Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[N:19]4[C:14]([CH:15]=[N:16][C:17](S(C)(=O)=O)=[N:18]4)=[CH:13][CH:12]=3)[C:4]=2[O:3]1.[OH-].[Na+].C(O)(=[O:29])C>O1CCCC1.O>[F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[N:19]4[C:14]([CH:15]=[N:16][C:17]([OH:29])=[N:18]4)=[CH:13][CH:12]=3)[C:4]=2[O:3]1
Reactant: CS(=O)(=O)c1ncc2ccc(-c3cccc4c3OC(F)(F)O4)n2n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ncc2ccc(-c3cccc4c3OC(F)(F)O4)n2n1
Temperature: 60 °C
Yield: 91.7 %

Procedure:
7-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (0.410 g) was suspended in Tetrahydrofuran (2.00 mL), 5.0 M of Sodium hydroxide in Water (1.00 mL, 5.00 mmol) was added and the mixture was heated in a vial, in a block at 60° C. for 3 h. The mixture was then treated with a solution of Acetic acid (0.500 mL, 8.79 mmol) in Water (5.50 mL), generating an orange ppt. The mixture was cooled, the solids collected, washing with 10 mL water. Dry on the Buchner to afford 7-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (0.310 g; Yield=78.6%). LCMS (HPLC): 0.97 min, m/z=292 (M+H); 1H-NMR (DMSO-d6): 11.97 (s, 1H), 9.10 (s, 1H), 8.38 (d, 1H, 8.0 Hz), 7.44 (d, 1H, J=7.9 Hz), 7.38 (m, 1H), 7.25 (d, 1H, J=4.8 Hz), 7.09 (d, 1H, J=4.8 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([C:17]([NH2:18])=[O:32])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccccc1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(phenylamino)pyrazine-2-carbonitrile (47 mg, 0.136 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (31 mg). MS 363.3 (M+H); UV 203.6, 248.7, 301.5 nm; t 0.477 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:13]=[C:14]([CH:18]([CH:25]2[CH2:27][CH2:26]2)[NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:15]=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]([CH:18]([CH:25]2[CH2:27][CH2:26]2)[NH:19][S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])[CH:15]=[N:16][CH:17]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccccc2Cl)c1)C1CC1
Temperature: 100 °C
Yield: 21.4 %

Procedure:
A mixture of 2-chlorophenylboronic acid (24 mg, 0.16 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (50 mg, 0.16 mmol), PdCl2(PPh3)2 (9 mg, 0.01 mmol) and Na2CO3 (2 M in water, 0.16 mL, 0.32 mmol) in DMF (1.5 mL) was heated at 100° C. for 2 h. After concentration, the residue was dissolved in DCM and filtered. The filtrates were concentrated and purified by flash column (EtOAc/Heptane, v/v, 0-40%) to give the title compound (12 mg, 23%); ESI-MS m/z: 351 [M+1]+, 1H-NMR (MeOD, 400 MHz) δ 8.65 (1H, d, J=2.0 Hz), 8.55 (1H, d, J=2.0 Hz), 8.04 (1H, t, J=2.0 Hz), 7.61-7.58 (1H, m), 7.48-7.44 (3H, m), 4.29 (1H, d, J=8.8 Hz), 3.02-2.89 (2H, m), 1.34-1.28 (1H, m), 1.28 (1H, t, J=7.2 Hz), 0.80-0.75 (1H, m), 0.67-0.60 (2H, m), 0.51-0.47 (1H, m)
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:26]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.O[NH:49][C:50](=[NH:52])[CH3:51]>CN(C=O)C.O>[CH3:51][C:50]1[N:52]=[C:20]([C:19]2[CH:18]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:26]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:25]=[CH:24][CH:23]=2)[O:21][N:49]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)O)c1)C2=O
Reactant: CC(=N)NO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C)no3)c1)C2=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic acid (180 mg, 0.49 mmol) obtained in Step 1 of Example 56 was suspended in DMF (3.0 mL), and the mixture was stirred at 100° C. for 6 hours after adding 1-hydroxybenzotriazole (200 mg, 1.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (280 mg, 1.46 mmol), and N-hydroxyacetamidine (108 mg, 1.46 mmol). Thereafter, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-5-[3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (183 mg, 91%).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][N:23]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]1>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:28][C:26]3[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cn1cc(N)cn1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)Nc2cnn(C)c2)cn1
Yield: 55 %

Procedure:
As described for example 19b, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted, using 1-methyl-1H-pyrazol-4-ylamine instead of L-2,2,2-trifluoro-1-(methyl)ethylamine, to the title compound (70 mg, 55%) which was obtained as a yellow oil after purification by chromatography (silica, heptane:ethyl acetate 9:1 to 1:1). MS: m/e=370.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([C:9]1[CH:10]=C([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1)C(O)=O)#[N:8].CN(C)C=O>ClCCl>[C:7]([C:9]1[CH:10]=[C:1]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1)[C:2]([Cl:4])=[O:3])#[N:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc(C(=O)O)ccc1OCC1CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)Cl)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Oxalyl chloride (0.040 ml, 0.460 mmol) was added to a stirred solution of 3-cyano-4-[(cyclopropylmethyl)oxy]benzoic acid (D24; 50 mg, 0.230 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at room temperature under nitrogen, and the mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo to give the title compound (54.2 mg) which was used in the subsequent step (D49) without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C:22]2[CH:23]=[C:24]([C:28]3[O:32][C:31]([C:33](=O)[CH3:34])=[CH:30][CH:29]=3)[CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:15][CH2:14]1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[C:33](/[C:31]1[O:32][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:20]([N:16]3[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]3)=[O:21])[CH:23]=2)=[CH:29][CH:30]=1)\[CH3:34]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CC(=O)c1ccc(-c2cccc(C(=O)N3CCCN(C)CC3)c2)o1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C/C(=C1\C(=O)Nc2ccc(Cl)cc21)c1ccc(-c2cccc(C(=O)N3CCCN(C)CC3)c2)o1
Yield: 42 %

Procedure:
A solution of 5-chlorooxindole (668 mg, 4 mmol), 1-(5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)ethanone (1.7 g of oil) and piperidine (394 μL, 4 mmol) in toluene (15 mL) was heated at reflux with a Dean-Stark receiver for 24 hours. After evaporation of the solvent, purification by silica column chromatography (methanol gradient in dichloromethane, 0 to 5% vol) gave (E)-5-chloro-3-(1-(5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)ethylidene)indolin-2-one (800 mg) as a E:Z mixture. LCMS (ES): m/z 476 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.O>CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 72.4 %

Procedure:
A solution of 61 g (0.5 mole) of 4-hydroxybenzaldehyde in 20 mL of dry DMF was added to a suspension of 0.5 mole of sodium hydride (from 24 g of 50% sodium hydride washed free of oil with hexane) in 500 mL of DMF. When the sodium hydride had completely dissolved, a solution of 53 mL (0.55 mole) of 4-fluoronitrobenzene was added and the reaction mixture was heated to 70°-80° C. for 2 hr. The mixture was then poured into water, the solid collected and recrystallized from iso-propanol. The solid was recrystallized again from ethanol to give 88 g (85% yield) of the title compound as a yellow solid, mp=101°-104° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=4)[N:30]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)=[O:11].[I-].[Na+]>C1COCC1.CC(N(C)C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:26]=[CH:27][C:28]5[N:29]([C:31]([C:34]([F:37])([F:35])[F:36])=[N:32][N:33]=5)[N:30]=4)[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(CCl)Nc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CN1CCN(CC(=O)Nc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 60 °C
Yield: 69.7 %

Procedure:
1-Methylpiperazine (140 μl, 1.27 mmol) was added to 2-chloro-N-[4-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]acetamide (139 mg, 0.317 mmol) and sodium iodide (10 mg, 0.063 mmol) in a mixture of THF (2 mL) and DMA (0.5 mL). The resulting solution was heated at 60° C. for 2 hours, then cooled and evaporated to give the crude product which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 2-(4-methylpiperazin-1-yl)-N-[4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]acetamide (111 mg, 70%) as a solid.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-:3].[Cl-:4].ClC(Cl)(Cl)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Cl:1][C:9]1[CH:10]=[C:11]([Cl:3])[C:12]([Cl:4])=[CH:13][C:8]=1[OH:7]
Reactant: [Cl-]
Reactant: ClC(Cl)(Cl)Oc1ccccc1
Agent: [Al+3]
Product: Oc1cc(Cl)c(Cl)cc1Cl
Yield: 24 %

Procedure:
Although aluminium chloride is a member of the class of Lewis acids, other Lewis acids have not been found effective or useful in the process of the invention. Ferric chloride did not effect significant demethylation. Only a 24% yield of 2,4,5-trichlorophenol was obtained when trichloroanisole was treated with a large excess of concentrated sulphuric acid for six hours at 75° C. in the absence of solvent. Other Lewis acids, viz. boron trichloride, boron trifluoride and pyridinium hydrochloride, are not economically attractive for this use. Thus aluminium trichloride is preferred as the demethylating agent.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[N:34]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH:13]=[N:12]2)[C:8]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][C:39]([OH:41])([CH3:42])[CH3:40])[N:34]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(=O)N2CCCC2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(=O)N3CCCC3)cc2=O)n1
Yield: 19 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-{6-oxo-4-[2-(pyrrolidine-1-carbonyl)-phenoxy]-6H-pyridazin-1-yl}-propionic acid (Intermediate 27) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-{6-oxo-4-[2-(pyrrolidine-1-carbonyl)-phenoxy]-6H-pyridazin-1-yl}-propionamide as a light yellow solid (24.6 mg, 19%); ES+-HRMS m/e calcd for C30H38N6O5 [M+H+] 563.2977 found 563.2974. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.08 (m, 7H) 1.25-2.03 (m, 13H) 2.19-2.40 (m, 1H) 3.21 (t, J=6.2 Hz, 2H) 3.28-3.36 (m, 2H) 3.89 (s, 2H) 4.67 (s, 1H) 5.47 (dd, J=11.1, 4.3 Hz, 1H) 5.79 (d, J=2.8 Hz, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.38 (d, J=8.1 Hz, 1H) 7.41 (t, J=7.5 Hz, 1H) 7.49-7.54 (m, 2H) 7.54-7.61 (m, 1H) 8.07 (d, J=2.8 Hz, 1H) 10.80 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[N:10]2)=[CH:5][CH:4]=1.[C:18]1([C@H:28]([NH2:30])[CH3:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.ClCCCl>[C:18]1([C@H:28]([NH:30][CH2:14][C:11]2[CH:12]=[CH:13][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=3)[N:10]=2)[CH3:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccn(-c2ccc(C(F)(F)F)cc2)n1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@@H](NCc1ccn(-c2ccc(C(F)(F)F)cc2)n1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with 1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbaldehyde 65 (0.200 g, 0.833 mmol), (R)-1-(naphthalen-1-yl)ethanamine 39 (0.171 g, 0.999 mmol), sodium triacetoxyborohydride (0.353 g, 1.67 mmol), 4 mL of DCE, and 3 drops of AcOH. This mixture was stirred overnight at room temperature and then quenched with saturated aqueous NaHCO3. The mixture was extracted with DCM, dried, and concentrated. Purification by column chromatography on silica gel (10% to 50% EtOAc in hexanes) gave ((1R)-1-(1-naphthyl)-N-({1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}methyl)ethanamine 66. Mass spectrum, calculated for C23H20F3N3 395.2; found 396.2 (M++1).
Reaction SMILES: Cl[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:3][N:4]=[C:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:4][N:3]=[C:2]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=1
Reactant: ClC(=NN=C(Cl)c1ccccc1)c1ccccc1
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: Brc1ccc(-n2c(-c3ccccc3)nnc2-c2ccccc2)cc1
Temperature: 135 °C
Reaction time: 5 h

Procedure:
4.5 g (16 mmol) of 1,2-bis(chloro(phenyl)methylene)hydrazine, 2.0 g (16 mmol) of 4-bromoaniline, and 30 mL of N,N-dimethylaniline were put into a 100 mL three-neck flask, and nitrogen substitution was performed on the contents of the flask. The mixture was stirred at 135° C. for 5 hours. After the reaction, a solid was precipitated out with the reactive solution being added to approximately 100 mL of 1 N diluted hydrochloric acid and the mixture being stirred for 30 minutes. Suction filtration was performed on the precipitated solid, and a solid was obtained. The obtained solid was dissolved in toluene and washed with water and a saturated sodium carbonate solution, in the order given. Magnesium sulfate was added to an organic layer, and the mixture was dried. Suction filtration was performed on the mixture to remove the magnesium sulfate, and thus a filtrate was obtained. The solid, which was obtained by condensation of the obtained filtrate, was recrystallized with a mixed solvent of ethanol and hexane, so that 2.3 g of a powdery white solid, which was the object of the synthesis, was obtained at a yield of 38%.
Reaction SMILES: C(O[CH:5]([C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:24]([CH2:34][CH2:35][CH2:36][CH3:37])=[N:23][CH:22]=1)[CH:6]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=O)C.C1(C)C=CC=CC=1>CCOCC>[CH2:34]([C:24]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:21](/[CH:5]=[C:6](\[CH2:11][C:12]2[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=2)/[C:7]([O:9][CH3:10])=[O:8])=[CH:22][N:23]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCc1ncc(C(OC(C)=O)C(Cc2ccc3c(c2)OCO3)C(=O)OC)n1Cc1ccccc1Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCc1ncc(/C=C(\Cc2ccc3c(c2)OCO3)C(=O)OC)n1Cc1ccccc1Cl
Yield: 91.3 %

Procedure:
A solution of methyl 3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-(3,4-methylenedioxyphenyl)methylpropanoate (1.36 g, 2.58 mmol), 1,8-diazobicyclo[5,4,0]undec-7-ene (1 mL, 6.48 mmol) and toluene (10 mL) was heated at 90 ° C. for 18 hours under argon. The cooled reaction mixture was diluted with ether, the solution was filtered and the filtrate was concentrated. Chromatography of the product over silica gel with a gradient of ethyl acetate in hexane provided 1.1 g (87%) of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5yl]-2-(3,4-methylenedioxyphenyl)methyl-2-propenoate as a low melting solid whose NMR showed the E or trans relationship of the ester group to the imidazole ring.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.C[Si](C)(C)[C:34]#[C:35][CH3:36].C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I.CN(C=O)C>[F:24][C:23]([F:26])([F:25])[C:22]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:34]#[C:35][CH3:36])[CH:3]=1)([OH:31])[C:27]([F:30])([F:29])[F:28]
Reactant: CC#C[Si](C)(C)C
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1
Temperature: 120 °C
Yield: 23.8 %

Procedure:
A glass microwave reaction vessel was charged with 2-(3-bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (128 mg, 0.23 mmol, Example 69, step 2), 1-(trimethylsilyl)-1-propyne (0.173 mL, 1.16 mmol, Sigma-Aldrich, St. Louis, Mo.), diethylamine (48 μL, 0.46 mmol, Sigma-Aldrich, St. Louis, Mo.), bis(triphenylphosphine) palladium(II) dichloride (15 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), triphenylphosphine (12 mg, 0.05 mmol, Sigma-Aldrich, St. Louis, Mo.), copper iodide (9 mg, 0.05 mmol, Strem Chemical Inc, Newburyport, Mass.), and DMF (1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 30 min. The reaction was diluted with EtOAc (about 10 mL) and water (about 10 mL). The organic layer was separated and washed with water (10 mL), dried (Na2SO4), concentrated and purified column chromatography (12 g silica, 0 to 20% EtOAc in hexanes to afford 1,1,1,3,3,3-hexafluoro-2-(3-(1-propyn-1-yl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (28 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.CCCCCC>[CH2:18]([N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCNCc1ccccc1
Reactant: O=C(Nc1cccc(Cl)c1)Oc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCN(Cc1ccccc1)C(=O)Nc1cccc(Cl)c1

Procedure:
A solution of 1.46 g of phenyl N-(3-chlorophenyl)carbamate in 15 ml of tetrahydrofuran was added to a solution of 1.92 g of N-benzyl-n-butylamine in 20 ml of tetrahydrofuran and the mixture stirred under reflux for hours. The mixture was diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane afforded 1-benzyl-1-(n-butyl)-3-(3-chlorophenyl)urea, m.p. 69°-70° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCBr
Reactant: COc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(OC)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A mixture of 2-bromo-4-methoxyphenol (available from Betapharma Inc.) (1.50 g, 7.39 mmol), 1-bromobutane (available from Aldrich) (0.95 mL, 8.87 mmol), and cesium carbonate (3.13 g, 9.60 mmol) in DMF (40 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 4.1 (1.49 g, 78% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.15 (d, J=2.7 Hz, 1H), 6.84 (d, J=9.0 Hz, 1H), 6.80 (dd, J=3.1, 9.0 Hz, 1H), 3.97 (t, J=6.5 Hz, 2H), 3.76 (s, 3H), 1.79 (m, 2H), 1.53 (m, 2H), 0.98 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[BH4-].[Na+]>CO.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 4-bromo-2-fluorobenzaldehyde (25 g, 0.123 mol) in methanol (250 ml) was added NaBH4 (7.02 g, 0.1847 mol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with 25 ml of water and solvent evaporated under reduced pressure. The compound was extracted with ethyl acetate, organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded the sub-title compound (25 g) as an oil. This was directly taken for next step without further purification.