Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11](C=O)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:30][C:31]([F:35])([F:34])[S:32]Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([S:32][C:31]([F:35])([F:34])[F:30])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)SCl
Reactant: COc1ccc(-c2cc(C=O)[nH]c2-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(-c2cc(SC(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a stirred mixture of 1.5 g (5 m mole) of 4,5-bis(4-methoxyphenyl)pyrrole-2-carboxaldehyde and 1.3 g sodium carbonate in 10 ml ether/10 ml THF at -78° was added 0.8 g of trifluoromethanesulfenyl chloride. The mixture was allowed to warm to room temperature with a dry-ice condenser attached to keep the trifluoromethanesulfenyl chloride from escaping. Excess trifluoromethanesulfenyl chloride was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the filtrate concentrated by rotary evaporation. The residue was purified by chromatography on 300 g Silic AR CC-7, eluting with toluene, to give 0.75 g (39%) of product, identical to that obtained by Method A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1.[H-].[Na+].[CH:26]1(Br)[CH2:30][CH2:29][CH2:28][CH2:27]1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[CH:4]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a mixture of 4-(2-quinolylmethoxy)phenylacetic acid methyl ester (6.36 g; 20.7 mmol) in DMF (10 ml) at 0° C. was added in portions sodium hydride (60% dispersion in mineral oil) (840 mg; 21 mmol). The mixture was stirred at room temperature for 1 hour. It was then recooled to 0° C. and cyclopentyl bromide (2.38 ml, 22.0 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 18 hours, and was then poured into water (50 ml). The product was extracted with ethyl acetate and purified by silica gel chromatography (hexane-ethyl acetate 3:1) to provide 5.5 g of 2-cyclopentyl-2-(4-(2-quinolylmethoxy)phenyl)acetic acid methyl ester.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH2:24][NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][N:36]=[C:35](Cl)[N:34]=4)=[CH:29][CH:28]=3)[CH:21]=2)[NH:16][CH:15]=1)#[N:13]>>[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH2:24][NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[N:34]=4)=[CH:29][CH:28]=3)[CH:21]=2)[NH:16][CH:15]=1)#[N:13]
Reactant: NCCCCCN1CCCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCCCN5CCCC5)n4)cc3)cc12

Procedure:
Using 5-(pyrrolidin-1-yl)-pentylamine (reference example 93d) and and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 522 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:48])=[C:9]([CH2:11][O:12][C:13]2[CH:47]=[CH:46][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH:23]=O)[C:20]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[N:36]=[C:37]([C:41]6[O:42][CH:43]=[CH:44][CH:45]=6)[O:38][C:39]=5[CH3:40])=[CH:29][CH:28]=4)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.C(OP([CH2:57][C:58]([O:60][CH2:61][CH3:62])=[O:59])(OCC)=O)C.[H-].[Na+]>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:48])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]3[CH:22]=[C:21](/[CH:23]=[CH:57]/[C:58]([O:60][CH2:61][CH3:62])=[O:59])[C:20]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]5[N:36]=[C:37]([C:41]6[O:42][CH:43]=[CH:44][CH:45]=6)[O:38][C:39]=5[CH3:40])=[CH:31][CH:32]=4)=[N:19]3)=[CH:46][CH:47]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccco5)oc4C)cc3)cc2C=O)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a mixture of 1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazol-4-carbaldehyde (14.09 g), ethyl diethylphosphonoacetate (5.88 g), and N,N-dimethylformamide (100 ml), sodium hydride (60%, oily, 1.01 g) was added at 0° C., and the mixture was stirred at room temperature for two hours. The reaction mixture was poured into ice water, and the obtained crystals were collected by filtration, and ethyl(E)-3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazol-4-yl]propenoate was obtained (13.91 g, yield: 89%). This was recrystallized from ethyl acetate-hexane. Melting point: 138–139° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:65])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:25]([O:59][CH3:60])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:57][CH3:58])[C@@H:35]([CH3:56])[C:36]([NH:38][C@@:39]1([C:48]([N:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)=[O:49])[CH2:41][C@@H:40]1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11].C(=O)([O-])O.[Na+].[O:71]=[C:72]1[CH:76]=[CH:75][C:74](=[O:77])N1C(OC)=O>O1CCOCC1.O>[O:71]=[C:72]1[CH:76]=[CH:75][C:74](=[O:77])[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:65])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:25]([O:59][CH3:60])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:57][CH3:58])[C@@H:35]([CH3:56])[C:36]([NH:38][C@@:39]1([C:48]([N:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)=[O:49])[CH2:41][C@@H:40]1[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
64 mg (70 μmol) of N-(6-aminohexyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 97) were taken up in 3 ml of 1:1 dioxane/water, then adjusted to pH 9 with 4 ml of saturated sodium hydrogencarbonate solution and subsequently admixed with 16.3 mg (110 μmol) of methyl 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate. The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. Then another 8 mg (55 μmol) of methyl 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate were added, and the reaction mixture was adjusted again to pH 9 and stirred at RT for a further hour. This was followed by concentration and purification of the remaining residue by means of preparative HPLC. At first, 31 mg of an as yet uncyclized intermediate were obtained. 27 mg of this intermediate were taken up again in 2 ml of 1:1 dioxane/water and then admixed with 250 μl of saturated sodium hydrogencarbonate solution. After stirring at RT for 2 hours, the reaction mixture was concentrated and the residue was purified by means of preparative HPLC. After lyophilization, 20 mg (29% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[I:20](O)(=O)(=O)=O.II.S([O-])([O-])=O.[Na+].[Na+]>CO.ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[I:20]
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)cc2F)n1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1I
Yield: 38.9 %

Procedure:
Methyl 6-amino-2-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylate (6.17 g, 21.91 mmol, see US 20090088322 for preparation) was diluted with methanol (100 ml). Periodic acid (2.10 g, 9.21 mmol) and iodine (5.26 g, 20.72 mmol) were added and the reaction was heated at reflux overnight. The cooled reaction mixture was diluted with dichloromethane and poured into a 1N solution of sodium sulfite. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with 1N sodium sulfite, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated onto celite. Purification by flash chromatography (SiO2, 30% EtOAc:Hex) provided the title compound (1.46 g, 16% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) d 3.89 (s, 3H), 7.34-7.46 (m, 1H), 7.53 (dd, J=10.7, 2.0 Hz, 1H), 7.89 (t, J=8.4 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) d −110.23; ESIMS m/z 408 ([M+H]+), 406 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:10]1)[CH2:6][CH2:7][CH3:8])=[O:4].[CH3:22][C:23](C)([O-])C.[K+].C(I)C>CS(C)=O>[CH2:22]([O:19][C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH2:18][CH:9]([N:5]([CH2:6][CH2:7][CH3:8])[C:3](=[O:4])[C:2]([F:20])([F:21])[F:1])[CH2:10]2)=[CH:15][CH:14]=1)[CH3:23]
Reactant: CC(C)(C)[O-]
Reactant: CCCN(C(=O)C(F)(F)F)C1CCc2ccc(O)cc2C1
Agent: [K+]
Solvent: CCI
Solvent: CS(C)=O
Product: CCCN(C(=O)C(F)(F)F)C1CCc2ccc(OCC)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-acetamide (1.0 g, 3.32 mmol) in DMSO (30 mL) under an inert atmosphere was added a slurry of potassium t-butoxide (392 mg, 3.49 mmol, 1.05 eq.) in DMSO (10 mL). The reaction was stirred at room temperature for 30 min. and then ethyl iodide (0.32 mL, 3.98 mmol, 1.2 eq.) was added dropwise. The reaction mixture was stirred for 2 h, quenched with water, and extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated onto silica gel (10 g). This was placed on top of a flash column and eluted with 20% acetone in hexanes to afford N-(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-2,2,2-trifluoro-N-propyl-acetamide as an oil (660 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:24]=[CH:23]2)=[CH:18][CH:17]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[N:24]=[CH:23]2)=[CH:18][CH:17]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(OC(CC(C)C)c2ccc(-n3cnc(C(F)(F)F)c3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CC(Oc1ccc(C(=O)O)cc1)c1ccc(-n2cnc(C(F)(F)F)c2)cc1
Reaction time: 8 h
Yield: 103.6 %

Procedure:
Methyl 4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzoate (65 mg, 0.15 mmol) was dissolved in methanol (1.5 mL) and 1M NaOH (0.75 mL) was added at room temperature. The resulting mixture was stirred overnight. The reaction mixture was diluted with water (10 mL), acidified with 1M HCl (1 mL) and extracted with ethyl acetate (2×10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give (+/−)-4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzoic acid (65 mg, 100%) as a gum. 1H NMR (400 MHz, CDCl3, δ): 7.98 (d, J=9 Hz, 2H), 7.88 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.58 (s, 1H), 7.39 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.33 (dd, J=9, 4.6 Hz, 1H), 2.05 (m, 1H), 1.96-1.83 (m, 1H), 1.67-1.60 (m, 1H), 1.04 (d, J=6.6 Hz, 3H), 0.99 (d, J-6.6 Hz, 3H). MS (M+1): 419.0.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:34]1([CH2:38][O:39][C:40]2[N:45]=[C:44]([C:46]([OH:48])=O)[CH:43]=[N:42][C:41]=2[N:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)[CH2:37][CH2:36][CH2:35]1.[CH3:54][CH:55]([CH3:59])[CH2:56][CH2:57][NH2:58].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:54][CH:55]([CH3:59])[CH2:56][CH2:57][NH:58][C:46]([C:44]1[CH:43]=[N:42][C:41]([N:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)=[C:40]([O:39][CH2:38][CH:34]2[CH2:35][CH2:36][CH2:37]2)[N:45]=1)=[O:48]
Reactant: CC(C)CCN
Reactant: O=C(O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCNC(=O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Reaction time: 0.33 h
Yield: 51.7 %

Procedure:
A solution of PyBOP (156.1 mg, 0.3 mmol) in N,N-dimethylformamide (0.5 mL) was added to a solution of the 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (62.7 mg, 0.2 mmol) in N,N-dimethylformamide (1 mL) and the reaction mixture was left to stand for 20 minutes. 3-methyl butylamine (34.9 mg, 0.4 mmol) and N-ethyldiisopropylamine (103.4 mg, 0.8 mmol) were added and the reaction mixture was shaken for 16 hours. The solvent was removed in vacuo and the crude product was purified by preparative HPLC to afford 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (3-methyl-butyl)-amide as a solid 35.8 mg (52% yield) LC@215 nm; Rt 2.63: 100%, m/z (ES+): 347 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH:31]=O>>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH2:31][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[N:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cc(Br)ccc1F
Product: Fc1ccc(Br)cc1CNc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 5-bromo-2-fluorobenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 517.9.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[N:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[N:28][C:23]=2[NH:22][CH:21]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:27]3[N:28]=[C:23]4[NH:22][CH:21]=[N:20][C:24]4=[CH:25][CH:26]=3)=[O:30])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccc2nc[nH]c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccc2nc[nH]c2n1
Yield: 54.9 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.060 g, 0.215 mmol), 3H-imidazo[4,5]pyridine-5-carboxylic acid (0.035 g, 0.215 mmol), DIPEA (0.112 ml, 0.646 mmol), HOBt hydrate (0.050 g, 0.323 mmol) and EDCI (0.062 g, 0.323 mmol) using the method of Example 274 affording 0.050 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.22 (d, 3H), 4.46 (m, 3H), 6.99 (d, 1H), 7.81 (d, 1H), 7.89 (m, 3H), 8.09 (d, 1H), 8.63 (s, 1H), 8.80 (d, 1H), 13.00 (bs, 1H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CCN(CC)CC>C(Cl)Cl>[N:14]1([C:20]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.6 %

Procedure:
To a stirred solution of tert-butyl 1-piperazinecarboxylate (2.50 g, 13.42 mmol) in CH2Cl2 (75 mL) cooled in an ice-water bath was added 4-morpholinecarbonyl chloride (1.57 mL, 13.42 mmol) followed by Et3N (3.74 mL, 26.84 mmol), and the reaction mixture was allowed to warm to room temperature. After 15 h, the reaction mixture was washed with 1.0 N HCl (50 mL), saturated NaHCO3 (75 mL), and brie (50 mL), dried, and concentrated to give the title compound (3.80 g, 95%) as a white solid. Mp: 171-173° C. 1H NMR: δ3.69 (t, J=4.9 Hz, 4H, CH2OCH2), 3.46-3.40 (m, 4H, CH2NCH2), 3.28 (t, J=4.9 Hz, 4H, CH2NCH2), 3.25-3.20 (m, 4H, CH2CH2), 1.47 (s, 9H, t-Bu). MS (DCI/CH4): m/z (rel itensity) 300 (MH+, 73), 272 (28), 244 (100), 200 (73). Anal. (C14H25N3O4): C, H, N.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH:14]([CH3:15])[CH3:16]
Reactant: CCOC(=O)C1(CCC(C)C)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CCC(C)C)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-iso-pentyl-cyclopentane carboxylate (6.84 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.66 ml) was slowly added, then benzoyl chloride (5.33 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 11.73 g of brown liquid. MS: m/e 332(M+), 287(M+—OCH2CH3), 259(M+—CO2CH2CH3), 227(M+—C6H5CO), 211 (M+—C6H5CO2), 182, 171, 140, 105(base), 7
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[N:12]1([CH2:11][CH2:10][CH2:9][O:8][C:5]2[CH:4]=[C:3]([CH2:2][CH:21]3[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]3)[O:7][N:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: ClCc1cc(OCCCN2CCCCC2)no1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: c1c(OCCCN2CCCCC2)noc1CC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
1-[3-(5-Chloromethyl-isoxazol-3-yloxy)-propyl]-piperidine (0.15 g, 0.80 mmol) was dissolved in DCM (5 mL) and piperidine (0.24 mL, 2.4 mmol) was added slowly. The reaction mixture was stirred overnight at rt and then was concentrated to yield the crude product (0.140 g). The crude product was purified (SiO2: 0-5% 2 M NH3 in MeOH/DCM) to give the final product (0.118 g, 47.6%). MS (ESI): exact mass calcd. for C17H29N3O2, 307.23; m/z found 308.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 5.75 (s, 1H), 4.25-4.20 (m, 2H), 3.53 (s, 2H), 2.47-2.31 (m, 10H), 1.98-1.90 (m, 2H), 1.61-1.52 (m, 8H), 1.45-1.35 (m, 4H).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:26][C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][C:28]=1[N+:36]([O-])=O>>[CH3:26][C:27]1[S:31][C:30]([S:32](=[O:34])(=[O:33])[NH2:35])=[CH:29][C:28]=1[NH:36][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1sc(S(N)(=O)=O)cc1[N+](=O)[O-]
Product: Cc1sc(S(N)(=O)=O)cc1NC(=O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-methyl-thiophene-2-sulfonic acid amide (example B.11) according to general procedure II. Yellow solid. MS (ISP) 530.0 [(M−H)−]; mp 313° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=3)[CH2:26][CH2:25]2)=[CH:14][CH:13]=1.Cl>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)(=[O:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Agent: Cl
Product: CC(=O)c1cccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.41 (s, 1H), 7.72–6.84 (m, 12H), 5.18–5.10 (m, 1H), 3.62–3.50 (m, br, 2H), 3.00–2.92 (m, 2H), 2.90–2.58 (m, 4H), 2.54 (s, 3H), 2.50–2.12 (m, 2H), 2.02–1.70 (m, br, 6H), 1.64–1.50 (m, br, 1H), 1.50–1.14 (m, br, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 575.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3([N+:21]([O-])=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]3[OH:20])[CH:5]=[CH:4][C:3]1=2.Cl>O.C(O)C.[Fe]>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]3[OH:20])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C3([N+](=O)[O-])C=CC=CC3O)ccc21
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C3(N)C=CC=CC3O)ccc21
Yield: 85 %

Procedure:
Compound 27 was suspended in water (2 ml) and ethanol (6 ml), and the suspension was added with concentrated hydrochloric acid (0.5 ml). The mixture was added with iron powder (220 mg) and then heated under reflux for 30 minutes. The reaction mixture was filtered to remove solid materials and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was then evaporated under reduced pressure to give o-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtalenyl)-2-aminophenol (Compound 28, 80.5 mg, 85%).