O>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:29]2[N:28]=[N:27][C:26]([C:20]3[C:21](=[O:22])[N:12]4[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]4=[N:1][CH:19]=3)=[N:30]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1ccnc(N)c1
Reactant: CCOC(=O)C(=CN(C)C)c1nnn(Cc2ccc(OC)cc2)n1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccn2c(=O)c(-c3nnn(Cc4ccc(OC)cc4)n3)cnc2c1
Temperature: 130 °C
Yield: 53.9 %

Procedure:
Ethyl 2-aminoisonicotinate (6.5 g, 39.23 mmol) was added with acetic acid (500 ml) and ethyl 3-(dimethylamino)-2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-2-propenoate (13 g, 39.23 mmol) and refluxed by heating at 130° C. for 5 hours. The reaction solution was returned to room temperature and poured into water, and this was extracted with chloroform. The resulting organic layer was washed with saturated brine, and the collected organic layer was dried over magnesium sulfate. The organic layer was concentrated under reduced pressure and subjected to azeotropy with toluene, and the resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=80:1→50:1→30:1) to obtain 8.6 g of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].[NH:22]([C:29](=[O:33])[C:30](O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[NH:22]([C:29](=[O:33])[C:30]([N:16]1[CH2:17][CH2:18][C@H:13]([NH:12][C:10]([C:5]2[NH:6][C:7]([CH2:8][CH3:9])=[C:3]([Cl:2])[N:4]=2)=[O:11])[C@H:14]([O:19][CH2:20][CH3:21])[CH2:15]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)C(=O)Nc1ccccc1
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(C(=O)C(=O)Nc2ccccc2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 48.3 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol) and anilino(oxo)acetic acid (49 mg, 0.30 mmol) were suspended in DMF (3 mL). The suspension was subjected to the same operation as in Example (138a) to obtain 64.3 mg of the title compound as a colorless solid (48%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:43][CH:44]([CH3:55])[CH2:45][C@H:46]([NH:53][CH3:54])[CH2:47][N:48]1[CH2:51][CH:50]([OH:52])[CH2:49]1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([N:53]([C@@H:46]([CH2:45][CH:44]([CH3:55])[CH3:43])[CH2:47][N:48]1[CH2:49][CH:50]([OH:52])[CH2:51]1)[CH3:54])=[O:16]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CN[C@@H](CC(C)C)CN1CC(O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(F)c(F)c1
Reaction time: 0.05 h
Yield: 65.1 %

Procedure:
DIPEA (0.252 mL, 1.45 mmol) was added to a stirred suspension of 3,4-difluorobenzoic acid (76 mg, 0.48 mmol) and TBTU (155 mg, 0.48 mmol) in DCM (2 mL) at rt. The suspension was stirred for 3 min. A solution of (S)-1-(4-methyl-2-(methylamino)pentyl)azetidin-3-ol (Compound G2.4) (100 mg, 0.48 mmol) in DCM (1 mL) was added and the reaction was stirred at rt overnight. The reaction was washed with an 8% aq. solution of NaHCO3 (1.5 mL). The organic layer was concentrated and purified by preparative HPLC affording the title compound (102 mg, 65%). Mixture of rotamers:
Reaction SMILES: C([O:3][C:4]([C:6]1([S:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH2:10][CH2:11]2)(=[O:28])=[O:27])=[CH:30][CH:31]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3cccc(Oc4ccccc4)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3cccc(Oc4ccccc4)c3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic ethyl ester (10.7 g, 24 mmol) dissolved in TIF:Methanol (75:50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 5.0 g (76%); off white solid; MS: 524.3 (M+H)+
Reaction SMILES: CO[C:3]1[CH:35]=[CH:34][C:6]2[NH:7][CH:8]([CH2:32][CH3:33])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:21][S:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)(=[O:24])=[O:23])=[O:20])=[CH:12][CH:11]=3)[C:5]=2[CH:4]=1.[OH-:36].[Na+]>Br>[CH2:32]([C:8]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:24])=[O:23])=[O:20])=[CH:12][CH:11]=2)[C:5]2[CH:4]=[CH:3][C:35]([OH:36])=[CH:34][C:6]=2[N:7]=1)[CH3:33]
Reactant: [OH-]
Reactant: CCC1Nc2ccc(OC)cc2N1c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Br
Agent: [Na+]
Product: CCc1nc2cc(O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-methoxy-1H-benzimidazole (step 5 of Example 71, 600 mg, 1.9 mmol) in 48% hydrobromic acid (60 mL) was stirred at 100° C. for 6 h. After cooling, the mixture was neutralized with 2N aqueous NaOH and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to afford 890 mg (quant.) of the title compound as pale yellow solids: 1H-NMR (CDCl3) δ 7.64 (4H, s), 7.16 (2H, m), 6.97-7.01 (1H, m), 3.86 (2H, t, J=7.1 Hz), 3.30 (2H, t, J=7.1 Hz), 2.92 (2H, q, J=7.8 Hz), 1.29 (3H, t, J=7.8 Hz).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][CH:13]2[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:15]1[CH2:16][CH:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC(CNC(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CNC1)OCc1ccccc1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 1,1-dimethylethyl 3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-azetidinecarboxylate (17.2 mmoles, 5.5 g) in DCM (100 mL) at RT was added TFA (50 mL). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to give the title compound (3.59 g, 95%) as a light yellow oil: LC-MS (ES) m/e 221 (M+H)+.