Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30]([C:34]([O:36]CC)=[O:35])=[CH:29][CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1.C(O)C.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30]([C:34]([OH:36])=[O:35])=[CH:29][CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1
Reactant: CCOC(=O)c1cccc2cc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)cc1
Temperature: 100 °C
Yield: 84 %

Procedure:
A solution of ethyl 6-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (0.110 g, 0.187 mmol) in tetrahydrofuran (2 mL) was placed in a microwave reaction tube. Ethanol (1 mL) was added followed by 1 N sodium hydroxide (0.36 mL, 0.36 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 500 seconds. Additional sodium hydroxide solution (0.2 mL, 0.2 mmol) was added and the solution was heated in a microwave reactor to 100° C. for another 500 seconds. The solution was neutralized and concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was concentrated to yield the title compound as a white solid (0.088 g, 83.8%). 1H NMR (DMSO-d6): δ 13.14 (s, 1H), 8.91 (d, J=9 Hz, 1H), 8.27 (d, J=1 Hz, 1H), 8.20 (d, J=8 Hz, 1H), 7.96 (dd, J=2, 9 Hz, 2H), 7.80 (d, J=9 Hz, 2H), 7.58 (m, 1H), 7.43 (d, J=8 Hz, 2H), 7.26 (m, 1H), 7.15 (d, J=9 Hz, 2H), 4.98 (s, 2H), 3.35 (septet, J=7 Hz, overlapping H2O, 1H), 3.25-3.20 (m, 2H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)#[CH:18]>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:21]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(C#Cc3ccc(F)cc3)c2c2ccccc12
Yield: 54.8 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 1-ethynyl-4-fluorobenzene (0.07 mL, 0.65 mmol) to provide 250 (74 mg, 54% yield) as a tan solid. LC-MS (M+H=315 obsd.=315).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([O:18]CC)=[O:17])(=[O:12])=[O:11])=[CH:5][CH:4]=1.C(O)C.[OH-].[Na+].Cl>O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([OH:18])=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the product of Step A was added ethanol (25 mL) followed by a solution of NaOH (1.93 g, 48.3 mmol) in water (25 mL). The reaction was stirred at ambient temperature for 1.5 hours. To the mixture was added dropwise 1 N HCl (95 mL), and the mixture was stirred at ambient temperature overnight. The solids were collected by filtration, washed with water (2×20 mL), and dried in a vacuum oven at 45° C. overnights to give 3-({[4-(trifluoromethyl)phenyl]amino}sulfonyl)benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.28 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.71 (t, J=7.8 Hz, 1H), 8.03 (ddd, J=7.8, 1.9, 1.1 Hz, 1H), 8.15 (dt, J=7.8, 1.4 Hz, 1H), 8.34 (t, J=1.7 Hz, 1H), 10.98 (s, 1H), 13.54 (s, 1H); MS (EST) m/z 344 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3].C1COCC1.[H-].[Na+].Cl[CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>O>[CH3:3][CH:2]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[C:11]3=[N:16][S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][N:12]3[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)c1ccc(OCc2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(OCC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 1 h
Yield: 36.8 %

Procedure:
A mixture of 3-{[4-(1-methylethyl)phenoxy]methyl}pyridin-2-amine (600 mg) and dehydrated THF (10 ml) was added to a mixture of sodium hydride (60%, 495 mg), 2-chloroethanesulfonyl chloride (1211 mg) and dehydrated THF (10 ml) at room temperature. The reaction mixture was stirred for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate) to give the title compound (303 mg) as a white solid. The obtained solid was crystallized from THF-diisopropyl ether to give a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S-:7])=[CH:3][CH:2]=1.[K+].Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[O:19][CH3:20]>CN(C)C=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([S:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[C:11]([O:19][CH3:20])[CH:12]=1)([O-:18])=[O:17]
Reactant: [S-]c1ccncc1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1Sc1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A solution of potassium 4-pyridinethiolate (20.00 g, 134 mmol) and 2-chloro-5-nitroanisole (20.91 g, 112 mmol) in dimethylformamide (80 mL) was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water and a brown solid was collected by filtration. The solid was stirred with 3N HCl (400 mL) for 30 minutes, and the solution filtered. The filtrate was basified with ammonium hydroxide with cooling in an ice bath. Filtration of the basic solution yielded the title anisole as an orange solid (26.23 g, 90%); mp 133°-135° C. 1H-NMR (300 MHz, d6-DMSO): 3.95 (s, 3H, OCH3) 7.24 (dd, 2H, J=4.6, 1.7 Hz, aromatic) 7.53 (d, 1H, J=8.3 Hz, aromatic) 7.88 (dd, 2H, J=8.3, 2.3 Hz, aromatic) 8.48 (dd, 2H, J=4.7, 1.3 Hz, aromatic). MS (CI, CH4): 263 (M+1).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[CH2:8][CH2:9][NH:10][C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1.C(N(CC)CC)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>C(Cl)Cl>[CH3:29][C@:26]12[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:43])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:31])([CH3:32])[C:20]([C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14][C@@H:13]1[C@H:12]1[C@H:44]([C:47]([CH3:49])=[CH2:48])[CH2:45][CH2:46][C@:11]1([NH:10][CH2:9][CH2:8][N:2]1[CH2:3][C@@H:4]3[CH2:7][C@H:1]1[CH2:6][N:5]3[S:58]([CH3:57])(=[O:60])=[O:59])[CH2:28][CH2:27]2
Reactant: CS(=O)(=O)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CN4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CN4S(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (75.2 mg, 0.113 mmol) and triethyl amine (0.078 mL, 0.563 mmol) in DCM (3 mL) was added methanesulfonyl chloride (10.67 μl, 0.135 mmol). The reaction mixture was stirred at rt. After 1.5 h, the reaction mixture was diluted with DCM (25 mL) and washed with H2O (2 mL). The aqueous layer was extracted with DCM (15 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give methyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a light brown solid (69.0 mg, 78% yield). LC/MS: m/e 746.8 (M+H)+, 246 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.88 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H), 5.25 (d, J=4.6 Hz, 1H), 4.71 (s, 1H), 4.57 (s, 1H), 4.26 (s, 1H), 3.86 (s, 3H), 3.69 (br. s., 1H), 3.58 (d, J=9.5 Hz, 1H), 3.19 (dd, J=9.4, 1.8 Hz, 1H), 2.97 (dd, J=9.8, 2.0 Hz, 1H), 2.85 (s, 3H), 2.80 (dd, J=8.3, 4.2 Hz, 2H), 2.65 (d, J=9.8 Hz, 1H), 2.61-2.44 (m, 2H), 2.07 (dd, J=17.1, 6.4 Hz, 2H), 1.95-1.68 (m, 6H), 1.66 (s, 3H), 1.65-1.37 (m, 9H), 1.31-1.06 (m, 7H), 1.04 (s, 3H), 0.96 (s, 3H), 0.94 (s, 3H), 0.89 (s, 6H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[C:9]([CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])(=[S:11])[NH2:10]>O1CCOCC1>[S:11]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=2[N:10]=[C:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C1CCCCC1Br
Reactant: COC(=O)c1cccc(OCC(N)=S)c1
Solvent: C1COCCO1
Product: COC(=O)c1cccc(OCc2nc3c(s2)CCCC3)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.3 %

Procedure:
After a mixture of 2-bromocyclohexanone (865 mg, 4.9 mmol), methyl 3-(thiocarbamoylmethoxy)benzoate (1.00 g, 4.4 mmol) and 1,4-dioxane (10 ml) was stirred at room temperature for 5 hours and then at 80° C. for 12 hours, it was cooled and concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the resulting residue and the product formed was extracted with ethyl acetate. The extract was washed with water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (eluent=hexane:ethyl acetate=4:1) to give methyl 3-(4,5,6,7-tetrahydrobenzothiazol-2-ylmethoxy)benzoate (369 mg, 1.2 mmol, 27%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([P:23]([O:29][CH:30]([CH3:32])[CH3:31])(=[O:28])[O:24][CH:25]([CH3:27])[CH3:26])[P:13]([O:19][CH:20]([CH3:22])[CH3:21])(=[O:18])[O:14][CH:15]([CH3:17])[CH3:16])[CH:6]=[C:7]([CH2:9]Br)[CH:8]=1.[C:33]([O-:36])(=[S:35])[CH3:34].[K+]>CN(C=O)C>[C:33]([S:35][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([P:23]([O:29][CH:30]([CH3:32])[CH3:31])(=[O:28])[O:24][CH:25]([CH3:27])[CH3:26])[P:13]([O:19][CH:20]([CH3:22])[CH3:21])(=[O:18])[O:14][CH:15]([CH3:17])[CH3:16])[CH:6]=[C:7]([CH2:9][S:35][C:33](=[O:36])[CH3:34])[CH:8]=1)(=[O:36])[CH3:34]
Reactant: CC([O-])=S
Reactant: CC(C)OP(=O)(OC(C)C)C(Cc1cc(CBr)cc(CBr)c1)P(=O)(OC(C)C)OC(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SCc1cc(CSC(C)=O)cc(CC(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
To a solution of bisphosphonate 17 (2 g, 3.2 mmol) in 12 ml of anhydrous DMF under nitrogen is added at 0° C. via a cannula a solution of potassium thioacetate (1.1 g, 9.6 mmol) in 15 ml of anhydrous DMF. The mixture is stirred for 1.50 h at 0° C., quenched with water and extracted with EtOAc. The organic layer is dried over Na2SO4, filtered and evaporated. The residue is purified by flash chromatography (silica gel, MeOH:CH2Cl2 /0:100-2:98) to give bisthioacetate 18 (1.38 g, 70%) as a light yellow oil. IR (neat) 2980, 2932, 2230, 1692, 1600 cm-1 ; 1H NMR (CDCl3): δ 1.16 (6H, d, J=6.2 Hz), 1.18 (6H, d, J=6.2 Hz), 1.23 (12H, d, J=6.2 Hz), 2.26 (6H, s), 2.40 (1H, tt, J=24, 6.3 Hz), 3.07 (2H, td, J=16.5, 6.3 Hz), 4.00 (4H, s), 4.67 (4H, m), 6.95 (1H, s), 6.99 (2H, s); 13C NMR (CDCl3): δ 23.72, 23.75, 23.78, 23.84, 23.87, 23.90, 24.14, 30.25, 31.35 (t, J=4.8 Hz), 33.17, 40.59 (t, J=134 Hz), 70.98 (d, J=3 Hz), 71.01 (d, J=3 Hz), 71.15 (d, J=3 Hz), 71.28 (d, J=3 Hz), 127.24, 128.55, 137.62, 140.99 (t, J=7.6 Hz), 194.77; MS (APCI) m/z (relative intensity) 611 (MH+, 100), 569 (63), 527 (58), 485 (37), 453 (31)); MS (FAB) m/z (relative intensity) 611 (MH+, 100); HRMS calcd for C26H45O8P2S2 (MH+) 611.2031, found 611.2029.
Reaction SMILES: [CH3:1][C:2]1(CC)[O:7]C(=O)CC(=O)[O:3]1.[CH:12](=O)[C:13]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=1.C(O)=O>C(N(CC)CC)C>[CH3:17][O:16][C:15]1[CH:14]=[C:13]([CH2:12][CH2:1][C:2]([OH:7])=[O:3])[CH:22]=[CH:21][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCC1(C)OC(=O)CC(=O)O1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 95 °C

Procedure:
3.95 g (0.025 mol) of 2-methyl-2-ethyl-1,3-dioxane-4,6-dione and 4.15 g (0.025 mol) of veratraldehyde were weighed in to 25 ml of the mixture of formic acid and triethylamine prepared as described in Example 1. The reaction mixture was heated to 95° C. during 1 hour and maintained at the same temperature for 2 hours, then Example 1 was followed.
Reaction SMILES: [C:1]([C:3]([OH:21])([CH2:5][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14]C(=O)C)[C:10]([CH3:18])=[C:9]([CH3:19])[C:8]=1O)[CH3:4])#[N:2].S(=O)(=O)(O)O>CO>[C:1]([C:3]1([CH3:4])[CH2:5][CH2:6][C:7]2[C:8](=[C:9]([CH3:19])[C:10]([CH3:18])=[C:11]([OH:14])[C:12]=2[CH3:13])[O:21]1)#[N:2]
Reactant: CC(=O)Oc1c(C)c(C)c(O)c(CCC(C)(O)C#N)c1C
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#N)O2
Reaction time: 72 h

Procedure:
A solution of 5.31 g. of (±)-2-cyano-4-(5-acetoxy-2-hydroxy-3,4,6-trimethylphenyl)butan-2-ol in 60 ml. of methanol was cooled in an ice bath under N2. Sulfuric acid (3.8 ml.) was added over 5 minutes. The light yellow solution was stirred at 23° for 72 hours and then at reflux for 5 hours, cooled, poured into ice-H2O and filtered. The solid was washed with H2O and crystallized from ether-30°-60° petroleum ether to give (±)-2-cyano-6-hydroxy-2,5,7,8-tetramethylchroman as a white needle, m.p. 152.5°-153° .
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10](OC)(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[SH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10](=[O:18])[N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(Br)c2)sc2ccccc12
Yield: 20.6 %

Procedure:
A mixture of 3-bromobenzonitrile (2.00 g, 11 mmol), methyl thiosalicylate (2.87 g, 17 mmol), triethylamine (1.95 g, 19 mmol) and toluene (10 ml) was heated and refluxed under a nitrogen flow for 40 hours. The precipitated crystals were taken by filtration and recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (0.72 g, 21%) as crystals.
Reaction SMILES: CS(C)=O.[OH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1.[NH2:27][OH:28]>O>[OH:28][N:27]=[C:23]([NH2:24])[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][OH:5])[CH2:14][CH2:13]2)=[CH:26][CH:25]=1
Reactant: NO
Reactant: N#Cc1ccc(OCCCC2CCN(CCCO)CC2)cc1
Solvent: O
Solvent: CS(C)=O
Product: NC(=NO)c1ccc(OCCCC2CCN(CCCO)CC2)cc1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a dimethylsulfoxide (43 mL) suspension of 4.27 g of 4-{3-[1-(3-hydroxypropyl)-4-piperidinyl]propoxy}benzonitrile was added 4.32 mL of a 50% hydroxylamine aqueous solution at room temperature, which was then stirred at 40 to 50° C. for 3 hours and 30 minutes. The reaction mixture was cooled down to room temperature, to which 50 mL of water was then added dropwise over a period of 10 minutes, followed by stirring at room temperature for 30 minutes. The precipitate was collected by filtration and washed with water to provide 4.59 g of N′-hydroxy-4-{3-[1-(3-hydroxypropyl)-4-piperidinyl]propoxy}benzamidine as white solid form.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:33]([C:30]4[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=4)(=[O:35])=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 4-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-4-methylbenzenamine (0.82 g, 4.4 mmol) in anhydrous CH2Cl2 (40 mL) was added 3-(trifluoromethyl)benzoyl chloride (0.72 ml, 4.85 mmol) and triethylamine (2.5 ml, 17.6 mmol). The mixture was stirred overnight at room temperature. The saturated NaHCO3 (80 mL) was added and the mixture was stirred for 5 min. The organic layer was separated and aqueous was extracted with CH2Cl2 (3×20 mL). The combined organic solution was dried (Na2SO4). The solvent was removed in vacuo. The title compound was afforded as a yellow solid (1.48 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC(O)=O.[O:16]([C:18]#[N:19])[Na].[OH-].[Na+]>O>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:18]([OH:16])[N:19]=[C:4]2[OH:5]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: N#CO[Na]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Oc1nc(O)c2cccc(Br)c2n1
Temperature: 35 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a 2000 mL flask charged with 2-amino-3-bromobenzoic acid (67.0 g, 310 mmol) was added water (750 mL) and AcOH (18.8 mL). The suspension was heated to 35° C. A solution of NaOCN (30.82 g, 403 mmol, 85% purity) in water (250 mL) was added dropwise at 35° C. The reaction mixture was stirred at 35° C. for 2 hrs. NaOH (415 g, 10.38 mol) was added in portions, the reaction temperature was kept below 40° C. during the addition. The mixture turned clear for a short time, then an off-white suspension was formed. The reaction mixture was cooled to room temperature, and filtered. The obtained solid was dissolved in hot water, pH was adjusted to 5 by addition of 6 N HCl. The resulting mixture was cooled to room temperature, and the precipitate was collected by filtration, rinsed with a small amount of DCM, cold MeOH, ether, then dried in vacuo to yield the title compound as a off-white solid (43.32 g, 58%). 1HNMR (DMSO-d6, 400 MHz): δ 11.60-11.40 (br s, 1H), 10.40-10.20 (br s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.12 (dd, J=7.6, 8.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: [H][H]
Reactant: Cn1cnc2c(N)nc(C#CCCO)nc21
Agent: [Pd]
Solvent: CCO
Product: Cn1cnc2c(N)nc(CCCCO)nc21

Procedure:
To a solution of 4-(6-amino-9-methyl-9H-purin-2-yl)-but-3-yn-1-ol (1.5 g, 6.88 mmol) in ethanol (30 ml) was added palladium 10% on graphite (1.35 g, 20% in weight). The mixture was stirred for 16 h in autoclave at 50° C. under 4 atm of hydrogen. The catalyst was filtered through a small pad of Celite and the solution obtained was evaporated under reduced pressure, to give a residue that was used for the following reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:6]=1.[F:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24](F)[CH:25]=1>>[F:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:6]=[C:2]2[CH3:1])[CH:25]=1
Reactant: Cc1nc(C#Cc2cccc(C(F)(F)F)c2)c[nH]1
Reactant: Fc1cncc(F)c1
Product: Cc1nc(C#Cc2cccc(C(F)(F)F)c2)cn1-c1cncc(F)c1

Procedure:
The title compound, MS: m/e=346.3 (M+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(3-trifluoromethyl-phenylethynyl)-1H-imidazole and 3,5-difluoro-pyridine.
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][O:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:36]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine dihydrochloride (135.0 mg, 0.29 mmol), 3-methyltetrahydro-4H-pyran-4-one (100 mg, 0.88 mmol) and triethylamine (0.1.6 mL, 1.2 mmol) in methylene chloride (10 mL) was added sodium triacetoxyborohydride (190 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1) to give desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give isomer 1 and isomer 2. MS calculated for C24H36F3N5O2: (M+H) 484; found 484.1.