Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([NH:6][CH2:7][C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28].C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:8]([CH2:7][NH:6][C:5]2[CH:24]=[CH:25][C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:35]=3)=[CH:3][CH:4]=2)=[CH:9][C:10]([C:20]([F:23])([F:22])[F:21])=[N:11]1
Reactant: FC(F)(F)c1cc(CNc2ccc(Br)cc2)n(-c2ccccc2Cl)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CS(=O)(=O)c1cccc(-c2ccc(NCc3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2)c1
Temperature: 140 °C

Procedure:
A mixture of 225 mg of 4-bromo-N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)aniline (0.52 mmol), 160 mg of 3-(methylsulfonyl)phenylboronic acid (0.82 mmol), 27 mg of PdCl2(dppf).CH2Cl2 (33 μmol), and 0.5 mL of 3.5 M aqueous K2CO3 (1.75 mmol) in DME (2.5 mL) was placed in a 5 mL microwave reaction vial and heated to 140° C. for 10 minutes in the Biotage Initiator microwave reactor. After cooling to room temperature the vial was opened and the lower aqueous layer was removed by means of a glass pipet. The resulting dark organic solution was diluted with EtOAc, treated with Na2SO4 filtered and concentrated in vacuo to afford a dark oil. The crude product was purified by silica gel flash chromatography on a 12 g column using gradient elution from 0% to 90% EtOAc/hexane. Appropriate fractions were combined and concentrated in vacuo to afford N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3′-(methylsulfonyl)biphenyl-4-amine as a white foam, yield 150 mg (57%): 1H NMR (400 MHz, CDCl3): δ 8.10-8.06 (m, 1H), 7.83-7.77 (m, 2H), 7.61-7.55 (m, 2H), 7.52-7.41 (m, 5H), 7.67 (s, 1H), 6.64-6.59 (m, 2H); MS (ESI) m/z 506.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C:18]([OH:20])=O)=[C:6]2[O:21][CH:22]([CH3:24])[CH3:23].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32].C(N(CC)CC)C.O>O1CCCC1>[OH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:18]([C:7]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:5]([C:6]=1[O:21][CH:22]([CH3:24])[CH3:23])=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:20]
Reactant: COc1ccc2c(c1)c(OC(C)C)c(C(=O)O)n2-c1ccccc1
Reactant: Nc1ccccc1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(OC(C)C)c(C(=O)Nc1ccccc1O)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
The procedure described in Example 16 is used to prepare the acyl chloride of 5-methoxy-3-(1-methylethoxy)-1-phenyl-1H-indole-2-carboxylic acid (4.0 g, 12 mmol). A solution of the crude acyl chloride in 45 mL of tetrahydrofuran is cooled in ice and treated dropwise with a solution of 2-aminophenol (1.3 g, 12 mmol) in 20 mL of tetrahydrofuran, followed by dropwise addition of triethylamine (1.7 mL, 1.2 g, 12 mmol). The mixture is stirred at room temperature for 2 hours and added to 300 mL of water. The mixture is extracted with dichloromethane, and the combined organic layers are washed with brine, dried (anhydrous sodium sulfate), and evaporated. Trituration of the residue with tert-butyl methyl ether yields 3.5 g (69%) of product; mp 168°-170° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[OH-].[Na+].[I-].[K+].Br[CH2:11][CH2:12][CH:13]=[CH2:14]>CC(O)(CC)C>[CH2:14]([N:2]1[N:3]=[CH:4][CH:5]=[N:1]1)[CH2:13][CH:12]=[CH2:11]
Reactant: c1c[nH]nn1
Reactant: C=CCCBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: C=CCCn1nccn1
Yield: 3.5 %

Procedure:
1H-[1,2,3]Triazole (10.36 g, 0.15 mol), sodium hydroxide (6 g, 0.15 mol) and potassium iodide (2.49 g, 0.015 mol) were dissolved in 2-methyl-2-butanol (50 ml) and heated to reflux for 1 h. At this temperature 4-bromo-but-1-ene (20.25 g, 0.15 mol) in 2-methyl-2-butanol (20 ml) were added dropwise and the resulting mixture was heated at reflux temperature for 4 h. After removal of the solvent the residue was taken up in ethyl acetate (100 ml), washed with water (3×50 ml), dried over sodium sulfate and concentrated. The crude product was purified by destillation yielding 0.65 g 2-but-3-enyl-2H-[1,2,3]triazole (b.p. 90-100° C. at 10 mbar), 1H-NMR (400 MHz, [D6]-DMSO): δ=2.62 (q, 2H, CH2—CH═CH2), 4.48 (t, 2H, CH2-triazole), 4.97–5.06 (m, 2H, CH2—CH═CH2), 5.75 (m, 1H, CH2—CH═CH2), 7.75 (s, 2H, triazole) and 6.36 g (34%) 1-but-3-enyl-1H-[1,2,3]triazole (b.p. 106–108° C. at 10 mbar) as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl-].[C:18]([O:22][C:23](=[O:26])[CH2:24][Zn+])([CH3:21])([CH3:20])[CH3:19].CCOCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1COCC1>[C:7]([C:6]1[CH:9]=[C:2]([CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH:3]=[CH:4][C:5]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=1)#[N:8]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: N#Cc1cc(Br)ccc1-c1ccnc(F)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(-c2ccnc(F)c2)c(C#N)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a sealed tube were added 5-bromo-2-(2-fluoropyridin-4-yl)benzonitrile 206-3 (42 mg, 0.16 mmol), 0.5 M (2-tert-butoxy-2-oxoethyl) zinc(II) chloride 86-5 in ether (0.46 mL, 0.23 mmol), Pd(dba)2 (4.4 mg, 0.008 mmol), Q-phos (10.8 mg, 0.015 mmol) and THF (1 mL). The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 100° C. for 1 hour. After cooling to room temperature, all the solvents were evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography and eluted with 20% ethyl acetate in hexane to give tert-butyl 2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)acetate 206-5. MS m/z 313.2 (M+1).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH:13]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>O1CCCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[C:14](=[O:15])[N:5]=[C:2]([CH3:3])[N:4]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(C(Cl)C(=O)Cl)cc1
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(C)=NC2=O)cc1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 11.8 grams (0.10 mole) of acetamidine hydrochloride in 200 mL of tetrahydrofuran is cooled to about 15° C., and 41.8 grams (0.30 mole) of potassium carbonate is added portionwise. To this is then added portionwise 21.8 grams (0.10 mole) of 2-chloro-2-(4-methoxyphenyl)acetyl chloride. Upon completion of addition, the reaction mixture is stirred for 15 minutes at 15° C., then it is warmed to reflux where it stirred for about four hours. The reaction mixture is then cooled and filtered to collect the by-product potassium chloride. The filtrate is concentrated under reduced pressure, yielding 4-(4-methoxyphenyl)-2-methylimidazol-5-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: NCCCCO
Product: O=C(NCCCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-amino-1-butanol using methods similar to Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.28 (1H, t, J=7 Hz), 8.53 (1H, s), 8.17 (1H, s), 7.38 (2H, dd, J=6, 8 Hz), 7.11 (2H, t, J=9 Hz), 4.42 (1H, t, J=5 Hz), 4.36 (2H, t, J=5 Hz), 4.13 (2H, s), 3.47 (2H, t, J=7 Hz), 3.21-3.42 (6H, m), 2.00 (2H, t, J=6 Hz), 1.41-1.82 (8H, m); ES+ MS: 511 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].[C:14]([O:17][CH2:18][CH3:19])(=[O:16])[CH3:15].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11](=[O:13])[CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Reactant: CCOC(C)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C1CCC(C(=O)OC)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Cyclohexane-1,4-dicarboxylic acid monomethyl ester (26.9 mmol, 5.0 g) and N,N′-carbonyldiimidazole (33.6 mmol, 5.44 g) in anhydrous THF (80 mL) were stirred 16 h at room temperature under argon. In a separate, sealed and argon-flushed flask, lithium HMDS (1.0 M in THF, 56.5 ml) is added to 40 mL anhydrous THF stirring at −78° C. To this solution is added dropwise anhydrous ethyl acetate (57.8 mmol, 5.65 mL). This solution is allowed to stir at −78° C. for 1 hour prior to dropwise addition of original CDI/acid solution that had been stirring overnight. The reaction mixture was allowed to stir and warm to room temperature overnight. The reaction is then quenched with saturated NH4Cl(aq) (200 mL) and extracted with Et2O (100×2). The combined organics are then washed with water, saturated brine, and dried over Na2SO4. The solvent was removed in vacuo and the crude residue (8.5 g) was used in the next step without further purification.
Reaction SMILES: C[CH2:2][O:3][CH2:4][CH3:5].[CH2:6]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([NH:12][NH2:13])=O)[CH3:7]>C(#N)C>[CH2:6]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]1[N:12]=[C:10]([C:9]2[CH:8]=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:14]=2)[NH:13][N:12]=1)[CH3:7]
Reactant: CCc1ccccc1C(=O)NN
Reactant: CCOCC
Solvent: CC#N
Product: CCc1ccccc1-c1n[nH]c(-c2cccc(OC)c2)n1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A mixture of immino ether (85 mg, 0.474 mmoles) and 2-ethyl benzo-hydrazide (164 mg, 1 mmole) in acetonitrile (0.5 mL), was warmed under reflux. After 1 hour stirring, solvent was distilled and substituted by 2-ethoxyethanol (0.6 mL). The reaction mixture was refluxed for 3 hours, the solvent evaporated under vacuum and the residue, re-dissolved in CH2Cl2 (2 mL), was chromatographed on a silica gel column (10 g). As elution solvents, mixtures of CH2Cl2 and CH3COOC2H5 in varying proportion (99:1 to 95:5) were used. Fractions containing the desired product were collected, solvent evaporated to give 96,27 mg (72.6%) of compound (XIII). Of particular interest, was compound (XIV), which, can be synthesised according to the procedure hereafter reported in example 2.
Reaction SMILES: C([Cl:4])(=O)C.C(OC([N:12]1[CH2:18][CH2:17][CH2:16][C:15]([F:20])([F:19])[CH2:14][CH2:13]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[ClH:4].[F:19][C:15]1([F:20])[CH2:16][CH2:17][CH2:18][NH:12][CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCCC(F)(F)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: FC1(F)CCCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (3.9 mL) was added to methanol (90 mL) at 0° C. and stirred for 20 minutes before addition of 4,4-difluoro-azepane-1-carboxylic acid tert-butyl ester as a solution in methanol (10 mL). After 30 minutes, HCl in dioxane (4 N, 40 mL) was added cautiously and the mixture was stirred at room temperature for 3 hours. The solution was concentrated, triturated with ether, filtered and dried under vacuum overnight to afford the title compound as an off-white solid (2.1 g). 1H NMR (400 MHz, DMSO): δ 9.5 (s, 2H), 3.2-3.1 (m, 4H), 2.5-2.4 (m, 2H), 2.3-2.2 (m, 2H), 1.9-1.8 (m, 2H).
Reaction SMILES: [Tl].Cl[C:3]1[C:4]([I:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[H-].[Na+].IC.CN([CH:22]=[O:23])C>>[I:14][C:4]1[C:3]([O:23][CH3:22])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH:12]=[O:13])=[CH:7][NH:8]2
Reactant: O=Cc1c[nH]c2ccc(Cl)c(I)c12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Agent: [Tl]
Solvent: CI
Product: COc1ccc2[nH]cc(C=O)c2c1I

Procedure:
By employing thallium chemistry, the 4-iodo-5-methoxy-indole-3-carboxaldehyde was prepared according to the procedure of Moody, C. J.; Swann, E. J. Chem. Soc. Perkin I 1993, 21, 2561 and the 5-chloro-4-iodo-indole-3-carboxaldehyde according to the procedure of Ohta, T.; Yamato, Y.; Tahira, H.; Somei M., Heterocycles 1987, 11, 2817 (and references therein). These derivatives were subsequently reacted with NaH and iodomethane in DMF to provide the corresponding N-methyl derivatives, which were then used for the preparation of compounds 190, 280 and 212 following a procedure analogous to that described in example 1. Following the general procedure of Ohta, T.; Yamato, Y.; Tahira, H.; Somei M., Heterocycles 1987, 11, 2817 (and references therein), as used above for the preparation of the 5-chloro-4-iodo-indole-3-carboxaldehyde, the 4-halogenated derivatives for a number of commercially available 5 or 6 substituted indole-3-carboxyladehydes were prepared via thallium-mediated chemistry, using (i) reaction with thallium tris-trifluoro acetate, followed by (ii) reaction an electrophile, such as KI or CuBr2. The resulting 4,5− or 4,6− disubstituted indole-3-carboxaldehydes were subsequently methylated at the indole N-position, as described in examples 13 and 16. The products were used for condensation with appropriate pyrazolones as described in example 1, to provide the desired compounds. Compounds 203, 266, 267, 281, 214, 221, 220, 222, 223, 289, 218, 219, 225, 226, 227, 228, 229, and 230 were derived following the sequence of steps described above.
Reaction SMILES: [CH3:1][C:2]([O:4][C@@H:5]1[CH2:18][C:17]2[C@@:8]([CH3:24])([C@@H:9]3[C@@H:14]([CH2:15][CH:16]=2)[C@@H:13]2[CH2:19][CH2:20][C:21](=[O:22])[C@@:12]2([CH3:23])[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)=[O:3].[CH3:25][C:26](C)=[O:27].C(OC(C)=C)(=O)C>C(OC(C)=C)(=O)C.S(=O)(=O)(O)O>[C:2]([O:4][C@H:5]1[CH2:6][CH2:7][C@@:8]2([CH3:24])[C:17](=[CH:16][CH2:15][C@@H:14]3[C@@H:9]2[CH2:10][CH2:11][C@@:12]2([CH3:23])[C@H:13]3[CH2:19][CH:20]=[C:21]2[O:22][C:26](=[O:27])[CH3:25])[CH2:18]1)(=[O:3])[CH3:1]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reactant: CC(C)=O
Agent: C=C(C)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)OC1=CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
300 g (0.9 mole) of dehydroepiandrosterone acetate are dissolved in 1160 ml of isopropenyl acetate, whereupon a solution of 4 ml of concentrated sulfuric acid in 100 ml of isopropenyl acetate is added. The temperature of the reaction mixture is raised slowly (in two hours) to the boiling temperature of isopropenyl acetate, and continuously 400 ml of an acetone/isopropenyl acetate mixture are distilled off. After heating and continuous distillation for 6 hours, the solution is cooled to room temperature and added to 10000 ml of ice water, under stirring. The precipitous solution is allowed to stand at 5° to 10° C. for 12 hours, whereupon the precipitate is filtered off, washed acid-free with water, dried at room temperature and the crude product is crystallized from methanol.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[N:48]([CH:51]([CH3:53])[CH3:52])=[C:49]=[O:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:49]([NH:48][CH:51]([CH3:53])[CH3:52])=[O:50])[CH2:42][CH2:41]1
Reactant: CC(C)N=C=O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 2-isocyanatopropane as starting materials in 41% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.33 (s, 1H), 9.31 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.73 (s, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 6.09 (m, 1H), 3.95 (m, 2H), 3.72 (m, 1H), 2.83 (m, 4H), 2.62 (m, 2H), 2.27 (m, 2H), 1.91 (m, 1H), 1.62 (m, 2H), 1.12 (m, 2H), 1.00 (d, 6H). LCMS for C29H35ClN7O3 (M+H)+: m/z=548.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[C:16]1([C:22]2([CH2:27][CH2:28][OH:29])[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([N:24]1[CH2:25][CH2:26][C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:27][CH2:28][OH:29])[CH2:23]1)=[O:6]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1OC
Reactant: OCCC1(c2ccccc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(=O)N2CCC(CCO)(c3ccccc3)C2)c(OC)c1OC

Procedure:
Combine 2,3,4-trimethoxybenzoyl chloride (10 mmol) and 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (2.1 g, 9.2 mmol) in acetone (70 mL). Add water (25 mL) and potassium carbonate (1.93 g, 14 mmol). Dilute the reaction mixture with ethyl acetate and extract with aqueous sodium bicarbonate solution and brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.[CH3:17][NH2:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:18][CH3:17])[CH2:8][CH2:7]1
Reactant: CN
Reactant: O=C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 72 h

Procedure:
To a solution of 1-(3,4-Dichloro-benzyl)-piperidin-4-one (3.1 g) in dichloromethane (50 ml) and acetic acid (0.69 ml) was added methylamine (6 ml of a 1M solution in tetrahydrofuran). The mixture was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (3 g) and the resulting mixture stirred for 72 hours. Sodium bicarbonate solution (100 ml) added and the mixture stirred vigorously for 5 minutes before extraction of the product with dichloromethane (2×200 ml). The organics were separated, bulked and dried, (MgSO4). Purification by Biotage® 40S eluting 10%MeOH/0.5% 800 ammonia/dichloromethane gave the sub-title compound (1.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7](OCC)=[O:8])[N:4]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][C:25]([F:28])([F:27])[F:26])[CH:15]=[CH:16][CH:17]=2)[N:3]=1.CC(C[AlH]CC(C)C)C>>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][OH:8])[N:4]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][C:25]([F:27])([F:26])[F:28])[CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1cccc(-c2ccccc2OC(F)(F)F)c1
Agent: CC(C)C[AlH]CC(C)C
Product: Cc1cc(CO)n(-c2cccc(-c3ccccc3OC(F)(F)F)c2)n1

Procedure:
The titled compound was prepared by reacting ethyl 3-methyl-1-[2′-(trifluoromethoxy)-1,1′-biphenyl-3-yl]-1H-pyrazole-5-carboxylate (EXAMPLE 21) with DIBALH in a manner described in EXAMPLE 123. MS (ESI): m/e 349 (M+1)+
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].ClC(N(C)C)=C(C)C.[NH2:17][C:18]1[CH:23]=[C:22]([O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([NH:35][C:36]([NH:38][C:39]3[N:43]([C:44]4[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=4)[N:42]=[C:41]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:40]=3)=[O:37])=[CH:27][CH:26]=2)[CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C.N>C(Cl)Cl.CO>[C:51]([C:41]1[CH:40]=[C:39]([NH:38][C:36](=[O:37])[NH:35][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([O:24][C:22]3[CH:21]=[CH:20][N:19]=[C:18]([NH:17][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]=3)=[CH:26][CH:27]=2)[N:43]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:42]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(N)c3)c3ccccc23)cc1
Agent: CC(C)=C(Cl)N(C)C
Agent: N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(NC(=O)CS(C)(=O)=O)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a suspension of methanesulfonylacetic acid (40 mg, 0.29 mmol) in DCM (2.0 mL) under nitrogen was added 1-chloro-N,N,2-trimethylpropenylamine (48 μL, 0.37 mmol), and the mixture was stirred at RT for 2 hr. The resulting mixture was added to a solution of (Intermediate Q) (37 mg, 0.07 mmol) and DIPEA (51 μL, 0.29 mmol) in DCM (2.0 mL) and stirring continued at RT for 3 hr. The reaction mixture was stirred with 1% NH3 in MeOH (3.0 mL) for 45 min and then evaporated in vacuo. The residue was subjected to SCX capture and release and was then purified by flash column chromatography (SiO2, 12 g, 0-70% [5% MeOH in EtOAc] in isohexane, gradient elution) to afford the title compound (Example 51) as a white powder (13 mg, 28%): m/z 627 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.39 (3H, s), 3.10 (3H, s), 4.36 (2H, s), 6.40 (1H, s), 6.71 (1H, dd), 7.33-7.38 (3H, overlapping m), 7.47 (2H, m), 7.56 (1H, m), 7.65 (1H, m), 7.69 (1H, m), 7.85 (1H, d), 7.96 (1H, d), 8.11 (1H, d), 8.22 (1H, d), 8.91 (1H, br s), 9.23 (1H, br s), 10.96 (1H, br s).
Reaction SMILES: C(OC([N:11]1[CH2:14][CH2:13][C@H:12]1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH:27]3[CH:25]([CH2:26]3)[CH2:24]2)[CH:20]=[N:21][CH:22]=1)=O)C1C=CC=CC=1.[C:29]([OH:38])(=[O:37])[C@@H:30]([C@H:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31]>CO.[Pd]>[C:34]([C@@H:32]([C@H:30]([C:29]([OH:38])=[O:37])[OH:31])[OH:33])([OH:36])=[O:35].[NH:11]1[CH2:14][CH2:13][C@H:12]1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:24][CH:25]3[CH:27]([CH2:26]3)[CH2:28]2)[CH:20]=[N:21][CH:22]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@H]1COc1cncc(N2CC3CC3C2)c1
Agent: [Pd]
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Product: c1ncc(N2CC3CC3C2)cc1OC[C@@H]1CCN1
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a solution of 3-[5-[[1-(benzyloxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-azabicyclo[3.1.0]hexane (395 mg, 1.04 mmol) in methanol (30 mL) in a 100 mL round-bottom flask were added L-tartaric acid (156 mg, 1.04 mmol) and 10% palladium on carbon (40 mg). The atmosphere was exchanged with H2 (3 times), and the mixture was stirred under H2 (1 bar) for 3 h. The mixture was filtered through a cotton plug, and the filtrate was concentrated. The residue was further dried with an oil pump at room temperature to give the product as a brittle, tan foam (404 mg, 91%). Anal. Calcd. for C14H19N3.O1.09C6H4O6.1.06H2O (FW 428.0): C, 51.52; H, 6.51; N, 9.82. Found: C, 51.61; H, 6.60; N, 9.72.