Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:6]=[CH:5][N:4]([C:7]([O:9][CH2:10][CH:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:8])[CH2:3][CH2:2]1.[CH2:31]([Zn]CC)C.ICI>CCOCC>[CH:6]12[CH2:31][CH:5]1[N:4]([C:7]([O:9][CH2:10][CH:11]1[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]3[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:8])[CH2:3][CH2:2][N:1]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC[Zn]CC
Reactant: CC(C)(C)OC(=O)N1C=CN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: ICI
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C2CC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a pre-dried round bottom flask, tert-butyl 9H-fluoren-9-ylmethyl 2,3-dihydropyrazine-1,4-dicarboxylate (1.5 g, 3.69 mmol) was dissolved in anhydrous ether (80 ml) under N2. Diethylzinc (27.4 ml, 27.4 mmol) in ether (1M) was added in via syringe. Diiodomethane (1.904 ml, 23.60 mmol) was added. Let reaction stir at room temperature overnight. On next day, reaction was quenched by adding 5 mL of saturated aqueous NH4Cl. Reaction mixture was filtered over a pad of Celite® and filtering cake was washed with ether (25 mL×2). Then layers were separated and aqueous portion was extracted with ether (50 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4. Concentration at reduced pressure afforded crude product that was purified by silica gel column chromatography (40 gram silica gel column, eluted with 0-100% EtOAc/Hexane gradient). Removing solvent gave the title compound. 1H NMR (ppm) (500 MHz, CDCl3): δ 7.76 (2H, d, J=7.59 Hz), 7.66-7.53 (2H, m), 7.40 (2H, t, J=7.50 Hz), 7.31 (2H, t, J=7.45 Hz), 4.52-4.44 (2H, m), 4.26 (1H, t, J=7.13 Hz), 3.62-2.90 (6H, m), 1.50 (9H, s), 1.25-0.89 (1H, m). 0.55-0.39 (1H, m); LC/MS (M+23)+=443.13;
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7](N3CCNCC3)=[CH:8][C:9]=2[CH2:11][CH2:12][CH3:13])[S:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][N:24]1[CH2:30][CH2:29][CH2:28][C@H:25]1[CH2:26][OH:27].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:27][CH2:26][CH:25]3[CH2:28][CH2:29][CH2:30][N:24]3[CH3:23])=[CH:8][C:9]=2[CH2:11][CH2:12][CH3:13])[S:4][C:3]=1[C:20]([NH2:22])=[O:21]
Reactant: CN1CCC[C@H]1CO
Reactant: CCCc1cc(N2CCNCC2)nc2sc(C(N)=O)c(N)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1cc(OCC2CCCN2C)nc2sc(C(N)=O)c(N)c12
Temperature: 25 °C
Yield: 55 %

Procedure:
A mixture pyridine-triflate intermediate (see Example 1) (10 mg) and N-methyl-L-prolinol (40 mg) in dioxane was heated under Ar at 90° C. for 3 h. The mixture was cooled to room temperature, and Na2CO3 (2 M, 0.2 mL) was added. The mixture was heated at 100° C. under Ar for 10 h, cooled to room temperature and diluted with water (1 mL). The mixture was extracted with EtOAc, dried with Na2SO4 and concentrated. The residue was purified by preparative silica gel chromatography to give 6 mg of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]([CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5].Br[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:3]([O:6][C:7]([C:9]([CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5]
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)C(=O)OCC=C
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCCCC(=O)OCC)(Cc1ccc(C#N)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
1.69 g (70.43 mmol) of sodium hydride are added in portions to a solution of 20 g (64.03 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonylheptanedioate from Example 82A in 140 ml of dimethylformamide at 0° C. The reaction mixture is then allowed to reach room temperature and is stirred for 30 min. The reaction solution is cooled to 0° C. again and, after addition of 16.32 g (83.24 mmol) of 4-bromomethylbenzonitrile in 140 ml of DMF, stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture and, after extraction three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography an silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1→1:1). 20.08 g (46.97 mmol, 73% yield) of a colorless solid are obtained.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[CH:32]1([C:35]([CH:43]2[CH2:45][CH2:44]2)=[N:36][S@@:37]([C:39]([CH3:42])([CH3:41])[CH3:40])=[O:38])[CH2:34][CH2:33]1.C(O)(=O)C>O1CCCC1>[CH:43]1([C:35]([CH:32]2[CH2:34][CH2:33]2)([C:19]2[S:20][C:16]([C:14]3[CH:13]=[C:12]([NH:21][C:22]4[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH:11]=[C:10]([CH3:9])[CH:15]=3)=[CH:17][N:18]=2)[NH:36][S@@:37]([C:39]([CH3:41])([CH3:42])[CH3:40])=[O:38])[CH2:45][CH2:44]1
Reactant: CC(C)(C)[S@@](=O)N=C(C1CC1)C1CC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(N[S@](=O)C(C)(C)C)(C3CC3)C3CC3)s2)c1
Reaction time: 0.67 h
Yield: 76.3 %

Procedure:
To a solution of lithium diisopropylamide (1.8 M, 2.12 mL, 3.81 mmol) in tetrahydrofuran (5 mL) at −78° C. was added a solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 24, 564 mg, 1.68 mmol) in tetrahydrofuran (5 mL) over 8 minutes. After 40 minutes, a solution of (R)—N-(dicyclopropylmethylidene)-2-methylpropane-2-sulfinamide (0.325 g, 1.52 mmol) in tetrahydrofuran (4 mL) was added all at once. After 90 minutes, acetic acid (0.275 mL) was added and the reaction mixture was partitioned between ethyl acetate (45 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The layers were separated and the organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the crude material using silica gel flash chromatography (ethyl acetate/hexanes) yielded (R)—N-{dicyclopropyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-methylpropane-2-sulfinamide (638.6 mg, 1.16 mmol, 76% yield) as a yellow film. MS ESI: [M+H]+ m/z 550.1.
Reaction SMILES: Br.[F:2][C:3]1[C:8]([O:9]C)=[C:7]([CH:11]=[O:12])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20]>C(O)(=O)C>[F:2][C:3]1[C:8]([OH:9])=[C:7]([CH:11]=[O:12])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20]
Reactant: COc1c(C=O)ccc(-c2ccc(F)cc2F)c1F
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1ccc(-c2ccc(F)cc2F)c(F)c1O
Temperature: 120 °C
Reaction time: 16 h
Yield: 94.5 %

Procedure:
48% hydrobromic acid (22.0 mL) was added at room temperature to an acetic acid (120 mL) solution of 2,2′,4′-trifluoro-3-methoxybiphenyl-4-carbaldehyde (5.14 g), and the mixture was stirred at 120° C. for 16 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then, the solvent was distilled off under reduced pressure. The obtained residue was neutralized with a 1 M aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was passed through a short silica gel column (hexane/ethyl acetate) to obtain the title compound (4.60 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1([CH2:9]Br)[CH2:8][CH2:7][CH2:6]1>>[CH:5]1([CH2:9][NH:4][CH2:3][CH2:2][OH:1])[CH2:8][CH2:7][CH2:6]1
Reactant: NCCO
Reactant: BrCC1CCC1
Product: OCCNCC1CCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:41])[CH:31]=[CH:32][C:33]=1[CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:41][C:15]2[N:14]=[CH:13][C:12]3=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:17]3[N:16]=2)[CH:31]=[CH:32][C:33]=1[CH:34]1[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]1
Reactant: COc1cc(N)ccc1C1CCN(C)CC1
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc(C5CCN(C)CC5)c(OC)c4)nn23)cn1

Procedure:
Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.138 g, 0.369 mmol) and 3-Methoxy-4-(1-methyl-piperidin-4-yl)-phenylamine (0.102 g, 0.461 mmol) were reacted in an analogous manner to Example 908D at room temp for 72 h. The reaction mixture was concentrated, taken up in EtOAc, and washed with brine. The EtOAc layer was dried, filtered over MgSO4, and concentrated. The resulting residue was purified by Gilson RP-HPLC and lyophilized. HPLC rt=2.455 min, purity=98%, LCMS=445.0 (M+H). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.47 (s, 1H), 9.29 (bs, 1H), 9.02 (s, 1H), 8.99 (d, 1H), 7.47 (s, 1H0, 7.23 (d, J=7.5 Hz, 1H), 7.17 (d, J=4.8 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 7.17 (d, J=4.8 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.98 (s, 1H), 6.96 A (d, J=4.1 Hz, 1H), 3.93 (s, 3H), 3.71 (s, 3H), 3.49 (d, J=11.7 Hz, 2H), 3.11-3.05 (m, 3H), 2.80 (d, J=4.0 Hz, 3H), 1.95-1.76 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:21]\[C:20]1[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=1)/[C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1
Product: COc1cc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc(OC)c1OC

Procedure:
5-fluoro-2-methylindene-3-acetic acid (see Example 1, Part D) is allowed to react with 3,4,5-trimethoxybenzaldehyde according to the procedure of Example 1, part E to obtain (Z)-5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenylacetic acid. C22H21FO5 : 384.40; m.p. 168° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:18])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
55.1 g (324.2 mmol) of a benzene compound represented by the above formula (19) was added dropwise to a dichloromethane solution (350 ml) containing 51.8 g (388.6 mmol) of aluminum chloride and 60.5 g (324.3 mmol) of benzoyl chloride cooled to 0° C. After addition, the resulting mixture was stirred for 2 hours. After a reaction, the reaction product was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (40) as 63.1 g (196.9 mmol, yield of 61%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: O=Cc1cc(Cl)ccc1OCCCCCBr
Yield: 10225.9 %

Procedure:
A mixture of 7.82 g (50 mmol) of 5-chlorosalicylaldehyde, 92.1 g (0.4 mmol) of 1,5-dibromopentane, 22.1 g (0.15 mol) of anhydrous granular potassium carbonate, and 360 mL of acetonitrile was stirred and refluxed for 20 hr. The resulting slurry was cooled and diluted with 300 mL of ether. The solids were removed by suction filtration and washed thoroughly with ether. The filtrate and washes with combined and concentrated under water aspirator pressure. The excess 1,5-dibromopentane was removed by distillation under high vacuum. Flash chromatography of the residue on silica gel (eluting with 4:1 hexane-ether) afforded 12.5 g (81.8%) of 2-[(5-bromopentyl)oxy]-5-chlorobenzaldehyde as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O1CCCC1.[CH3:28][C:29]1[N:33]=[C:32]([NH:34][C:35]([C:37]2[C:42]([S:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]=O)=[CH:46][CH:45]=3)=[CH:41][CH:40]=[C:39]([S:54][C:55]3[N:59]([CH3:60])[CH:58]=[N:57][N:56]=3)[N:38]=2)=[O:36])[S:31][N:30]=1>O.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH2:52][CH2:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([S:43][C:42]2[C:37]([C:35]([NH:34][C:32]3[S:31][N:30]=[C:29]([CH3:28])[N:33]=3)=[O:36])=[N:38][C:39]([S:54][C:55]3[N:59]([CH3:60])[CH:58]=[N:57][N:56]=3)=[CH:40][CH:41]=2)=[CH:49][CH:48]=1
Reactant: CNC
Reactant: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OCC=O)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OCCN(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.25 ml of 2 M dimethylamine/tetrahydrofuran solution and 0.21 mg of sodium triacetoxyborohydride were added to a tetrahydrofuran solution of 166 mg of N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]-3-{[4-(2-oxoethoxy)phenyl]thio}pyridine-2-carboxamide obtained in the step 1, and stirred at room temperature for 30 minutes. Chloroform and saturated saline water were added to it, and extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure, and the residue was purified through reversed-phase middle-pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water/acetonitrile/0.1% trifluoroacetic acid). The solvent of the resulting fraction was evaporated away under reduced pressure to obtain 190 mg of the entitled compound as its trifluoroacetate. The obtained salt was neutralized, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure, and the residue was purified through partitioning thin-layer chromatography (NH-PLC05 by Fuji Silicia Chemical, chloroform/methanol=95/5) to obtain 115 mg of the entitled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[S:29][C:28]([S:30]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[S:29][C:28]([S:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)(=[O:31])=[O:32])=[CH:27][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(S(=O)(=O)N5CCN(C)CC5)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (168 mg, 0.5 mmol) and 1-(5-bromo-thiophene-2-sulfonyl)-4-methyl-piperazine (example B.50) (163 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (220 mg, 76%). MS (ISP) 580.0 [(M+H)+]; mp 229° C.
Reaction SMILES: C([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:16][CH:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1
Reactant: OC1CCC(CNCc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NCC1CCC(O)CC1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
To a stirred solution of N-benzyl-N-(4-hydroxycyclohexyl methyl)amine (8.5 g, 0.039 mol) in methanol (300 ml) under N2 was added ammonium formate (9.8 g, 0.0155 mol), followed by 10% palladium on carbon (1.0 g). The reaction mixture was refluxed for 3 hours, cooled to room temperature and filtered. The filtrate was evaporated to dryness and the residue was dissolved in CH2Cl2, filtered and the filtrate was evaporated to afford 1.3 g of 4-hydroxycyclohexylmethylamine.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=3)=[C:10]([CH3:23])[CH:9]=2)=[N:5][N:4]=1)[CH3:2].[CH3:24][N:25]1[CH2:30][CH2:29][C:28]2([C:42]3[C:33](=[CH:34][C:35]4[CH2:36][CH2:37][CH2:38][NH:39][C:40]=4[CH:41]=3)[O:32][CH2:31]2)[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:30][CH2:29][C:28]2([C:42]3[C:33](=[CH:34][C:35]4[CH2:36][CH2:37][CH2:38][N:39]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:11]6[CH:12]=[CH:13][C:8]([C:6]7[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=7)=[CH:9][C:10]=6[CH3:23])=[CH:19][CH:18]=5)=[O:21])[C:40]=4[CH:41]=3)[O:32][CH2:31]2)[CH2:27][CH2:26]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCCC3
Reactant: CCc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Product: CCc1nnc(-c2ccc(-c3ccc(C(=O)N4CCCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
The title compound was prepared from 4'-(5-ethyl-1,3,4-oxadiazol-2-yl)-2'-methylbiphenyl-4-carboxylic acid (D32) and 2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10) using a procedure similar to that of Example 1 (19%). This was converted to its hydrochloride salt, as a white solid. M.p. 241-3° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:28][C:29]([F:36])([F:35])[CH2:30][S:31](Cl)(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>ClC(Cl)C>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:31]([CH2:30][C:29]([F:36])([F:35])[F:28])(=[O:33])=[O:32])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: c1ccc(Cc2ccc(NCc3cccnc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(4-benzylphenyl)pyrid-3-ylmethylamine (0.517 g, 1.88 mmol) dissolved in 8 mL dichloroethane and 4 mL pyridine at 0° C. was added 2,2,2-trifluoroethylsulfonyl chloride (0.313 mL, 2.83 mmol). The reaction was stirred at ambient temperature overnight. The mixture was treated with 1.5 g anhydrous K2CO3 and stirred for 2 h. Then the mixture was filtered and concentrated. The residue was chromatographed on silica gel with 3:1 to 2:1 DCM/EtOAc to give an amorphous white solid. 1H NMR: 8.52 (br d,J=3.3 Hz, 1H), 8.32 (br s,1H), 7.71 (dt,J=6.8, 1.4 Hz, 1H), 7.33-7.20 (m,4H), 7.18-7.10 (m,6H), 4.88 (s,2H), 3.95 (s,2H), 3.79 (q,J=9.3 Hz, 2H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][CH:8]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>ClCCl.O>[N:25]([CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][CH:8]=1)=[N+:26]=[N-:27]
Reactant: OCc1cnc(C(F)(F)F)nc1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: [N-]=[N+]=NCc1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 5-(hydroxymethyl)-2-(trifluoromethyl)pyrimidine (Description 119; 580 mg, 3.26 mmol) and triethylamine (0.55 ml, 3.91 mmol) in anhydrous dichioromethane (15 ml) cooled in an ice-bath was added dropwise methanesulfonyl chloride (0.28 ml, 3.59 mmol), and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water and sat NaCl, dried over Na2SO4, filtered and evaporated. The residue was dissolved in anhydrous N,N-dimethylformamide (15 ml), sodium azide (233 mg, 3.59 mmol) was added and the resulting mixture stirred at room temperature overnight. The mixture was poured into water (100 ml) and extracted with EtOAc (3×15 ml). The combined EtOAc layers were washed with water (2×50 ml), saturated NaCl (25 ml), dried over Na2SO4, filtered and evaporated to give the title compound (660 mg, 100%).
Reaction SMILES: O1CCCCC1[O:7][C:8]([C:10]12[CH2:17][CH2:16][C:13]([NH:18][CH2:19][C:20]([N:22]3[CH2:26][C@@H:25]([F:27])[CH2:24][C@H:23]3[C:28]#[N:29])=[O:21])([CH2:14][CH2:15]1)[CH2:12][CH2:11]2)=[O:9]>C(O)(=O)C>[C:8]([C:10]12[CH2:17][CH2:16][C:13]([NH:18][CH2:19][C:20]([N:22]3[CH2:26][C@@H:25]([F:27])[CH2:24][C@H:23]3[C:28]#[N:29])=[O:21])([CH2:14][CH2:15]1)[CH2:12][CH2:11]2)([OH:9])=[O:7]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Solvent: CC(=O)O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(2S,4S)-1-[[N-[4-(2-Tetrahydropyranyl)oxycarbonylbicyclo[2,2,2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (71.6 mg) was dissolved in acetic acid (4 mL) and the solution was stirred at room temperature for 6 hours. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was suspended in dichloromethane and was collected by filtration. This gave (2S,4S)-1-[[N-(4-carboxybicyclo[2,2,2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (31.4 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1.Cl.ClC1C=CN=CC=1.ClCCl>O1CCOCC1>[Cl:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([N:1]2[CH:13]=[CH:17][CH:16]=[CH:15]2)[CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1c(N)cccc1Cl
Reactant: COC1CCC(OC)O1
Agent: Cl
Agent: Clc1ccncc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1c(Cl)cccc1-n1cccc1
Yield: 87.8 %

Procedure:
A solution of 2-amino-6-chloro-benzonitrile (30 g), 2,5-dimethoxytetrahydrofuran (30 g) and 4-chloropyridine hydrochloride (17 g) in dioxane was heated to 70° C. for 2.5 h. The solvent was evaproated in vacuo. Dichloromethane was then added to the residue and the spent 4-chloropyridine hydrochloride filtered off. The dichloromethane was evaporated in vacuo to give 1-(3′chloro-2′-cyanophenyl)pyrrole (35 g)