Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH2:24])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33]1([S:43](Cl)(=[O:45])=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:24][S:43]([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:45])=[O:44])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.159 g (0.7 mmol) of 1-naphthalenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1). Yield 47 mg. MS (ES+): m/e=541.3 (M+H+).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])[CH3:7].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26](F)[CH:27]=1)[C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+]>O>[C:23]([C:22]1[CH:25]=[C:26]([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][C:6]([CH3:5])([CH3:7])[CH3:8])[CH2:18][CH2:17]2)[CH:27]=[C:20]([F:19])[CH:21]=1)#[N:24]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(F)cc(C#N)c2)CC1
Temperature: 100 °C
Yield: 85 %

Procedure:
A DMSO (25 mL, 0.1M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 3,5-difluorobenzonitrile (348 mg, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vacuo. The resulting solid was purified via flash chromatography using 1:1 hexanes/EtoAc as the mobile phase. Isolated 677 mg (2.12 mmol, 85% yield).
Reaction SMILES: C(O/[N:5]=[C:6](/[C:8]1[CH:9]=[C:10]([C:15]2([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[OH:14])\[CH3:7])(=O)C.N1C=CC=CC=1.O>CN(C=O)C>[CH3:7][C:6]1[C:8]2[CH:9]=[C:10]([C:15]3([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16]3)[CH:11]=[CH:12][C:13]=2[O:14][N:5]=1
Reactant: COC(=O)C1(c2ccc(O)c(/C(C)=N/OC(C)=O)c2)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)C1(c2ccc3onc(C)c3c2)CC1
Yield: 81.9 %

Procedure:
A solution of (E)-methyl 1-(3-(1-(acetoxyimino)ethyl)-4-hydroxyphenyl)cyclopropane carboxylate (10.5 g, 39.6 mmol) and pyridine (31.3 g, 396 mmol) in DMF (150 mL) was heated at 125° C. for 10 h. The cooled reaction mixture was poured into water (250 mL) and was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 50:1) to give methyl 1-(3-methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylate (7.5 g, 82%). 1H NMR (CDCl3 300 MHz) δ 7.58-7.54 (m, 2H), 7.48 (dd, J=1.5, 8.1 Hz, 1H), 3.63 (s, 3H), 2.58 (s, 3H), 1.71-1.68 (m, 2H) 1.27-1.23 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=O)[CH3:2].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[CH:19]=CC(/C=C/CSCCO)=[CH:16][CH:15]=2)[CH:8]=1.[OH2:27]>>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:1]([O:4][CH2:5][CH2:6][OH:27])=[CH:2][CH:19]=2)[CH:8]=1
Reactant: CCOC(C)=O
Reactant: OCCSC/C=C/c1ccc(Cc2cccnc2)cc1
Reactant: O
Product: OCCOc1ccc(Cc2cccnc2)cc1
Yield: 89.5 %

Procedure:
In 3 ml of ethanol was dissolved 310 mg of potassium hydroxide, and 0.37 ml of mercaptoethanol was added to the resulting solution. To this solution was dropwise added the N,N-dimethylformamide solution obtained in (1) above with ice-cooling, and the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, 30 ml of ethyl acetate and 20 ml of water were added to the reaction mixture, and the organic layer was separated, washed with three 20-ml portions of water, thereafter washed with 20 ml of a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 340 mg (yield 89.5%) of colorless crystals of (E)-2-[3-[4-(pyridin-3-ylmethyl)phenyl]allylthio]ethanol having a melting point of 73°-74° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][CH2:11][CH2:12][CH2:13][C:14]1[C:18]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=2[O:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CN(C)C=O>[ClH:10].[ClH:10].[F:23][C:21]1[CH:20]=[CH:19][C:18]2[C:14]([CH2:13][CH2:12][CH2:11][N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]3)=[N:15][O:16][C:17]=2[CH:22]=1
Reactant: OCCN1CCNCC1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: OCCN1CCN(CCCc2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 75.5 %

Procedure:
To 50 ml of dimethylformamide was added 2.6 g of 4-(2-hydroxyethyl)piperazine, 6.4 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 10.0 g of milled potassium carbonate, and 0.01 g of potassium iodide. The mixture was stirred at 90° C. for five hrs, cooled, filtered, and evaporated to an oil. The oil was stirred with 100 ml water for ten mins, and extracted with ether. The ether extract was washed with water (2×), saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering, ethereal hydrogen chloride was added, and the precipitate was collected and dried to give 4.3 g (57%) of product. Two recrystallizations from ethyl acetate/methanol, gave the analytical sample, mp 228° C. (dec).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].[Br:21][C:22]([CH2:24]Br)=[CH2:23].O>ClCCl>[Br:21][C:22](=[CH2:23])[CH2:24][NH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=1[O:10][CH3:9]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C=C(Br)CBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(Br)CNCc1ccc(OC)cc1OC
Reaction time: 18 h
Yield: 50.3 %

Procedure:
Triethylamine (16.0 mL, 114 mmol) was added to a solution of 2,4-dimethoxybenzylamine hydrochloride (11.1 g, 54.5 mmol) and 2,3-dibromopropene (10.9 g, 54.5 mmol) in dichloromethane (200 mL). After 18 h, water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (7.85 g).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)C(C)C)(C)C.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15]>C(Cl)Cl>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:4][CH2:1][C:2]#[CH:3])(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C#CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A solution of propargylamine (2 mL, 29 mmol) and N,N-diisopropylethylamine (10 mL, 57.4 mmol) in methylene chloride (100 mL) was cooled to 0° C. 2-nitrobenzenesulfonyl chloride (6.46 g, 29.2 mmol) was added portionwise. Upon complete addition, the solution was allowed to warm to room temperature and was further stirred at room temperature overnight. The reaction solution was concentrated in vacuo and the residue obtained was directly purified on silica chromatography (20-50% EtOAc/hexane) to afford Intermediate 14 as white solid (5.90 g, 84%). LC-MS: (FA) ES+241; 1H NMR (400 MHz, CDCl3) δ 8.22-8.17 (m, 1H), 7.94-7.89 (m, 1H), 7.79-7.73 (m, 2H), 5.71 (s, 1H), 4.02 (dd, J=5.9, 2.4 Hz, 2H), 1.97 (t, J=2.5 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][C:22]([F:25])([F:24])[F:23].C(O)(=[O:28])C.OO.[OH2:32]>>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([C:22]([F:25])([F:23])[F:24])(=[O:28])=[O:32]
Reactant: O
Reactant: Cn1c(-c2ccccc2SC(F)(F)F)nc2cc(C(F)(F)F)cnc21
Reactant: CC(=O)O
Agent: OO
Product: Cn1c(-c2ccccc2S(=O)(=O)C(F)(F)F)nc2cc(C(F)(F)F)cnc21
Temperature: 80 °C

Procedure:
A mixture of 3-methyl-6-trifluoromethyl-2-(2-trifluoromethylsulfanylphenyl)-3H-imidazo[4,5-b]pyridine (0.25 g) and acetic acid (7 ml) was heated to 80° C., and 30% of an aqueous solution of hydrogen peroxide (3 ml) was added dropwise thereto. The mixture was heated to 100° C., and then stirred with heating for 5 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 76 mg of 3-methyl-6-trifluoromethyl-2-(2-trifluoromethylsulfonylphenyl)-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 20).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:51]=[CH:50][C:26]([C:27]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([NH:39][CH:40]5[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]5)=[C:35]([N+:47]([O-:49])=[O:48])[CH:34]=4)(=[O:32])=[O:31])=[O:28])=[C:25]([O:52][C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([O:59]COC)[CH:54]=4)[CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1>O1CCCC1.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:51]=[CH:50][C:26]([C:27]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([NH:39][CH:40]5[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]5)=[C:35]([N+:47]([O-:49])=[O:48])[CH:34]=4)(=[O:32])=[O:31])=[O:28])=[C:25]([O:52][C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([OH:59])[CH:54]=4)[CH:24]=3)[CH2:21][CH2:22]2)=[CH:4][CH:3]=1
Reactant: COCOc1cccc(Oc2cc(N3CCN(CC4=C(c5ccc(Cl)cc5)CC(C)(C)CC4)CC3)ccc2C(=O)NS(=O)(=O)c2ccc(NC3CCN(C)CC3)c([N+](=O)[O-])c2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCC(Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCN(CC5=C(c6ccc(Cl)cc6)CC(C)(C)CC5)CC4)cc3Oc3cccc(O)c3)cc2[N+](=O)[O-])CC1

Procedure:
A suspension of EXAMPLE 176E (35.5 mg) in tetrahydrofuran (3 mL) and HCl (1.25M in methanol, 2 mL) was stirred for 1 hour at 60° C. The product was concentrated. The crude product was purified by RP HPLC(C8, 30%-100% CH3CN/water/0.1% TFA) to yield the product. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 9.31 (s, 1H), 8.10 (s, 11-f), 7.66-7.73 (m, 2H), 7.56 (d, 1H), 7.34-7.38 (m, 2H), 7.02-7.09 (m, 2H), 6.95-7.02 (m, 1H), 6.65 (dd, 1H), 6.34 (s, 1H), 6.29 (d, 1H), 6.20 (d, 1H), 6.14 (d, 1H), 4.14 (dd, 1H), 3.75 (s, 1H), 3.05 (d, 4H), 2.68-2.80 (m, 3H), 2.20 (d, 6H), 2.08 (d, 2H), 1.97 (s, 2-), 1.69-1.79 (m, 2H), 1.63 (s, 1H), 1.39 (d, 2H), 1.21-1.36 (m, 9H), 0.94 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:10]([C:12]2([CH3:15])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.N1C=CN=N1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:10]([C:12]2([CH3:15])[CH2:14][CH2:13]2)[OH:11])=[CH:4][CH:3]=1
Reactant: CC1(C(=O)C(=Cc2ccc(Cl)cc2)n2cncn2)CC1
Agent: c1c[nH]nn1
Product: CC1(C(O)C(=Cc2ccc(Cl)cc2)n2cncn2)CC1

Procedure:
The NMR spectrum of the starting material, II-A isomer of 3-(4-chlorophenyl)-1-(1-methylcyclopropyl)-2-(1,2,4-triazole-1-yl)-2-propene-1-one, is as follows: 8.28 (1H, s, triazole proton), 8.07 (1H, s, triazole proton), 7.32 (4H, s, phenyl proton), 7.19 (1H, s, olefin proton), 1.45-1.15 (2H, m, methylene proton of cyclopropyl group), 1.25 (3H, s, methyl proton), 0.99-0.75 (2H, m, methylene proton of cyclopropyl group).
Reaction SMILES: C1C2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)C=2C=CC=1.CN(C(ON1N=N[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][C:64]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][O:94][CH2:95][CH2:96][O:97][CH2:98][CH2:99][P:100](=[O:107])([O:104][CH2:105][CH3:106])[O:101][CH2:102][CH3:103]>C(Cl)Cl>[CH2:105]([O:104][P:100]([CH2:99][CH2:98][O:97][CH2:96][CH2:95][O:94][CH2:93][CH2:92][O:91][CH2:90][CH2:89][NH:88][C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=2[C:10]2[C:11]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([O:101][CH2:102][CH3:103])=[O:107])[CH3:106]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2-dodecanamido-3-(dodecyloxy)propyl)thio)propanoic acid (1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by diethyl (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)phosphonate (1.2 eq, from example 18, step 4). The reaction was stirred at room temperature for 2 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give the title product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OCC)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC1CCN(c2ccc(Cl)nn2)CC1
Agent: Cl
Product: NC1CCN(c2ccc(Cl)nn2)CC1
Yield: 82 %

Procedure:
A mixture of 6 parts of ethyl [1-(6-chloro-3-pyridazinyl)-4-piperidinyl]carbamate and 60 parts of concentrate hydrochloric acid was stirred and refluxed for 24 hours. The reaction mixture was evaporated. Water was added and the whole was treated with concentrate ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 3.8 parts (82%) of 1-(6-chloro-3-pyridazinyl)-4-piperidinamine: mp. 260° C. (dec.) (compound 225).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[C:10]([F:19])[CH:9]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[C:10]([F:19])[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:16]=2[O:15]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCC1Cc2cc(F)cc(-c3ccccc3Cl)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cc(F)cc(-c3ccccc3Cl)c2O1)OCc1ccccc1

Procedure:
Treatment of (±)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.92 g, 10.5 mmol) with diisopropylethylamine (1.70 g, 13.1 mmol) and benzyl chloroformate (1.97 g, 11.6 mmol) generally according to the procedure described for Intermediate 12 provided 3.02 (70%) of (±)-benzyl[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. Rf=0.76 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C23H19ClFNO3.0.5H2O: C, 65.64; H, 4.79; N, 3.33. Found: C, 65.28; H, 4.73; N, 3.18. Chiral HPLC separation of (±)-benzyl[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:ethanol 1:1) provided two fractions. Fraction 1 (Rt=9.322 min, Chiralcel OJ, hexane:ethanol 1:1); Fraction 2 (Rt=13.646 min, Chiralcel OJ, hexane:ethanol 1:1).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>S(=O)(=O)(O)O.ClCCl>[C:17]([O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])[CH3:18]
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2 g of benzoin with 15 ml of acetic anhydride and a few drops of sulphuric acid are added to a reactor with stirring and at room temperature (25° C.) for 15 hours. Water and dichloromethane are added to the reaction mixture. The organic phase is recovered after separating by settling, dried over sodium sulphate, filtered and then concentrated to dryness under vacuum.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[O:10][C:9]([CH2:11][CH:12]=O)=[CH:8][CH:7]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O1CCCC1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[O:10][C:9]([CH2:11][CH2:12][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=CCc1ccc(C2OCCO2)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc(NCCc2ccc(C3OCCO3)o2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 20.3 %

Procedure:
Next, the resulting (5-[1,3]dioxolan-2-yl-furan-2-yl)-acetaldehyde (1.57 g), aniline (0.94 mL, 10.3 mmol) and triacetoxy sodium borohydride (3.76 g, 17.2 mmol) were suspended in a mixture solution of tetrahydrofuran (30 mL) and acetic acid (1 mL) at 0° C., and the mixture was stirred at room temperature for 19 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (453 mg, 1.75 mmol, 14%) was obtained as a brown oil.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[ClH:1].[ClH:1].[NH2:23]/[C:22](=[N:25]\[OH:26])/[C:21]1[C:15]2[S:14][C:13]([C:11]([NH:10][C@@H:4]3[CH:5]4[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]4)[CH2:3]3)=[O:12])=[CH:17][C:16]=2[CH:18]=[CH:19][CH:20]=1
Reactant: N#Cc1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N/C(=N\O)c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Temperature: 80 °C

Procedure:
120 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-cyano-1-benzo-thiophene-2-carboxamide hydrochloride, 45.0 mg (0.65 mmol) of hydroxylamine hydrochloride and 119.2 mg (0.86 mmol) of potassium carbonate in 1.5 ml of an 8:1 mixture of water and ethanol are heated at 80° C. for 18 h. The mixture is purified by preparative HPLC. The product fractions are combined and concentrated, acetonitrile and 1N aqueous hydrochloric acid (3:1) are added and the mixture is then again concentrated and dried under high vacuum. 58 mg (30.3% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=O.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1.O>C1(C)C=CC=CC=1>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([C:6]2[C:8]3[N:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[N:30]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:33])[F:32])=[CH:25][CH:26]=3)[N:31]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Reactant: NNc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c2cccnc2c(-c2cccc(C(F)(F)F)c2)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
A suspension of 2-(3-trifluoromethylbenzoyl)nicotinic acid (1.5 g) and 4-trifluoromethylphenylhydrazine (1.34 g) in toluene was stirred at reflux temperature for 3 hours (water was removed azeotropically from the mixture).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH:13]=1)[C:5](N(OC)C)=[O:6].Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([CH3:28])[CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([CH3:28])[CH:21]=2)=[O:6])[CH:11]=[C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18]2)[CH:13]=1
Reactant: CON(C)C(=O)c1cc(Br)cc(OCC2CC2)c1
Reactant: COc1ccc(Br)cc1C
Product: COc1ccc(C(=O)c2cc(Br)cc(OCC3CC3)c2)cc1C
Yield: 76 %

Procedure:
In analogy to the procedure described for the preparation of the Building Block AU, the reaction of the 3-bromo-5-cyclopropylmethoxy-N-methoxy-N-methyl-benzamide and 4-bromo-1-methoxy-2-methyl-benzene, beforehand transformed to the Grignard reagent, yielded the title compound as a colourless oil (yield: 76% of theory). Mass (calculated) C19H19BrO3 [374]; (found) [M+H]+=375, 377.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1>C1C=CC=CC=1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:17])=[CH:11][CH:10]=1
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc(Br)cc1

Procedure:
To 4.9 grams (0.05 mole) of 2 -imino-1 -methylpyrrolidine in anhydrous benzene is added, dropwise with stirring, 9.9 g. (0.05 mole) of p-bromophenylisocyanate, dissolved in anhydrous benzene. Solid material forms as the reaction mixture is stirred at room temperature overnight. This solid, 1 -p-bromophenyl-3 -(1 -methyl-2 -pyrrolidylidene)urea, is collected, (m.p. = 135°-137° C). A second crop (m.p. = 134°-136° C) is also obtained from the mother liquor. The two crops are combined and recrystallized from isopropanol-ether to give pure 1 -p-bromophenyl-3 -(1 -methyl-2 -pyrrolidylidene)urea, m.p. = 136°-138° C.