Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]([CH:25]3[CH2:27][CH2:26]3)[CH3:24])[CH:17]=2)=[CH:10][CH:9]=1)[CH3:7])C.[OH-].[K+]>C(O)C.O1CCCC1>[CH:25]1([N:23]([CH2:22][C:18]2[CH:17]=[C:16]([C:15]#[C:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:28])=[O:3])=[CH:9][CH:10]=3)[CH:21]=[CH:20][CH:19]=2)[CH3:24])[CH2:26][CH2:27]1
Reactant: CCOC(=O)C=C(C)c1ccc(C#Cc2cccc(CN(C)C3CC3)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=CC(=O)O)c1ccc(C#Cc2cccc(CN(C)C3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 31.5 %

Procedure:
A solution of 3-(4-{3-[(cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-but-2-enoic acid ethyl ester (Intermediate 93, 0.17 g, 0.46 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 3.4M solution of potassium hydroxide (1 mL, 3.4 mmol) and the resulting reaction mixture was stirred at ambient temperature for 36 h. The reaction mixture was extracted with diethyl ether, and the aqueous phase was neutralized with 10% aqueous hydrochloric acid and evaporated to a solid. The solid was subjected to flash column chromatography using ethyl acetate as the eluent to afford the title product as a white solid (0.05 g, 32%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=[O:39])[NH:32][C:33]2([C:36]([OH:38])=O)[CH2:35][CH2:34]2)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.C1(C2C=CC=CC=2)C=CC=CC=1.[C:52]1([P:58](=[CH:60][C:61]#[N:62])=[O:59])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]1([C:15]2[CH:16]=[CH:17][CH:22]=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.[C:61]([C:60](=[P:58]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:59])[C:36]([C:33]1([NH:32][C:31]([NH:30][C@@:15]([C:4]2[CH:5]=[C:6]([O:8][C:9]([F:13])([F:14])[CH:10]([F:11])[F:12])[CH:7]=[C:2]([F:1])[CH:3]=2)([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:39])[CH2:34][CH2:35]1)=[O:38])#[N:62]
Reactant: O=C(NC1(C(=O)O)CC1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: N#CC=[P+]([O-])c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccc(-c2ccccc2)cc1
Product: N#CC(C(=O)C1(NC(=O)N[C@](Cc2ccccc2)(c2ccc(F)cc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)CC1)=[P+]([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 81.3 %

Procedure:
To a solution of (R)-1-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)-cyclopropanecarboxylic acid (84 mg, 0.153 mmol), prepared by the method described in Procedure 30, in DCM (0.5 mL) was added 2-(phenylphosphinylidene)acetonitrile compound with biphenyl (1:1) (51 mg, 0.168 mmol), EDCI (32 mg, 0.168 mmol) and DMAP (3 mg, 0.024 mmol). The reaction mixture was stirred at room temperature for 4.5 h, concentrated under reduced pressure and purified by ISCO chromatography (12 g column, eluting with 0-100% hexane/EtOAc) to yield (R)-1-(1-(2-cyano-2-(phenylphosphinylidene)acetyl)cyclopropyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea compound with biphenyl (1:1) as a white solid (53 mg, 42% yield). LCMS: RT=3.49 min [M+H] 836.4 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 50-100% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) ppm 0.78-1.00 (m, 2H), 1.34-1.49 (m, 2H), 3.79-3.95 (m, 2H), 5.62-5.98 (m, 3H), 6.67-6.94 (m, 7H), 6.98-7.20 (m, 5H), 7.37-7.66 (m, 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([NH2:15])[CH2:7][C:8]([CH2:13][F:14])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([NH2:15])[CH2:7][C@:8]([CH2:13][F:14])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(CF)C[C@@H](N)c2ccc(Cl)cc2O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@]1(CF)C[C@@H](N)c2ccc(Cl)cc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
A solution of (4R)-7-chloro-2-(fluoromethyl)-2-methylchroman-4-amine (2.21 g, 9.62 mmol) in THF (10 ml) was cooled to 0° C. Lithium bis(trimethylsilyl)amide (1M in THF, 20.2 mL, 20.2 mmol) was added slowly and the reaction was warmed to room temperature. After 4 hours, the reaction mixture was diluted with EtOAc (200 mL) and washed with 2N NaOH (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was purified on SiO2 (3% MeOH/EtOAc) to give the title compound (715 mg, 32%). MS (ESI+) M/Z 230 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[CH2:6][C@@H:5]2[C:7]([CH3:12])([CH3:11])[CH:8]=[CH:9][CH2:10][C@:4]2([CH3:13])[O:3]1>C(O)(=O)C.[Pt]=O>[O:1]=[C:2]1[CH2:6][C@@H:5]2[C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][CH2:10][C@:4]2([CH3:13])[O:3]1
Reactant: CC1(C)C=CC[C@]2(C)OC(=O)C[C@H]12
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC1(C)CCC[C@]2(C)OC(=O)C[C@H]12
Reaction time: 23 h
Yield: 90 %

Procedure:
Compound (13) (1.00 g, 5.55 mmoles) was dissolved in dry acetic acid, and platinum oxide (0.10 g) was added to the solution. The mixture was shaken for 23 hours under hydrogen pressure (30 atms.). The catalyst was separated by filtration, and the filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate, and the ethyl acetate solution was washed with an aqueous solution of sodium hydrogen-carbonate, water and an aqueous solution of sodium chloride in this order, dried over magnesium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (10 g of silica gel; n-hexane/ethyl acetate) to give crystalline (3aR,7aS)-isomer (14) (0.910 g, yield 80%). Recrystallization from n-hexane gave 0.669 g of the purified compound (14).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:14][CH2:13][CH:12]2[CH2:11][N:10]([CH3:15])[CH2:9]3)=[CH:4][CH:3]=1.C([O-])(=O)/C=C/[C:19]([O-])=[O:20]>>[CH3:19][O:20][C:3]1[CH:4]=[C:5]([C:8]23[CH2:14][CH2:13][CH:12]2[CH2:11][N:10]([CH3:15])[CH2:9]3)[CH:6]=[CH:7][CH:2]=1
Reactant: Cc1ccc(C23CCC2CN(C)C3)cc1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: COc1cccc(C23CCC2CN(C)C3)c1

Procedure:
1(p-methylphenyl)-3-methyl-3-azabicyclo[3.2.0]heptane, fumarate
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][CH2:11][CH2:12][O:13][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:7][CH:8]=1
Reactant: OCCC#Cc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCC#Cc1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 1G], 4-(4-trifluoromethyl-phenyl)-but-3-yn-1-ol and methanesulfonyl chloride gave the title compound as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.C([O-])(=O)C.[Cl:19][C:20]1[CH:21]=[C:22]([I+2:26])[CH:23]=[CH:24][CH:25]=1.[F:27][B-:28]([F:31])([F:30])[F:29].[Na+]>C(Cl)Cl>[F:27][B-:28]([F:31])([F:30])[F:29].[Cl:1][C:2]1[CH:3]=[C:4]([I+:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc([I+2])c1
Reactant: OB(O)c1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cccc([I+]c2cccc(Cl)c2)c1
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
Borontrifluoride diethyl etherate (16.51 g, 116.3 mmol) was added slowly to 3-chlorophenyl boronic acid (17.37 g, 111.0 mmol) in DCM (170 mL) at −5° C., while stirring. After 15 minutes, the title compound of Example 15.1 (37.71 g, 105.8 mmol) in DCM (150 mL) was added slowly. The reaction stirred for 1 h at 0° C. and sodium tetrafluoroborate (225 g in 300 mL water) was added and stirred for 1 h. The organic layer was separated, dried over sodium sulphate, filtered and concentrated and triturated with ether to afford the title product (31.6 g, 68%) as a light brown solid.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37]>CN(C=O)C>[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])=[O:37]
Reactant: O=C(O)CCCCBr
Reactant: Nc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCCBr)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.5 %

Procedure:
WSC (2.1 g, 11 mmols), and HOBt (1.49 g, 11 mmols) were added to a DMF (30 ml) solution of 2,4-difluoroaniline (1.29 g, 10 mmols) and 5-bromopentanoic acid (2.7 g, 15 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through preprative thin-layer chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 2.0 g (yield: 68%) of 5-bromo-N-(2,4-difluorophenyl)pentanamide as colorless needle-like crystals.
Reaction SMILES: [F:1][C:2]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]2)[CH2:27][O:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH:36][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:32]2)[CH2:27][O:26]1
Reactant: Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 50.6 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.254 g, 0.79 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.187 g, 0.95 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.795 g, 1.80 mmol). The mixture was stirred at 0° C. and triethylamine (0.194 g, 1.90 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 10% to 70% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-fluoro-3-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.200 g, 51%) as a tan solid: HR-ES-MS m/z calculated for C26H33FN4O5 [M+H]+ 501.2508, observed 501.2511, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.36-1.49 (m, 1H), 1.49-1.64 (m, 1H), 1.68-1.83 (m, 1H), 2.29 (s, 3H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.04-4.16 (m, 2H), 4.21 (d, J=18.7 Hz, 1H), 4.35 (quin, J=5.8 Hz, 1H), 4.59 (d, J=18.7 Hz, 1H), 4.85 (s, 1H), 4.85-4.92 (m, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.13-7.34 (m, 3H), 7.60 (d, J=2.1 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][O:22][CH2:23][C:24](O)=[O:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[CH3:21][O:22][CH2:23][C:24]([NH:11][CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)=[O:25]
Reactant: NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: COCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
A mixture of 8.6 g of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine (obtained according to PREPARATION (I), step (b)), 2.46 g of methoxyacetic acid, 5.55 g of triethylamine in 50 ml of dichloromethane is cooled to 0° C. and 14.5 g of BOP is added thereto.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH2:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.[N:27]([CH2:30][C:31]([O:33]CC)=[O:32])=[C:28]=[O:29]>ClCCl>[CH2:13]([N:7]1[C:8]([OH:12])=[C:9]([C:28]([NH:27][CH2:30][C:31]([OH:33])=[O:32])=[O:29])[C:10](=[O:11])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN1C(=O)CC(=O)N(CCCC)C1=O
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCn1c(O)c(C(=O)NCC(=O)O)c(=O)n(CCCC)c1=O
Reaction time: 24 h
Yield: 64 %

Procedure:
A mixture of 1,3-dibutyl-2,4,6(1H,3H,5H)-pyrimidinetrione (1.3 g mg, 5.5 mmoles) and diisopropylethylamine (1.9 mL, 11.0 mmoles) in dichloromethane (20 mL) was treated with ethyl isocyanatoacetate (673 uL, 6.0 mmoles) and stirred for 24 hours. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The residue was taken up in ethanol (5 mL) and treated with 6 molar sodium hydroxide (3 mL) and stirred for 2 hours. The mixture was acidified with 1 molar hydrochloric acid and stirred for 30 minutes to give a solid which was recrystallized from acetic acid-water to afford the title compound (1.2 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.11 (t, J=6.19 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 3.81 (t, 4 H), 1.43-1.63 (m, 4 H), 1.14-1.41 (m, 4 H), 0.89 (t, J=7.33 Hz, 6 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[C:20]([CH3:19])[CH:21]=[CH:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cccc(C)c3)cccc2c1N

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (450 mg, 1.46 mmol) and 3-methylphenyl boronic acid (408 mg, 3.00 mmol) according to Method A to afford an off-white solid (321 mg, 69%). 1H NMR (300.132 MHz, CDCl3) δ 8.58 (t, J=5.0 Hz, 1H), 7.85 (dd, J=8.3, 1.4 Hz, 1H), 7.79 (dd, J=7.3, 1.4 Hz, 1H), 7.71 (dd, J=8.1, 7.3 Hz, 1H), 7.50 (s, 1H), 7.48 (s, 2H), 7.39 (t, J=7.9 Hz, 1H), 7.23 (s, 1H), 3.46 (q, J=6.7 Hz, 2H), 2.44 (s, 3H), 1.67 (sextet, J=7.3 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=321 (M+H). HPLC 1.90 min.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=4)[CH2:15]3)=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[CH2:34]([C:36]1([OH:40])[CH2:39][NH:38][CH2:37]1)[CH3:35]>>[CH2:34]([C:36]1([OH:40])[CH2:39][N:38]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH:16]3[CH2:15][N:14]([C:12]([C:10]4[O:11][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[N:8][N:9]=4)=[O:13])[CH2:17]3)=[CH:26][CH:25]=2)[CH2:37]1)[CH3:35]
Reactant: CCC1(O)CNC1
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCC1(O)CN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)cc2)C1
Yield: 30 %

Procedure:
Using a similar protocol as described in Example 70 employing 71A and 70A as starting materials afforded 185 mg (30%) of 71 as a solid. 1H NMR (500 MHz, CDCl3): δ 0.95 (t, 3H), 1.76 (q, 2H), 3.02 (d, 2H), 3.26 (d, 2H), 3.58 (s, 2H), 4.29 (m, 1H), 4.61 (m, 1H), 4.72 (m, 1H), 5.10 (m, 2H), 6.71 (d, 2H), 7.21 (d, 2H), 7.51 (t, 2H), 7.55 (t, 1H), 8.13 (d, 2H), MS (APCI+) m/z 435 [M+H]+, LC purity: 94%.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[CH3:13].O1CCCC1.[CH3:20][S:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=O)=[CH:27][CH:26]=1)(=[O:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:13][C:7]1[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][CH:3]([N:2]([CH3:1])[C:32](=[O:34])[CH2:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24][S:21]([CH3:20])(=[O:22])=[O:23])=[CH:30][CH:29]=1)[CH3:14]
Reactant: CNC(C)COc1cc(C)ccc1C
Reactant: CS(=O)(=O)Nc1ccc(CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(C)c(OCC(C)N(C)C(=O)Cc2ccc(NS(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution containing 0.52 g (2.7 mmol) of N-methyl-2-(2,5-dimethylphenoxy)-1-methylethylamine (Example 45) in 15 ml of tetrahydrofuran 0.63 g (2.7 mmol) of 4-methanesulfonamido-phenylacetic acid (Example 32) and 0.63 g (3.05 mmol) of dicyclohexylcarbodiimide are added and the reaction mixture is stirred at room temperature for 16 hours. After filtration of the mixture, the filtrate is evaporated under reduced pressure and the pale yellowish resin of about 4.5 g obtained is purified by column chromatography by using a mixture of ethyl acetate and hexane as eluent. Thus, 0.76 g (70%) of the title compound is obtained as an amorphous material.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:16]=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]3[CH:23]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].[C:32]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:18][CH:23]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]([CH3:32])[C:27](=[O:31])[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cn4ccccc4n3)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1nn(Cc2cccc(=O)n2C)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-carboxamide (11 mg, 0.027 mmol; prepared as in Example 17, Step A) in DMF (2 mL) was added K2CO3 (7.4 mg, 0.053 mmol) and iodomethane (19 mg, 0.13 mmol). The reaction mixture was stirred for one hour and concentrated under reduced pressure to remove DMF. Silica gel chromatography (DCM/MeOH 10:1) provided the desired product (3 mg). MS (ES+APCI) m/z=427 (M+H).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]([OH:13])=[C:10]1[OH:11].[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[CH:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[CH:22][CH2:23][CH2:24][CH2:25][O:11][C:10]1[C:9]([O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]=1[OH:13])=[O:8]
Reactant: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=CCCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 90 °C

Procedure:
0.71 mL (5.1 mmol) of triethylamine was added and dissolved in a suspension of 0.82 g (4.63 mmol) of ascorbic acid in acetonitrile (9 mL). The above crude product of (5,9,13,17-tetramethyloctadec-4-enyl)tosylate was added at room temperature, and the reaction mixture was heated for 2 hours at 90° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.C(N(CC)CC)C.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH2:19]([N:6]1[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH3:11])=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: ClCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of methyl (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylate hydrochloride (674 g) in dichloromethane (3.5 l) were added dropwise triethylamine (1.19 l) and benzyl chloride (552 ml) at 10°-20° C. under stirring and the mixture was refluxed for 6 hours. The mixture was cooled to ambient temperature, and the precipitates were removed by filtration. The filtrate was poured into 1N sodium hydroxide and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give methyl (2S,4R)-1-benzyl-4-hydroxy-2-pyrrolidinecarboxylate (663 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[C:12]([Cu])#[N:13]>CN1C(=O)CCC1>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Brc1ccc2cnccc2c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2cnccc2c1
Temperature: 170 °C

Procedure:
6-Bromoisoquinoline (0.876 g, 4.18 mmol) purchased from Gateway Chemical Technology, Inc. was mixed with CuCN (1.12 g, 12.54 mmol) in 5 mL NMP in a microwave heating tube. The tube was heated under microwave to 150° C. for 1 hour and 170° C. for one hour. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3. After removing the solvent, the remaining residue was passed through a silica gel plug using 5% 2M ammonia in MeOH in DCM as the eluant. The crude product (100 mg) was used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[C:23](Cl)(Cl)=[S:24].C(=O)([O-])O.[Na+]>O1CCCC1>[N:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]2)=[CH:17][CH:18]=1)=[C:23]=[S:24]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccc(N=C=S)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
Triethylamine (5.1 mL, 36.6 mmol) was added to a solution of 4-(4-methylpiperazin-1-ylmethyl)phenylamine (F652-02, 3.14 g, 15.3 mmol) in tetrahydrofuran (250 mL), and after cooling by ice, thiophosgene (1.11 mL, 14.6 mmol) was added. After stirring at room temperature overnight, aqueous sodium hydrogencarbonate was added to the mixture. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and the solvent was distilled off under reduced pressure to obtain brown oil. The brown oil was purified by silica gel column chromatography (chloroform, methanol) to obtain 1-(4-isothiocyanatobenzyl)-4-methylpiperazine (F652-03, brownish oil, 2.64 g, 70%).