Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6](=[O:38])[CH2:5]1)[CH:2]=C.O=C1N2C(CC=C2C(OCC2C=CC=CC=2)=O)C1.[N+:57]([CH2:60][CH2:61][SH:62])([O-:59])=[O:58].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:57]([CH2:60][CH2:61][S:62][CH:2]1[CH2:1][CH:4]2[N:7]([C:6](=[O:38])[CH2:5]2)[CH:8]1[C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])([O-:59])=[O:58]
Reactant: O=[N+]([O-])CCS
Reactant: C=CCC1CC(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(OCc1ccccc1)C1=CCC2CC(=O)N12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1C(SCC[N+](=O)[O-])CC2CC(=O)N21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An ethyl acetate solution of 4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemthyl)azetidin-2-one (37) (1.46 g) was ozonolysed and cyclized as described in Example 53. The crude product (13) was dissolved in dry dimethylformamide (5 ml) and a solution of 2-nitroethanethiol (0.30 g) in dimethylformamide (2 ml) was added, followed by powdered potassium carbonate (0.19 g). The reaction was stirred at room temperature for 2 hours and the solvent was then stripped off under high vacuum. The residue was partitioned between ethyl acetate and brine and the organic phase was separated, dried over sodium sulphate and concentrated. It was chromatographed on silica gel 60 (<230 mesh) eluting with ethyl acetate/60°-80° petroleum ether 3:7 grading to 7:3, and fractions containing the required products were rechromatographed on the same support using ethyl acetate/60°-80° petroleum ether 4:6. This gave two isomers of benzyl 3-(2-nitroethylthio)-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (122) and (123). The less polar compound was the 2α, 3α-isomer (122) (0.025 g); νmax (CHCl3) 3020, 2960, 1770, 1750sh and 1560 cm-1 ; τ(CDCl3) 2.66(5H, s, phenyl), 4.82(2H, s, benzyl CH2), 5.60(2H, t J7 Hz, CH2NO2), 5.65(2H, d, J61/2 Hz, C2-H), 5.9-6.4(2H, m, C3-H and C5-H), 6.70(1H, dd J15 and 41/2 Hz, C6-H), 6.94 and 6.96(2H, 2t J7 Hz, SCH2), 7.26(1H, dd J15 and 2 Hz, C6-H), 7.41(1H, dt J13 and 6 Hz, C4-H), and 8.44(1H, ddd J13, 9 and 7 Hz, C4-H); (M+ at m/e 350. C16H18N2O5S requires 350). The more polar product was the 2β, 3α-isomer (123) (0.010 g); νmax (CHCl3) 3000, 2940, 1770, 1740 and 1560 cm-1 ; τ(CDCl3) 2.65(5H, s, phenyl), 4.72 and 4.89 (2H, ABq J12 Hz, benzyl CH2) 5.64(2H, t J61/2 Hz, CH2NO2), 5.89(1H, d J7 Hz, C2-H), 6.1-6.5(2H, m, C3-H and C5-H), 6.7-7.1(3H, m, C6-H and SCH2 ), 7.18(1H, dd J15 and 21/2 Hz, C6-H), 7.73(1H, dt J12 and 6 Hz, C4-H) and 8.09(1H, td J12 and 10 Hz, C4-H); M+ m/e 350. C16H18N2O5S requires 350).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:17])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].C(O)(=O)C>O>[CH2:15]([N:12]1[C:9]2=[N:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]([OH:17])=[C:8]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCn1ncc2c(O)c(C(=O)O)cnc21

Procedure:
47 g of 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.2 mol) are saponified by means of 400 ml of aqueous sodium hydroxide (2.5 N) by refluxing the mixture for 1 1/2 hours. After cooling of the filtering solution and diluting with 300 ml of water, it is acidified with glacial acetic acid. The precipitated 1-ehyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid is filtered under suction, washed with water and dried at 120°. Yield 37 g (89%), recrystallization from glacial acetic acid, and has a melting point of 201°-292°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[F:18].[NH2:19][C:20]1[C:21]([N:29]2[CH2:34][C@H:33]([CH3:35])[C@@H:32]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@H:31]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:30]2)=[C:22]2[CH2:28][CH2:27][O:26][C:23]2=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:37]([O:36][C@@H:32]1[C@@H:33]([CH3:35])[CH2:34][N:29]([C:21]2[C:20]([NH:19][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:17])=[CH:25][N:24]=[C:23]3[O:26][CH2:27][CH2:28][C:22]=23)[CH2:30][C@H:31]1[NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:38])[CH3:39]
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (13.3 mg, 0.0525 mmol), tert-butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (16.7 mg, 0.0349 mmol) and HATU (46.2 mg, 0.122 mmol) was added DMF (2.0 mL) followed by DIPEA (70.0 μL, 0.402 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a brown solid (24.9 mg). LCMS calc. for C36H47F3N5O5Si (M+H)+: m/z=714.3. found 714.3.
Reaction SMILES: [BH4-].[Na+].[O:3]1[CH2:5][CH:4]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[C:6]1([CH2:4][CH2:5][OH:3])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(C2CO2)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: OCCc1ccccc1
Temperature: 25 °C

Procedure:
8.9 g (0.066 mole) of diethylene glycole monoethyl ether was added dropwise to a mixture consisting of 1.3 g (0.034 mole) of sodium borohydride, 10 ml of xylene and 5 g (0.042 mole) of 1,2-epoxyethyl benzene at 90° C. over 1.5 hours while agitating the mixture. Subsequently, the mixture was agitated at the same temperature for 1.5 hours. After cooling to room temperature, the mixture was neutralized with dilute sulfuric acid. As a result, phenylethyl alcohol was quantitatively obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][OH:14])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][O:14][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NO
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A solution of {1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (2) (2.5 g, 10 mmol) in dichloromethyl (125 ml) was treated with benzoic acid (1.36 g, 11 mmol), EDCI (2.14 g, 11 mmol), HOBT (1.37 g, 10 mmol) and triethylamine (1.35 ml, 11 mmol) and stirred at room temperature overnight. Reaction mixture was washed with saturated sodium bicarbonate solution and then water and dried over Na2SO4. Solvent evaporated under reduced pressure, crude purified by mplc eluting with 1% triethylamine in 2:3 v/v ethyl acetate and heptane mixture to give yellow solid (850 mg); MS: MH+ 352.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][CH:15]2[CH2:18][N:17](C(C3CC3)=O)[CH2:16]2)=[O:10])=[C:4]([F:25])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:40]2[CH:49]=[C:48]3[C:43]([CH:44]=[CH:45][CH:46]=[N:47]3)=[CH:42][CH:41]=2)O1.O1CCOCC1>C(O)CC.O.C(OCC)(=O)C.ClCCl.CO>[NH:17]1[CH2:16][CH:15]([CH2:14][C:13]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:40]4[CH:49]=[C:48]5[C:43]([CH:44]=[CH:45][CH:46]=[N:47]5)=[CH:42][CH:41]=4)=[CH:3][C:4]=3[F:25])[C:9](=[O:10])[NH:11][N:12]=2)[CH2:18]1
Reactant: O=C(CC1CN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1F
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1[nH]nc(CC2CNC2)n1-c1ccc(-c2ccc3cccnc3c2)cc1F
Temperature: 130 °C
Yield: 45.5 %

Procedure:
In a round bottom flask equipped with reflux condenser, a mixture of N-(4-bromo-2-fluorophenyl)-2-{[1-(cyclopropylcarbonyl)-3-azetidinyl]acetyl}hydrazine carboxamide (4.77 mmol) and potassium carbonate (23.84 mmol) in 1-propanol (10 mL) and water (100 mL) was stirred at vigorous reflux (oil bath, 130° C.) for 22 h. The pale yellow solution was cooled to room temperature and concentrated in vacuo. Water (12 mL) was added to the flask followed by 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (5.24 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.24 mmol) and 1,4-dioxane (30 mL). The flask containing the reaction mixture was equipped with stir bar and reflux condenser, and the reaction was stirred at 100° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (50 mL), and the layers were separated. The aqueous layer was adjusted to pH˜5 using 1N HCl solution and extracted with ethyl acetate (2×100 mL). The organic layers were combined, dried over magnesium sulphate, and concentrated in vacuo. The aqueous layer was lyophilized to give a solid, which was taken up into methanol (25 mL), dichloromethane (25 mL) and ethyl acetate (25 mL) and filtered to remove the salts. The mother liquor was concentrated in vacuo. Methanol (5 mL) was added and a precipitate formed. The precipitate was filtered off and the mother liquor was concentrated in vacuo to provide the title compound as an oil (815 mg, 67% pure, 31% yield). MS(ES)+ m/e 376.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.ClCCl.Cl[S:38]([C:41]1[S:45][C:44]([C:46]([O:48][CH3:49])=[O:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39]>C(N(CC)CC)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:38]([C:41]3[S:45][C:44]([C:46]([O:48][CH3:49])=[O:47])=[CH:43][CH:42]=3)(=[O:39])=[O:40])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: Oc1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(Nc3cc(O)nc4ccc(C(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc34)CC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol (150 mg, 0.31 mmol, 1.00 equip), dichloromethane (20 mL), triethylamine (0.5 mL), and methyl 5-(chlorosulfonyl)thiophene-2-carboxylate (76 mg, 0.32 mmol, 1.00 equip). The resulting solution was stirred for 1 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield methyl 5-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-sulfonyl]thiophene-2-carboxylate as a yellow solid. LCMS (ES, m/z) 682 [M+H]+
Reaction SMILES: [I-].[K+].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[CH2:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:18]>CN(C=O)C>[CH2:17]([N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[CH3:18]
Reactant: CS(=O)(=O)Nc1ccc(CCBr)cc1
Reactant: CCCCCCCNCC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCN(CC)CCc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of potassium iodide (4.15 g, 0.025 mol), N-[4-(2-bromoethyl)phenyl]methanesulfonamide as prepared in Preparation 5 above (7.0 g, 0.025 mol), ethylheptylamine (7.16 g, 0.05 mol) and 120 ml of DMF, under N2, is allowed to stir at ambient temperature. After 18 hours the reaction mixture is concentrated under reduced pressure and the residue is combined with cold dilute NaOH. The alkaline mixture is extracted with Et2O, neutralized to pH 7 with dilute HCl and extracted with CH2Cl2. The CH2Cl2 extracts are concentrated and the residue chromatographed over silica gel with 5% MeOH-0.5% NH4OH--CH2Cl2 to give N-[4-[2-(ethylheptylamino)ethyl]phenyl]methanesulfonamide, a gum. MS calc'd for C18H32N2O2S (M+): 340.2184. Found: 340.2170.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CCN(CC)CC.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>ClCCl>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:14][O:15][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a stirred of 1-(4-trifluoromethyl-phenyl)-cyclopentyl]-methanol (239) (15 g, 61.47 mmol) in dichloromethane (200 mL) was added Et3N (17.1 mL, 123 mmol) followed by mesyl chloride (5.7 mL, 73.77 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. After completion, the reaction was quenched by the addition of water. The reaction mixture was diluted with dichloromethane. The organic part was washed with water, separated, dried over Na2SO4 and finally concentrated. The crude product was purified by 100-200 silica column chromatography using 10% ethyl acetate in hexane as the eluent to give methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240) (14 g, 70.6%) as a white solid.
Reaction SMILES: [ClH:1].[CH2:2]([O:6][CH:7]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])[C@H:8]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33])[NH:9][C:10](=[O:27])[C@H:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:12]C(OCC1C=CC=CC=1)=O)[CH2:3][CH2:4][CH3:5].[H][H]>CO.[Pd]>[ClH:1].[CH2:2]([O:6][CH:7]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])[C@H:8]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:34])[NH:9][C:10](=[O:27])[C@H:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:12])[CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(C)C
Yield: 79.9 %

Procedure:
After N-benzyloxycarbonyl-L-leucyl-L-argininal dibutylacetal hydrochloride (0.92 g, 1.60 mmol) was dissolved in methanol (100 ml), palladium black (1 g) was added to the solution. The mixture was stirred at room temperature for 2 hours in a hydrogen flow. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to give 0.56 g (80%) of L-leucyl-L-argininal dibutylacetal hydrochloride as oil.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[C:16]=1[Cl:17]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(-c3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 405 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:18]([NH:20][NH2:21])=[O:19])=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.O.C1C[O:39][CH2:38]C1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:18]1[O:19][C:38](=[O:39])[NH:21][N:20]=1)=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2c(N3CCCCC3)nc3ccc(Cl)cc3c2-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-4-phenyl-2-piperidin-1-yl-quinoline-3-carboxylic acid hydrazide (30 mg, 70.9 μmol, Eq: 1.00) and N,N′-carbonyldiimidazole (13.8 mg, 85.1 μmol, Eq: 1.2) were dissolved in THF (1 ml). Then triethylamine (10.0 mg, 13.8 μL, 99.2 μmol, Eq: 1.4) was added and the reaction mixture was stirred for 2 h at RT. Water was added and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, DCM/EtOAc 97:3) to afford the title compound as yellow solid (25 mg). MS (ESI): 407.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][CH2:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[C:5]=2[N:4]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[N:3]=1.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[H-].[Na+].[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C>[CH3:1][C:2]1[C:10]2[CH2:9][CH2:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[C:5]=2[N:4]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:20]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(O)cc2)c2c1CCc1ccccc1-2
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccc(OCCCN3CCCC3)cc2)c2c1CCc1ccccc1-2
Temperature: 70 °C
Yield: 40.6 %

Procedure:
4-(3-Methyl-4,5-dihydrobenzo[g]indazol-1-yl)phenol (48 mg, 0.174 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 1-(3-chloropropyl)pyrrolidine (31 mg, 0.21 mmol), sodium hydride (8 mg, 60% dispersion in mineral oil, 0.21 mmol) and sodium iodide (32 mg, 0.21 mmol) were added. The reaction was heated at 70° C. for 1.5 hours, then cooled to room temperature. Saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extracts were dried over MgSO4 and concentrated. SiO2 chromatography with ethyl acetate, then 2% triethylamine/10% methanol/ethyl acetate gave 27.4 mg of the desired product (40% yield). LC-MS (C25H29N3O calculated 387) m/z 388 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.39-7.34 (m, 2H), 7.27 (d, J=7.5 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.01-6.93 (m, 3H), 6.81 (d, J=7.8 Hz, 1H), 4.09 (t, J=6.3 Hz, 2H), 2.98 (t, J=6.9 Hz, 2H), 2.74-2.60 (m, 8H), 2.30 (s, 3H), 2.14-2.04 (m, 2H), 1.86-1.82 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=O.Cl.[CH3:13][NH:14][C:15](=NC)[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[N:14]([CH3:13])[C:15]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[N:7][N:6]=1
Reactant: C=CCCCC(=NC)NC
Reactant: NNC(=O)c1ccccc1F
Agent: Cl
Product: C=CCCCc1nnc(-c2ccccc2F)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.23 g yield starting from 2-fluorobenzoic hydrazide (0.44 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.50 g). MS (m/z): 245 [MH]+.
Reaction SMILES: COC1C=CC=C(OC)C=1C(N[C@H]1CCC[C@@H]1NC1C=CC(C(F)(F)F)=CN=1)=O.Cl.[NH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[NH:37][C:38](=[O:50])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N:45]1[N:49]=[CH:48][CH:47]=[N:46]1.Cl[C:52]1[CH:57]=[N:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][N:53]=1>>[N:49]1[N:45]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:38]([NH:37][C@H:33]2[CH2:34][CH2:35][CH2:36][C@@H:32]2[NH:31][C:52]2[CH:57]=[N:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][N:53]=2)=[O:50])[N:46]=[CH:47][CH:48]=1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Agent: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2,6-dimethoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 1) from N-[(1S,2S)-2-amino cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 100 mg, 0.33 mmol) and 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 59 mg, 0.33 mmol). The crude reaction was filtered through cotton wool before being purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20]>>[Cl:20][CH2:19][CH2:18][CH2:17][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: ClCCCBr
Product: O=C(c1ccccc1)C(CCCCl)c1ccccc1
Reaction time: 0.25 h

Procedure:
The compound is prepared from 19.6 g of desoxybenzoin, which is alkylated with 15.8 g of 3-bromo-1-chloropropane according to the procedure described in Example 17, method 1, except that the reaction time is only 15 min at room temperature. The product is recrystallized from methanol. The yield is 16.6 g (61%) of a product having m.p. 72°-4° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[C:13]([F:15])[C:12](Br)=[CH:11][C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[C:10]([F:17])=[CH:11][C:12]([N:28]2[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]2)=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cc(N(Cc2ccccc2)Cc2ccccc2)c(F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(N(Cc3ccccc3)Cc3ccccc3)cc2F)CC1
Temperature: 100 °C

Procedure:
A mixture of the product of Example 15A (5.12 g, 13.2 mmol), tert-butyl piperazine-1-carboxylate (2.95 g, 15.8 mmol), palladium diacetate (149 mg, 0.66 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (616 mg, 0.99 mmol) and cesium carbonate (8.61 g, 26.4 mmol) in toluene (100 mL) was heated at 100° C. under nitrogen for 16 hours. After cooling, the mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 5/1 petroleum ether/ethyl acetate to give the title compound. MS: 494 (M+H+).