Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C@@:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([OH:17])[C@H:8]([C:10]2[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=2)[CH3:9])[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:26][N:27]1[C:31]([CH:32]=[CH2:33])=[CH:30][CH:29]=[N:28]1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]1([CH2:6][C@@:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([OH:17])[C@H:8]([C:10]2[CH:15]=[CH:14][C:13](/[CH:33]=[CH:32]/[C:31]3[N:27]([CH3:26])[N:28]=[CH:29][CH:30]=3)=[CH:12][CH:11]=2)[CH3:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[C@@H](c1ccc(I)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: C=Cc1ccnn1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H](c1ccc(/C=C/c2ccnn2C)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 64.7 %

Procedure:
A stirred solution of (2R,3S)-1-(1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(4-iodophenyl)butan-2-ol (Preparation 12; 0.5 g, 1.1 mmol), 1-methyl-5-vinylpyrazole (Preparation 17; 0.14 g, 1.3 mmol), triethylamine (0.25 ml, 2 mmol), palladium acetate (130 mg, 0.6 mmol) and tri-o-tolylphosphine (340 mg, 1.2 mmol) in acetonitrile (25 ml) was heated under reflux for 1 hour and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (50 ml), then the organic phase separated, washed with saturated brine (30 ml), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of hexane:propan-2-ol (90:10 to 75:25), to give the title compound (0.31 g) as a white solid, m.p. 81-83° C., after crystallisation from aqueous ethanol. [α]D25 −55° (c=0.1, CH3OH).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](=[N:12][OH:13])[CH3:11].[H-].[Na+].[C:16]([NH:23][CH2:24][CH2:25][CH2:26]Cl)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C)C=O>[C:11]1([C:10](=[N:12][O:13][CH2:26][CH2:25][CH2:24][NH:23][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:2]2[NH:1][C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)[CH:11]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCCCCl
Reactant: CC(=NO)c1cc2ccncc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCON=C(c1ccccc1)c1cc2ccncc2[nH]1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
A mixture of 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanone oxime (Example 72) (100 mg, 0.42 mmol) and sodium hydride (18 mg of a 60% in mineral oil, 0.45 mmol) in N,N-dimethylformamide (4 mL) was stirred for 0.5 h. N-Boc chloropropylamine (86 mg, 0.44 mmol) was added dropwise and the reaction mixture was heated at 60° C. for 3 h. After stirring at room temperature for 12 h, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated to an oil. Purification by Biotage chromatography (30 to 100% ethyl acetate in hexanes) produced tert-butyl 3-[[[phenyl (1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]propylcarbamate (76 mg, 46%) as a white solid: mp 52-58° C.; ESI MS m/z 395 [C22H26N4O3+H]+; HPLC (Method A) 98.6% (AUC), tR=19.2 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([NH:29][C:30](=[O:46])[O:31][CH2:32][CH:33]2[C:45]3[CH:44]=[CH:43][CH:42]=CC=3C3[C:34]2=CC=CC=3)[C:13](=[O:28])[NH:14][C@H:15]([CH2:19][O:20][CH2:21]CCCCC=C)[CH:16]([CH3:18])[CH3:17])=[CH:7][CH:6]=1)C=C>ClCCl>[CH:16]([C@@H:15]1[NH:14][C:13](=[O:28])[C@H:12]([NH:29][C:30](=[O:46])[O:31][CH2:32][CH:33]2[C:34]3[CH:9]=[CH:10][CH:5]=[CH:6][C:7]=3[C:8]3[C:45]2=[CH:44][CH:43]=[CH:42][CH:11]=3)[CH2:11][C:8]2=[CH:9][CH:10]=[C:5]([CH:6]=[CH:7]2)[O:4][CH2:1][CH:32]=[CH:33][CH2:45][CH2:44][CH2:43][CH2:42][CH2:21][O:20][CH2:19]1)([CH3:17])[CH3:18]
Reactant: C=CCCCCCOC[C@@H](NC(=O)[C@@H](Cc1ccc(OCC=C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H]1COCCCCCC=CCOc2ccc(cc2)C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1
Yield: 181.1 %

Procedure:
A solution of 1.01 g (1.61 mmol) of 9H-fluoren-9-yl-methyl [(R)-2-(4-allyloxyphenyl)-1-((S)-1-hept-6-enyloxymethyl-2-methylpropylcarbamoyl)ethyl]carbamate and 0.15 g (0.24 mmol) of dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium (Hoyveda-Grubbs catalyst) in 460 ml of dichloromethane was stirred at 40° C. for 24 h. The reaction mixture was then concentrated, and the residue was purified by chromatography on silica gel. 0.87 g of the desired compound was obtained as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]([CH2:18]C)[CH2:14][CH2:15][O:16][CH3:17])=[N:10][C:9]=2[C:20]2[C:21]([F:36])=[C:22]([NH:26][S:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:37].[OH-]>O.Cl.C(Cl)Cl>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:20]2[C:21]([F:36])=[C:22]([NH:26][S:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)(=[O:28])=[O:29])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CCN(CCOC)c1nc(-c2cccc(NS(=O)(=O)C3CCCCC3)c2F)c(-c2ccnc(Cl)n2)s1
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)C3CCCCC3)c2F)n1
Temperature: 120 °C
Yield: 41 %

Procedure:
N-[3-(5-(2-Chloro-4-pyrimidinyl)-2-{ethyl[2-(methyloxy)ethyl]amino}-1,3-thiazol-4-yl)-2-fluorophenyl]cyclohexanesulfonamide (148 mg, 0.275 mmol) was suspended in NH4OH (4 mL) and heated in microwave reactor at 120° C. for 48 min. The reaction was diluted with water and neutralized with 5% aqueous HCl and solid formed. A solid was diluted with DCM and water. The organic layer was dried over Na2SO4, filtered, added silica gel and concentrated. The crude product was chromatographed on silica gel eluting with 100% DCM to 1:1 [DCM:(9:1 EtOAC:MeOH)]. The clean fractions were combined and concentrated. The product was triturated in diethyl ether and filtered to obtain the title compound as a yellow powder (58 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 7.87 (d, J=5.3 Hz, 1H), 7.43-7.62 (m, 1H), 7.09-7.41 (m, 2H), 6.35-6.74 (m, 2H), 5.80 (d, J=5.3 Hz, 1H), 3.68 (t, J=4.6 Hz, 4H), 3.43 (t, J=4.6 Hz, 4H), 2.81-3.02 (m, 1H), 1.69 (d, J=12.5 Hz, 2H), 1.51 (br. s., 1H), 1.33 (qd, J=12.1, 2.2 Hz, 2H), 0.89-1.22 (m, 5H). MS (ESI): 518.9 [M+H]+.
Reaction SMILES: I[C:2]1[N:14]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][N:10]1[C:9]2=[C:4]3[CH:3]=[C:2]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=4)[N:14]([S:15]([C:18]4[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=4)(=[O:17])=[O:16])[C:5]3=[N:6][CH:7]=[C:8]2[CH:12]=[N:11]1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)cnn4C)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cccc(S(C)(=O)=O)c3)cc3c4c(cnc32)cnn4C)cc1
Temperature: 90 °C
Yield: 126.7 %

Procedure:
A mixture of 7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.134 g, 0.296 mmol), 3-(methylsulfonyl)phenylboronic acid (0.711 g, 0.356 mmol, Combi-Blocks), Pd(PPh3)4 (0.24 g, 0.021 mmol, Strem), Na2CO3 (0.790 g, 0.741 mmol) in 1,4-dioxane:water (3:1, 10 mL) was heated to about 90° C. for about 5 h. The reaction mixture was filtered through a plug of Celite®. The filtrate was washed with water (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 1-methyl-7-(3-(methylsulfonyl)phenyl)-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.180 g, 0.375 mmol) that was dissolved in MeOH (3 mL) and treated with aqueous NaOH (5 N, 0.75 mL, 3.8 mmol) The reaction vessel was sealed and heated in a CEM microwave at about 120° C. for about 20 min (250 psi maximum pressure, 2 min ramp time, 300 max watts). The reaction mixture was filtered and washed with MeOH (3 mL). The filtrate was concentrated in vacuo, and purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to give 1-methyl-7-(3-(methylsulfonyl)phenyl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.65 g, 53%): LC/MS (Table 2, Method d) Rt=1.23 min; MS m/z: 327 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](C2C=CC=CC=2)=[N:4][NH:5][CH:6]=1.C1C=C[C:16](/[CH:19]=[CH:20]/[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:17][CH:18]=1.C1C=C[C:34](/[CH:37]=[CH:38]/[C:39](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd:67].[Pd].Cl>>[CH2:2]([C:3]1[N:4]([C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[CH:34]=[CH:37][CH:38]=[C:39]([OH:40])[CH:41]=2)[N:5]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]=1[C:21]1[CH:18]=[CH:17][CH:16]=[CH:19][CH:20]=1)[CH3:6].[Pd:67]
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Reactant: Brc1c[nH]nc1-c1ccccc1
Agent: [Pd]
Agent: Cl
Product: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1-c1ccccc1-c1cccc(O)c1
Reaction time: 1 h

Procedure:
The reaction of Example 1 (reaction scale: 10 mmol of bromophenyl pyrazole) was conducted with 0.15 mole % of Pd2(dba)3. After the reaction was judged to be essentially complete, the reaction mixture was neutralized with 1N aq. HCl to a pH of 7.0 to 7.5. After filtration, the crude solid was dissolved in acetone (25 mL/g of bromophenyl pyrazole starting material) at 55° C. TMT (0.05 equiv.) was added, and the mixture was stirred for 1 h while the temperature was allowed to decrease to 30° C. The resulting solution was filtered twice through a Darco zeta pad. The filtrate was concentrated by partial removal of the organic solvents. Recrystallization from acetone/water afforded 2′-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)-[1,1′]-biphenyl-3-ol containing 33 ppm of palladium.
Reaction SMILES: Br[CH2:2][CH:3]([F:5])[F:4].[Cl:6][C:7]1[CH:8]=[C:9]([OH:28])[CH:10]=[CH:11][C:12]=1[CH:13]([CH3:27])[C:14]([OH:26])([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)[C:15]([F:18])([F:17])[F:16]>>[Cl:6][C:7]1[CH:8]=[C:9]([O:28][CH2:2][CH:3]([F:5])[F:4])[CH:10]=[CH:11][C:12]=1[CH:13]([CH3:27])[C:14]([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)([OH:26])[C:15]([F:16])([F:18])[F:17]
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: FC(F)CBr
Product: Cc1cnc(C(O)(C(C)c2ccc(OCC(F)F)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 2-bromo-1,1-difluoroethane and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=411.0 (MH+).
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1)=O)(C)(C)C>O1CCOCC1>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH2:9])=[CH:12][CH:13]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)Nc1ccc(CN)cc1
Reaction time: 8 h
Yield: 83.9 %

Procedure:
Add 4M hydrogen chloride in dioxane (20 mL) to a solution of N-(tert-butoxycarbonyl)-4-(2,2-dimethyl-propionylamino)-benzylamine (2 g, 6.53 mmol) in anhydrous 1,4-dioxane (50 mL) at room temperature. Stir overnight and partition the reaction mixture between saturated aqueous NaHCO3 (200 mL) and DCM (500 mL). Extract the aqueous phase with DCM/iso-propanol (85:15, 2×100 mL) and then with DCM/iso-propanol (3:1, 2×100 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by SCX chromatography eluting with DCM and DCM/2M ammonia in methanol (1:1) to obtain the title compound as a waxy colorless oil (1.13 g, 84%). MS (ES−) m/z: 205.1 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[N:10]2[S:33]([CH3:36])(=[O:35])=[O:34])=[C:5]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:11](=[O:32])[N:10]2[S:33]([CH3:36])(=[O:34])=[O:35])=[C:5]([S:37]([CH3:40])(=[O:38])=[O:39])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(S(C)(=O)=O)[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(C)(=O)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
The reaction was carried out under argon. Allyl (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(methylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (288 mg, 0.482 mmol) and morpholine (1.5 eq., 63 mg, 0.723 mmol) were initially charged in dry THF (5 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 28 mg, 0.024 mmol) was added, and the reaction mixture was stirred at RT for 1.5 h (HPLC control). The mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→75:25). This gave the title compound as a solid (187 mg, 70% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[C:11]([Cl:18])[C:7]=1[C:8](O)=[O:9])=[O:5].[CH3:28][N:29]([CH3:39])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH3:38])[CH3:37])[CH:31]=1>>[CH3:37][N:36]([CH3:38])[C:32]1[CH:31]=[C:30]([N:29]([CH3:39])[CH3:28])[CH:35]=[CH:34][C:33]=1[C:4]1([C:3]2[CH:19]=[CH:20][C:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:22][C:2]=2[CH3:1])[C:6]2[C:7](=[C:11]([Cl:18])[C:12]([Cl:17])=[C:13]([Cl:16])[C:14]=2[Cl:15])[C:8](=[O:9])[O:5]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(C)c1
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(C)c1

Procedure:
In a manner similar to that of part B of Example 1 condensation of 2-(2-methyl-4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (22.4 g.) and N,N,N',N'-tetramethyl-m-phenylenediamine (8.20 g.) in contact with acetic anhydride (75 g.) and recrystallization of the resulting product from toluene afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X = (CH3)2N, Y2 = CH3, Y4 = (CH3CH2)2N, Z4 = Z5 = Z6 = Z7 = Cl) (m.p. 236°-238° C.; after slurrying in acetone, 237°-239° C.).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23]C)=O)=[O:14])=[CH:8][CH:7]=1>C(O)C.[Cl-].[Na+].O>[NH:2]([C:21]([C:17]1[S:18][CH:19]=[CH:20][C:16]=1[NH:15][C:13](=[O:14])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=1)=[O:23])[NH2:3]
Reactant: COC(=O)c1sccc1NC(=O)Cc1ccc(OC)cc1
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CC(=O)Nc2ccsc2C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.1 %

Procedure:
Hydrazine monohydrate (0.825 mL, 17.1 mmol) was added to a solution of methyl 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylate (3.48 g, 11.4 mmol) in ethanol (40 mL) and the resulting solution was stirred at room temperature for 24 h. The mixture was diluted with brine and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/ethyl acetate, 1/1 to 1/9) to give N-(2-(hydrazine-carbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide (1.71 g, 5.60 mmol, 49%). Retention time (min)=1.300, method [1], MS(ESI) 306.0 (M+H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[CH3:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][NH:27][C:23]2[N:22]=[C:21]([CH3:20])[CH:26]=[CH:25][N:24]=2)=[CH:14][CH:15]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: Cc1ccnc(N)n1
Agent: Cl
Product: Cc1ccnc(NCc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4-methylpyrimidin-2-amine. m/e+ 350 for C19H17ClN5[M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.18 (d, J=6.9 Hz, 1H), 7.95 (s, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.20 (m, 1H), 6.76 (dt, J=1.1, 6.9 Hz, 1H), 6.42 (d, J=5.1 Hz, 1H), 5.95 (s, 1H), 5.03 (d, J=5.1 Hz, 2H) 2.28 (s, 3H) ppm.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH3:25])[CH2:12][CH2:11]2)=[N:2]1.[CH3:26][C:27]([CH3:32])=[CH:28][C:29](Cl)=[O:30]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH3:25])[C:29](=[O:30])[CH:28]=[C:27]([CH3:32])[CH3:26])[CH2:12][CH2:11]2)=[N:2]1
Reactant: CNc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Reactant: CC(C)=CC(=O)Cl
Product: CC(C)=CC(=O)N(C)c1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 110.4 %

Procedure:
Starting from {2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-methyl-amine (300 mg, 0.84 mmol) and 3,3 dimethyl acryloyl chloride (97 μL, 0.88 mmol) and following the procedure as outlined in Example 1, 403 mg of 3-methyl-but-2-enoic acid {2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-methyl-amide was isolated as a low melting solid in 100% purity @ 254 nm; LCMS (APCI): 435 [M+H]+.
Reaction SMILES: ClC1N=C(F)N=C2C=1NC=N2.C(N)[C:13]1[CH:18]=[CH:17]C=CC=1.N[CH2:21][C:22]1[CH:27]=C[CH:25]=[CH:24][N:23]=1.NCC1C=NC=CC=1.NCC1C=CN=CC=1>CCCCO>[CH3:25][CH2:24][N:23]([CH:18]([CH3:17])[CH3:13])[CH:22]([CH3:27])[CH3:21]
Reactant: NCc1ccccc1
Reactant: NCc1ccccn1
Agent: Fc1nc(Cl)c2[nH]cnc2n1
Agent: NCc1cccnc1
Agent: NCc1ccncc1
Solvent: CCCCO
Product: CCN(C(C)C)C(C)C

Procedure:
For the synthesis of the 6-benzylamino-, 6-(pyridin-2-ylmethyl), 6-(pyridin-3-ylmethyl) and 6-(pyridin-2-ylmethyl)-intermediates, the initial step involved reaction of 6-chloro-2-fluoro-purine 29 [Gray, N. S.; Kwon, S.; Schultz, P. G. Tetrahedron Lett., 1997, 38 (7), 1161-1164] with either benzylamine, 2-(aminomethyl)pyridine, 3-(aminomethyl)pyridine or 4-(aminomethyl)pyridine, in n-BuOH the presence of DIPEA, to afford the corresponding 6-substituted intermediates 30. These compounds then underwent reaction with 2-bromopropane and K2CO3 in DMA [Havlicek, L.; Hunus, J.; Vesely, J.; Leclerc, S.; Meijer; L.; Shaw, G.; Strnad, M.; J Med Chem., 1997, 40 (4), 408412], to afford their corresponding N9-isopropyl substituted intermediates 31. These purine intermediates were finally reacted with the aminoalcohols (1-2, 15-22, and 27-28) in DMSO/n-BuOH/DIEA at 140° C. over 72 h to give their corresponding C2-substituted aminoalkyl analogues 32.
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(F)(F)F)CC3)C=2)C=1)(C)COP(=O)(O)O.Cl.C(OC(=O)[NH:38][C@:39]([CH3:79])([C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:68][C@H:69]3[CH2:74][CH2:73][C@H:72]([C:75]([F:78])([F:77])[F:76])[CH2:71][CH2:70]3)[C:60]=2[C:64]([F:67])([F:66])[F:65])[CH:55]=1)[CH2:40][O:41][P:42]([O:49]C(C)(C)C)([O:44]C(C)(C)C)=[O:43])(C)(C)C>>[NH2:38][C@@:39]([C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:68][C@H:69]3[CH2:74][CH2:73][C@H:72]([C:75]([F:78])([F:76])[F:77])[CH2:71][CH2:70]3)[C:60]=2[C:64]([F:67])([F:66])[F:65])[CH:55]=1)([CH3:79])[CH2:40][O:41][P:42](=[O:43])([OH:44])[OH:49]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1
Agent: C[C@](N)(COP(=O)(O)O)c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1
Agent: Cl
Product: C[C@](N)(COP(=O)(O)O)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1

Procedure:
Phosphoric acid mono-{(R)-2-amino-2-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propyl}ester was synthesized as per Phosphoric acid mono-{(R)-2-amino-2-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propyl} ester (Example 263) in 89% yield as HCl salt, using {(R)-2-(Di-tert-butoxy-phosphoryloxy)-1-methyl-1-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-ethyl}-carbamic acid tert-butyl ester as starting material. MS: m/z=516.30 [M+H]+. 1H NMR (400 MHz, METHANOL-d4) δ ppm: 8.26 (dd, J=9.4, 1.4 Hz, 1H), 8.16 (d, J=9.3 Hz, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.72 (dd, J=9.3, 2.3 Hz, 1H), 7.63 (d, J=9.3 Hz, 1H), 4.55-4.66 (m, 1H), 4.31 (dd, J=11.3, 4.8 Hz, 1H), 4.17 (dd, J=11.2, 5.1 Hz, 1H), 2.20-2.34 (m, 3H), 2.02-2.12 (m, 2H), 1.86 (s, 3H), 1.49-1.72 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH2:24]([N:26]1[C:30]([C:31](O)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1)[CH3:25]>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:31]([C:30]3[N:26]([CH2:24][CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=3)=[O:32])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: CCn1nc(C)cc1C(=O)O
Product: CCn1nc(C)cc1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(C)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=468.2.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[C:2]#[CH:3].[OH2:18].[K+].[Br-]>N1C=CC=CC=1CO.CC([O-])=O.CC([O-])=O.[Cu+2].O>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][CH2:1][C:2]#[C:3][C:3]#[C:2][CH2:1][NH:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[C:14]([F:15])([F:16])[F:17])=[C:6]([C:14]([F:15])([F:16])[F:17])[CH:7]=1)([O-:12])=[O:18]
Reactant: O
Reactant: C#CCNc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OCc1ccccn1
Product: O=[N+]([O-])c1ccc(NCC#CC#CCNc2ccc([N+](=O)[O-])cc2C(F)(F)F)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of Cu(OAc)2.H2O (4.5 g) in pyridinemethanol (1:1, 30 ml) was added N-(2-propynyl)-4-nitro-2-trifluoromethylaniline (3.01 g, 1.23×10-1 mole). The reaction mixture was stirred at 50° C. for two hours. The mixture was poured into excess water and filtered. The crude solid was recrystallized from nitromethane to afford pale pink crystals. Yield: 2.54 g (84%). The material does not melt below 200° C. but turns dark red at 135° C. I.R. (KBr): 3405 (NH), 1580 (Ar-NO2) and 1290 cm-1 (CF3).