Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12]S(C)(=O)=O)=[CH:9][CH2:8][CH:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[O:19])[C:6]1=[O:30].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.FC(F)(F)C([O-])=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][NH:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:9][CH2:8][CH:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[O:19])[C:6]1=[O:30]
Reactant: NCc1ccccc1
Reactant: COC(=O)CN1CC(CS(C)(=O)=O)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN1CC(CNCc2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To the crude product from the previous reaction, {6-[(methanesulfonyl)methyl]-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 23, (0.147 g, 0.32 mmol) in CH2Cl2 (1 mL), is added benzylamine (1 mL). The reaction is stirred at room temperature for 10 minutes, then the reaction is diluted with CH2Cl2. The organic layer is washed with saturated NaHCO3, saturated NaCl, and dried (Na2SO4). The solvent is removed in vacuo and the resulting crude material is purified by HPLC to afford 82 mg (44% yield) of the desired product as the trifluoroacetate salt. 1H (CDCl3) δ 8.82–8.79 (d, J=6.1 Hz, 1H), 8.61–8.59 (d, J=8.6 Hz, 1H), 8.33–8.31, (d, J=5.8 Hz, 1H), 8.01–7.99 (d, J=5.94 Hz, 1H), 7.95–7.82 (m, 2H), 7.77–7.72 (d, d, J=7.98, 7.98 Hz, 1H), 7.36–7.18 (m, 5H), 5.91 (bs, 1H), 5.40–5.39 (m, 1H), 4.67–4.61 (d, J=17.4 Hz, 1H), 4.55–4.49 (d, J=17.8 Hz, 1H), 4.19–4.05 (m, 1H), 3.88–3.83 (d, J=14.7 Hz, 1H), 3.77–3.57 (m, 3H), 3.50 (s, 3H), 2.84–2.78 (d, J=17.8 Hz, 1H), 2.50–2.40 (d, d, J=15.8, 14.5 Hz, 1H); 13C (CDCl3) 171.9, 171.5, 161.9, 161.4, 160.9, 160.6, 149.1, 139.1, 135.2, 134.7, 134.2, 131.3, 130.3, 130.2, 130.1, 129.6, 128.2, 127.9, 127.8, 127.4, 125.8, 121.5, 117.7, 113.8, 110.0, 53.5, 52.9, 51.6, 49.8, 48.3, 37.9, 31.6; MS 473 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH2:9][O:10][CH3:11])[N:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)(O)[O-].[Na+]>CCO>[Cl:8][C:6]1[CH:7]=[C:2]([N:23]2[CH2:24][CH2:25][N:20]([C:15]3[C:14]([C:13]([F:27])([F:12])[F:26])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:21][CH2:22]2)[N:3]=[C:4]([CH2:9][O:10][CH3:11])[N:5]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: COCc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COCc1nc(Cl)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Temperature: 25 °C

Procedure:
Combine 4,6-dichloro-2-methoxymethyl-pyrimidine (800 mg, 4.14 mmol), 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (960 mg, 4.14 mmol), sodium bicarbonate (500 mg), and EtOH (50 mL). Reflux for 4 hours, let cool to room temperature, vacuum filter, and evaporate the mother liquor. Purify the residue by column chromatography eluting with 20:1 DCM/MeOH to obtain 4-chloro-2-methoxymethyl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:24])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]([F:23])([F:22])[F:21])[CH2:8][CH2:7]1)C.[OH-].[Na+]>CCO.O>[F:22][C:20]([F:21])([F:23])[O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:25])=[O:3])[CH2:7][CH2:8]1)=[O:24]
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccccc2OC(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCC(C(=O)c2ccccc2OC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of [4-(2-trifluoromethoxy-benzoyl)-piperidin-1-yl]-acetic acid ethyl ester (0.36 g, 1 mmol, 1 eq.) in 5 mL of EtOH was added a solution of NaOH (0.08 g, 2 mmol, 2 eq.) in 5 mL of H2O. The resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was concentrated and treated with 1 N HCl to pH 5. The resulting mixture was freeze dried using a lyophilizer to remove H2O. The resulting yellow solids were washed with dichloromethane/methanol and filtered off NaCl. The filtrate was concentrated to give the title compound as a white solid (0.33 g, 99%). Exact mass calculated for C15H19F3N1O4332.1. MS (ESI) m/z 332.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:42]=[O:43])C>C1COCC1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:42]([OH:43])[N:7]([C:8]([CH3:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9])[C:5]2=[O:6]
Reactant: CC(C)(NC(=O)c1cccc(F)c1)c1ccccc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2cccc(F)c2C1O
Yield: 93.4 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-fluoro-N-(1-methyl-1-phenylethyl)benzamide (2.00 g, 7.77 mmol) was dissolved in THF (80 mL), and the solution was treated with TMEDA (3.8 mL, 24.9 mmol), sec-butyllithium-hexane solution (1.01 mol/L, 24.6 mL, 24.9 mmol) and DMF (1.30 mL, 17.1 mmol). The mixture was purified by slurry using diisopropylether to obtain 4-fluoro-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (2.07 g, yield 93%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(Cl)cc3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-chloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.03 min; [M+H]+=371.8.
Reaction SMILES: [Mg].CCOCC.II.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][CH:11]=1.[CH:18](=[O:22])[CH:19]([CH3:21])[CH3:20]>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:18]([OH:22])[CH:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)C=O
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)C(O)Cc1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
Magnesium (5.02 g, 0.206 mol) was covered in dry ether (50 mL, 0.5 mol) under an atmosphere of nitrogen. Iodine (0.254 g, 0.001 mol) was added to the reaction, followed by approximately 1 mL of a solution of 1-chloro-4-(chloromethyl)-benzene (32.20 g, 0.200 mol) in ether (25.0 mL, 0.238 mol). An exotherm was noted and the mixture reached reflux. The slow addition of solution was continued over 90 minutes to maintain a gentle reflux. On completion of the addition, the reaction was heated for 30 minutes at 45° C. The reaction was then cooled to 0° C. Isobutyraldehyde (25.19 mL, 0.2774 mol) in Ether (20 mL, 0.2 mol) was then added slowly over 2 hours at 0° C. On completion of the addition the reaction was allowed to warm to room temperature and stir overnight. The reaction was then quenched with ice (200 g) and acidified with 2M HCl (100 mL). The organic phase was separated and the aqueous was extracted twice with more ether. The combined organic phase was evaporated and the residue was purified by silica gel chromatography, eluting with 0 to 10% methanol in dichloromethane to yield the product, 17.8 g (45%). 1H NMR (300 MHz, CDCl3, δ): 7.22 (m, 4H), 3.56 (m, 1H), 2.81 (dd, J=3.3 Hz, 13.7 Hz, 1H), 2.58 (dd, J=9.4 Hz, 13.7 Hz, 1H), 1.74 (dt, J=6.5 Hz, 12.9 Hz, 1H), 1.45 (s, 1H), 1.00 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]#[N:13].[SH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[O-]CC.[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:12]([C:3]1[C:2]([S:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)#[N:13]
Reactant: N#Cc1c(Br)ccc2ncccc12
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc2ncccc2c1C#N

Procedure:
A solution of 6-bromoquinoline-5-carbonitrile (16b) (300 mg, 1.29 mmol), ethyl mercaptoacetate (212 μL, 1.93 mmol) and sodium ethoxide (122.6 mg, 1.80 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 15 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture. It was extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The intermediate ethyl 2-[(5-cyanoquinolin-6-yl)sulfanyl]acetate obtained was reacted with sodium ethoxide (122.6 mg, 1.80 mmol) in dimethylformamide (8 mL) by stirring at 90° C. for 3 hours. The reaction was cooled to room temperature and water was added (10 mL). The resulting precipitate was filtered and washed with water twice and dried under vacuum with phosphorus pentoxide to afford the desired product (16c) as a solid (299 mg, 1.10 mmol, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[C:12](=[O:32])[N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:14]2[C:19]([C:20]=1O)=[CH:18][CH:17]=[CH:16][N:15]=2)=O.O.[NH2:34][NH2:35].C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[C:11]2[C:12](=[O:32])[N:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20]=2[NH:35][N:34]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1Cl)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3Cl)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-(2-chlorophenylacetyl)-4-hydroxy-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (687 mg, 1.5 mmol) produced in Synthesis Example 35 in DMF (6 mL) was added hydrazine monohydrate (purity of 80%, 240 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-chlorobenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (632 mg, yield 93%).
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]=1[C:24]([O:26]CC)=O)=[O:9])C1C=CC=CC=1.C(N(CC)CC)C.Cl.[NH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>C1COCC1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][C:11]2[NH:10][C:8](=[O:9])[N:37]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:24](=[O:26])[C:12]=2[CH2:13]1)=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: NN1CCCC1
Reactant: CCOC(=O)C1=C(NC(=O)Oc2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(=O)n(N3CCCC3)c(=O)c2C1
Temperature: 68 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Under nitrogen, 1-tert-butyl 3-ethyl 4-(phenoxycarbonylamino)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (6.14 g) was dissolved in THF (50 ml) and 1-aminopyrrolidine hydrochloride (2.31 g), triethylamine (6.58 ml) and 1,8-diazabicyclo[5.4.0]und-7-ene (0.24 ml) were added, and the resultant mixture was stirred at room temperature for 2 hours. Thereafter, the reaction solution was stirred at 50° C. for 2 hours and 68° C. for 3 hours. After consumption of the raw materials was confirmed by TLC or LC/MS, to the reaction mixture 2 N sodium hydroxide solution (15.7 ml) was added at 0° C., and the resultant mixture was stirred at room temperature for two days. Thereafter, the solution was stirred at 50° C. for 3 hours and further 2 N sodium hydroxide solution (10 ml) was added at the same temperature. The reaction mixture was stirred at 68° C. for 2 hours. After the completion of the reaction was confirmed by TLC or LC/MS, the solution was cooled to room temperature, 2 N hydrochloric acid (30 ml) and a saturated ammonium chloride solution were added, the resultant mixture was extracted with ethyl acetate and dried over sodium sulfate. The solution was filtrated, concentrated and purified by silica gel chromatography to obtain desired tert-butyl-2,4-dioxo-3-(pyrrolidin-1-yl)-1,2,3,4,7,8-hexahydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate in an amount of 3.19 g (yield 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:19]=[CH:18][C:17](I)=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:17]2[CH:18]=[CH:19][C:11]([F:10])=[C:12]([CH:16]=2)[C:13]([NH2:15])=[O:14])[CH:5]=[N:4][CH:3]=1
Reactant: NC(=O)c1cc(I)ccc1F
Reactant: C#Cc1cncc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (51 mg, 0.07 mmol), copper (I) iodide (28 mg, 0.15 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (250 mg, 1.82 mmol) to a solution of 2-fluoro-5-iodobenzamide, (prepared as described in PREPARATION 44), (0.482 g, 1.82 mmol) in triethylamine (7 mL, 53 mmol) and heat at 70° C. After 10 minutes, add toluene (10 mL) to the solidified reaction mixture, heat at 70° C. for 1 h, cool to room temperature and stir overnight. Concentrate and purify the residue by silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes, to give the title compound as a white solid (260 mg, 32%).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[CH:30]=[C:29]([CH2:31][N:32](C2C(C)=C(C3C=CC(C(F)(F)F)=CC=3)N=CN=2)[CH2:33][CH2:34][CH3:35])[CH:28]=[CH:27][C:19]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:17][C:18]1[CH:30]=[C:29]([CH2:31][N:32]([C:2]2[C:7]([CH3:8])=[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:33][CH2:34][CH3:35])[CH:28]=[CH:27][C:19]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Reactant: COc1ccc(-c2ncnc(Cl)c2C)cc1
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(OC)cc2)c1C

Procedure:
Using 4-chloro-6-(4-methoxyphenyl)-5-methylpyrimidine (164 mg, 0.7 mmol) and the synthetic procedure described for Intermediate 80. Purification by Biotage™ chromatography (Si, 40 g) eluting 4:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (60 mg).
Reaction SMILES: [CH2:1]([C:3](=[CH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][O:23][C:17]=2[CH:16]=1)[CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH3:2].[CH2:24]([Mg]Br)[CH3:25]>>[CH2:24]([C:7]1([OH:11])[CH2:8][CH2:9][CH2:10][CH:6]1[CH2:5][CH2:4][C:3]([CH2:1][CH3:2])=[CH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][O:23][C:17]=2[CH:16]=1)[CH3:25]
Reactant: CCC(=CCCc1ccc2c(c1)OCO2)CCC1CCCC1=O
Reactant: CC[Mg]Br
Product: CCC(=CCCc1ccc2c(c1)OCO2)CCC1CCCC1(O)CC

Procedure:
2-[3-Ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-cyclopentanone can be treated with ethylmagnesium bromide according to the procedure of Example 2, part (c) to give 1-ethyl-2-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]cyclopentanol [XV; Ar is 3,4-methylenedioxyphenyl, Y is C(C2H5)=CHCH2CH2, R' is C2H5, m is 1. ].
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:33][C:34]1([F:38])[CH2:37][NH:36][CH2:35]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:36]4[CH2:37][C:34]([F:38])([F:33])[CH2:35]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:28][C:29]([F:31])([F:32])[CH2:30]2)=[O:26])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: FC1(F)CNC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(N4CC(F)(F)C4)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 134 using (1R,2R,4R)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 119) and 3,3-difluoroazetidine. Off-white solid. MS (EI): 563.1 (M+H)+.
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[C:4](=[O:24])[O:3]1>CO>[CH3:2][O:3][C:4](=[O:24])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[O:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)OCC(C)C
Yield: 48 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-N-isobutoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (48% yield); mp 55–56° C. 1HNMR 400 MHz (CDCl3) δ (ppm): mixture of rotamers: 0.99 (6H, d, J=7.1 Hz, CH3), 1.96 (1H, m, CH), 3.65 (2H, d, J=6.0 Hz, OCH2), 3.91 (3H, s, OCH3), 4.81 (2H, s, NCH2), 6.49 (1H, s, CH), 7.05 (2H, m, aromatics), 7.33 (2H, m, aromatics), 13.4 (1H, broad s, OH). HRMS (ES+) calculated for C16H21FNO5, [M+H]+: 326.140376. found: 326.139560.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH3:15][O:16][C:17]1[C:21](OC)=[N:20][S:19](=[O:24])[N:18]=1>CO>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:21]2[C:17]([O:16][CH3:15])=[N:18][S:19](=[O:24])[N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: COC1=NS(=O)N=C1OC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CO
Product: COC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (3.30 g; 15.4 mmoles) in 25 ml of methanol was added dropwise over a period of 14 minutes to a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.50 g; 15.4 mmoles) [prepared according to the procedure in Example 4, Step A] that was cooled to 12°-15° in an ice-water bath. The solution was stirred at ambient temperature for 1.5 hours to yield a methanolic solution of the title compound.
Reaction SMILES: [C:1]12([C:11]([NH:13][NH2:14])=[S:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=O>>[C:1]12([C:11]3[S:12][CH:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])[NH:14][N:13]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: NNC(=S)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)C=O
Product: CCOC(=O)C1NN=C(C23CC4CC(CC(C4)C2)C3)S1

Procedure:
The product of step (b) was treated with ethyl glyoxylate by the process of Example 3, step (a) to give the sub-title product (1.5 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([NH:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])([CH3:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Li+]>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:26]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])([CH3:27])[CH3:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: COC(=O)CCNC(C)(C)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(NCCC(=O)O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 3-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propan-2-ylamino)propanoate (0.067 g, 0.137 mmol) in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added 1 M lithium hydroxide solution (0.4 mL, 0.4 mmol) and stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the resulting slurry was diluted with water and neutralized (to pH=˜7) with aqueous 1 N HCl solution. The aqueous suspension was extracted with 15% MeOH/CHCl3; the organic extracts were combined, dried (K2CO3), filtered, and concentrated in vacuo to give a crude golden yellow solid (˜0.040 g). Trituration with MeOH afforded the title compound as an off-white amorphous solid. MS (ESI) m/z: Calculated: 475.5; Observed: 476.1 (M++1).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1.[H][H]>C(O)C.[Pd]>[O:1]=[C:2]1[C:8]2[CH2:9][CH2:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:23]=1
Reactant: CCOC(=O)/C=C/c1ccc(CN2C(=O)c3ccccc3Oc3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(CN2C(=O)C3=C(C=CCC3)Oc3ccccc32)cc1
Yield: 94 %

Procedure:
Compound 416 (0.364 g, 0.912 mmol) was dissolved in ethanol (10.0 mL) and the palladium on charcoal (0.037 g, 10% w/w) was added. The reaction mixture was stirred over 1 atmosphere of hydrogen at room temperature for 1 hour. The catalyst was filtered and the filtrate was concentrated to afford title compound 417 (346 mg, 95%) that was used crude for next step. MS (m/z): 402.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(O)(O)(=O)=O.Cl[C:22]1[NH:23][CH2:24][CH2:25][N:26]=1>C(#N)C.ClCCl>[CH3:1][O:2][C:3]1[S:7][C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:22]3[NH:26][CH2:25][CH2:24][N:23]=3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: ClC1=NCCN1
Reactant: COc1ccc(Cc2ccc(N)cc2)s1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(Cc2ccc(NC3=NCCN3)cc2)s1
Temperature: 80 °C
Yield: 69.6 %

Procedure:
To a solution of [4-(5-methoxythien-2-ylmethyl)-phenylamine (145 mg, 0.66 mmol) in acetonitrile (10 ml) was added 2-chloro-2-imidazoline sulfate (155 mg, 0.76 mmol) at 20-25° C. under nitrogen. The resulting suspension was heated at 80° C. for 1.5 hours. The mixture was diluted with dichloromethane and washed with 10% sodium hydroxide, water, dried (Na2SO4), and concentrated to dryness. Purification by preparative TLC, eluting with ethyl acetate/methyl alcohol/isoprolpylamine, gave 2-[4-(5-methoxythien-2-ylmethyl)phenyl]amino-imidazoline (132 mg, 70%) as a yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.12 (d,J=8.4 Hz, 2H), 6.93 (d,J=8.4 Hz, 2H), 6.39 (dt, J=3.7, 1.1 Hz, 1H), 5.98 (d,J=3.7 Hz, 1H), 3.92 (bs, 2H), 3.82 (S,3H), 3.52 (S,4H), 3.15-3.35 (broad, 2H).