Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[C:13]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=O)[CH3:14]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:14][CH2:13][C:16]1[S:17][CH:18]=[CH:19][N:20]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: CC(=O)c1nccs1
Product: S=C(NN=CCc1nccs1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (50 mg, 0.273 mmol) and 2-acetylthiazole (41 mg, 0.33 mmol) similar to Example 3 and isolated as an off-white solid (30 mg, 37%). 1H NMR (DMSO-d6): 9.98 (s, 1H), 9.62 (s, 1H), 7.89 (m, 2H), 7.77 (m, 1H), 6.16 (ddd, J=8.1, 5.1, 2.7 Hz, 2H), 4.23 (m, 1H), 3.04 (s, 2H), 2.23 (s, 3H), 1.87-1.50 (m, 4H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][C:24]=1[CH:25]=O.C(OC(N1CCC[C@H](NCC2C=C(C(F)(F)C)C=CC=2OC(F)(F)F)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:25][C:24]2[CH:27]=[C:28]([C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:30][C:23]=2[O:22][CH3:21])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(C(F)(F)C(F)(F)F)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This Compound was prepared from Compound 12 and Compound 40 in the same manner of Compound 26. This was employed in the next step without further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[I:34][C:35]1[S:36][CH:37]=[CH:38][C:39]=1[C:40]([OH:42])=O.[CH3:43][CH:44]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH2:55])[CH2:45][CH:46]([CH3:48])[CH3:47]>C(#N)C.O>[CH3:43][CH:44]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH:55][C:40]([C:39]1[CH:38]=[CH:37][S:36][C:35]=1[I:34])=[O:42])[CH2:45][CH:46]([CH3:47])[CH3:48]
Reactant: CC(C)CC(C)c1ccccc1N
Reactant: O=C(O)c1ccsc1I
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(C)c1ccccc1NC(=O)c1ccsc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.3 %

Procedure:
Under protective gas (argon), 0.56 ml (3.38 mmol) of N,N-diisopropylethylamine and 1.18 g (2.5 mmol) of bromotrispyrrolidinophosphonium hexafluorophosphate (PyBrop) are added to a solution of 516 mg (2.0 mmol) of 2-iodothiophene-3-carboxylic acid and 300 mg (1.7 mmol) of 2-(1,3-dimethylbutyl)phenylamine in 10 ml of acetonitrile. The reaction mixture is stirred at room temperature for 24 hours and, for work-up, added to water, extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. Column chromatography (cyclohexane/ethyl acetate gradient) gives 150 mg (21% of theory) of N-[2-(1,3-dimethylbutyl)phenyl]-2-iodothiophene-3-carboxamide [log P (pH 2.3)=4.14].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)[C:5]2=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=[CH:18][N:4]2[N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[N:35][CH:36]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[N:35][CH:36]=[C:37]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)[C:5]3=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[CH:18][N:4]3[N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1nc(CNc2nc(Cl)nn3ccc(-c4ccccc4)c23)cs1
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(CNc2nc(-c3cncc(S(=O)(=O)NC(C)(C)C)c3)nn3ccc(-c4ccccc4)c23)cs1
Temperature: 110 °C
Yield: 33.3 %

Procedure:
2-Chloro-N-((2-methylthiazol-4-yl)methyl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.300 g, 0.843 mmol) and N-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (0.574 g, 1.69 mmol) were dissolved in dioxane (25 mL) and water (3 mL). To the reaction mixture was added K2CO3 (0.350 g, 2.53 mmol) and the reaction mixture was degassed with nitrogen for 15 minutes. PdCl2(dppf)-CH2Cl2 (69.0 mg, 0.0840 mmol) was added and the resulting reaction mixture degassed with nitrogen for 20 minutes then heated to reflux at 110° C. for 14 h. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was diluted with CH2Cl2 (2×25 mL) and filtered through CELITE®. The filtrate was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 25% EtOAc/hexanes) to afford N-(tert-butyl)-5-(4-(((2-methylthiazol-4-yl)methyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.150 g, 28.0%). LCMS Condition B-82: retention time 2.35 min, [M+1]=534.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (s, 9H), 2.62 (m, 3H), 4.88 (d, J=4.8 Hz, 2H), 6.75 (t, J=5.2 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 7.36 (s, 1H), 7.42-7.57 (m, 5H), 7.94-7.97 (m, 2H) 8.91 (dd, J=2.0 Hz, J=2.4 Hz, 1H), 9.06 (d, J=2.4 Hz, 1H), 9.57 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([CH:8]=[O:9])=[CH:6][CH:7]=1)#[N:2].[BH4-].[Na+]>CCO>[C:1]([C:3]1[S:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(CO)s1
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
To a solution of 2-cyano-5-formyl-thiophene (6.9 g, 50 mmol) in EtOH (100 mL) was added sodium borohydride (1.9 g, 50 mmol) in portions. After 5 min of stirring, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and brine. The layers were separated and the organic phase was washed once with 1M citric acid and once with brine, then dried (MgSO4), filtered and concentrated in vacuo to give 6.1 g (88%) of 2-cyano-5-(hydroxymethyl)thiophene.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11](C4C=CN=CC=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH2:28]([O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH3:29]>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11]([C:33]4[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([O:30][CH2:28][CH3:29])[CH:32]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1nc(-c2ccncc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CCOc1cc(B(O)O)ccc1OC
Product: CCOc1cc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1OC
Yield: 32.5 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((3-cyclopropyl-6-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:, using instead (3-ethoxy-4-methoxyphenyl)boronic acid (80.5 mg, 0.41 mmol) as a starting material to afford 38.8 mg (32.5%) of (R)-4-((R)-1-((3-cyclopropyl-6-(3-ethoxy-4-methoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.232 (s, 1H), 7.723 (s, 1H), 7.61 (d, J=8.7 Hz 2H), 7.545 (s, 1H), 7.00 (d, J=8.4 Hz, 1H). 5.51 (t, J=5.6 Hz, 1H), 4.1 (q, J=6.9 Hz, 2H), 3.77 (s, 3H), 3.65 (d, J=3.3 Hz, 1H), 3.39 (t, J=9 Hz, 1H), 3.29 (s, 2H) 3.20 (t, J=8 Hz, 1H), 2.84 (d, J=6 Hz, 1H), 2.32 (d, J=8.7 Hz, 2H), 1.414-1.342 (m, 6H), 1.088-1.032 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C24H28N4O4:436.21; found 437.18.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14](=[O:16])[CH3:15])=[CH:9][C:8]=1[Cl:17])=[O:5])[CH3:2].[Se](=O)=O.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].Cl>O1CCOCC1.O.C(O)C.CCOCC>[ClH:17].[CH2:1]([O:3][C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([CH:14]([OH:16])[CH2:15][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][C:8]=1[Cl:17])=[O:5])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)Nc1c(F)cc(C(C)=O)cc1Cl
Agent: Cl
Agent: O=[Se]=O
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Nc1c(F)cc(C(O)CNC(C)(C)C)cc1Cl
Reaction time: 8 h

Procedure:
8.7 gm of 4'-ethoxycarbonylamino-3'-chloro-5'-fluoro-acetophenone were added in portions to a solution of 3.7 gm of selenium dioxide in 30 ml of dioxane and 1 ml of water at 60° C. while stirring. The mixture obtained was refluxed for 4 hours and, after cooling, 4.1 ml of tert. butylamine were added dropwise to the solution of 4'-ethoxycarbonylamino-3'-chloro-5'-fluoro-phenylglyoxal thus obtained while cooling with ice. The resulting mixture was diluted with 350 ml of ethanol and filtered. 5 gm of sodium borohydride were added in portions to the filtrate containing crude 4'-ethoxy-carbonylamino-3'-chloro-5'-fluoro-phenyl-glyoxylidene-tert.-butylamine, while stirring and cooling with ice. After allowing the mixture thus obtained to stand overnight at room temperature, the excess sodium borohydride was destroyed with acetone. The resulting mixture was admixed with water and extracted with chloroform. The chloroform extract was washed with water, dried over sodium sulfate and, after the addition of activated charcoal and rapidly heated to the boiling point filtered, and evaporated in vacuo. The solid residue consisting of 1-(4-ethoxy-carbonylamino-3-chloro-5-fluoro-phenyl)-2-tert. butylamino-ethanol was admixed with isopropanol, and the mixture obtained was acidified with ethereal hydrochloric acid to pH 4. After addition of ether, the precipitated crystals were suction-filtered off and washed with ether.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[CH:13]=[C:14]([C@:18]23[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:22][S:21][C:20]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:19]3)[CH:15]=[CH:16][CH:17]=1)([O-])=O.O>C(O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:20]1[S:21][CH2:22][C@@H:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C@:18]2([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH2:9])[CH:13]=2)[N:19]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc([N+](=O)[O-])c3)CCCC[C@H]2CS1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(N)c3)CCCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.2 %

Procedure:
A saturated solution of sodium dithionite (879 mg) was added to a solution of tert-butyl(−)-[(4aR*,8aS*)-8a-(3-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate (395 mg) in ethanol (20 mL) at room temperature. After stirring at room temperature for 10 minutes, ethanol (10 mL) was further added to the reaction solution. After stirring at room temperature for five minutes, water (10 mL) was further added. The reaction solution was warmed to 40° C. and stirred for 30 minutes. After confirming completion of the reaction, the reaction solution was cooled to room temperature. The excess of ethanol in the reaction solution was evaporated under reduced pressure and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (110 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]1=[O:15].[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][N:2]1[C:3](=[O:15])[CH:4]=[CH:5][C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:7]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cn1cc(C2CCC(=O)CC2)ccc1=O
Product: Cn1cc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)ccc1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-methyl-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].O>C(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH2:3][C:5]2[CH:14]=[CH:13][CH:12]=[CH:7][CH:6]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(OCC(=O)OC(C)(C)C)ccc2cc1O
Solvent: O=CO
Solvent: O
Product: COC(=O)c1cc2cc(OCC(=O)O)ccc2cc1OCc1ccccc1

Procedure:
7-tert-butoxycarbonylmethoxy-3-hydroxynaphthalene-2-carboxylic acid methyl ester (1.35 g, 3.2 mmol) in formic acid (5 mL) is stirred at RT for 2 h. The mixture is poured into water, filtered and washed with water. After it is air dried for 18 h, it is dissolved in EtOAc, dried with MgSO4, concentrated to give the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:26]4[CH:27]=[CH:22][CH:23]=[C:24]([N:28]5[CH2:29][CH2:30][CH:31]([N:34]6[CH2:35][CH2:36][O:37][CH2:38][CH2:39]6)[CH2:32][CH2:33]5)[CH:25]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: Brc1cccc(N2CCC(N3CCOCC3)CC2)c1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(N5CCC(N6CCOCC6)CC5)c4)nc23)cc1

Procedure:
4-[1-(3-Bromo-phenyl)-piperidin-4-yl]-morpholine was prepared from 4-piperidin-4-yl-morpholine (0.21 g, 1.2 mmol) and 3-bromophenylboronic acid (0.50 g, 2.5 mmol) in a manner analogous to Step 49a. The reaction product was isolated as a tan resin (0.238 g, 59%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.08 (t, J=7.1 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J=7.3 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 3.75-3.68 (m, 6H), 2.79-2.70 (m, 2H), 2.60-2.55 (m, 4H), 2.37-2.28 (m, 1H), 1.97-1.89 (m, 2H), 1.68-1.56 (m, 2H). MS=325, 327 (MH)+. 57b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-[1-(3-bromo-phenyl)-piperidin-4-yl]-morpholine (100.0 mg, 0.3075 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.035 g, 25%). MP=230-236° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.4 Hz, 1H), 8.26 (d, J=8.0 Hz, 2H), 8.08 (d, J=7.1 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.35 (s, 1H), 7.24-7.18 (m, 1H), 7.01 (d, J=6.7 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.60 (d, J=8.4 Hz, 1H), 3.81 (d, J=11.7 Hz, 2H), 3.77-3.72 (m, 4H), 3.10 (s, 3H), 2.78 (t, J=11.8 Hz, 2H), 2.63-2.58 (m, 4H), 2.40-2.30 (m, 1H), 1.97 (d, J=12.7 Hz, 2H), 1.74-1.62 (m, 2H). MS=533 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:23]=[CH:22][C:10]([O:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:9][C:8]=2[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:6][CH2:5]1)[CH3:2]>C1COCC1>[CH2:1]([O:3][C:4]1([C:7]2[CH:23]=[CH:22][C:10]([OH:11])=[CH:9][C:8]=2[C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C(C)(C)C)CC1
Solvent: C1CCOC1
Product: CCOC1(c2ccc(O)cc2C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.8 %

Procedure:
To a solution of [4-(1-ethoxycyclopropyl)-3-tert-butyl-phenoxy]-triisopropyl-silane (Intermediate 108, 600.0 mg, 1.54 mmol) in 3 mL THF at 0° C. was added tetra,butylammonium fluoride (802.8.0 mg, 3.07 mmols; 3.1 mL of a 1 M solution in THF). The solution was stirred at 0° C. for 30 minutes and then quenched by the addition of H2O. The mixture was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound (400 mg, 88%) was isolated from the residue by column chromatography (4-10% EtOAc-hexanes) as a colorless solid.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[C:7]([CH:29]=[CH:30][CH2:31][CH2:32][CH3:33])=[C:6]([CH:34]([CH3:36])[CH3:35])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:16]=2)[C:7]([CH:29]=[CH:30][CH2:31][CH2:32][CH3:33])=[C:6]([CH:34]([CH3:35])[CH3:36])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1cccc(OCc2ccccc2)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(OCc2ccccc2)c1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.74 (t, J=7.4 Hz, 3 H), 1.25 (m, 14 H), 1.90 (m, 2 H), 3.39 (m, 2 H), 4.39 (d, J=6.0 Hz, 2 H), 5.07 (s, 2 H), 5.32 (m, 1 H), 5.97 (m, 1 H), 6.74 (m, 2 H), 6.95 (m, 1 H), 7.35 (m, 7 H). FAB-MS: calculated for C30H37NO2, 444; found 444 (M+H, 100%). Elemental analysis: calculated for C30H37NO2: C 81.22; H 8.41; N 3.16, found: C 80.51; H 8.41; N 3.36. Rf 0.5 (25% ethyl acetate/n-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][NH:10][C:11](=[O:22])C1C=CC(C(F)(F)F)=CC=1)=O.ClC1C=CSC=1C(NN)=O.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:43]=[CH:42][C:38](C(Cl)=O)=[CH:37][CH:36]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:22][CH2:11][N:10]([C:38]2[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:43][CH:42]=2)[N:9]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(NNC(=O)c1sccc1Cl)c1ccc(C(F)(F)F)cc1
Agent: NNC(=O)c1sccc1Cl
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc(N2COC(c3sccc3Cl)=N2)cc1
Yield: 93 %

Procedure:
N-(3-Chloro-thiophene-2-carbonyl)-N′-(4-trifluoromethylbenzoyl)-hydrazine: A solution of 3-chloro-2-thiophenecarboxylic acid hydrazide (70.4 mg, 0.4 mmol), 4-trifluoromethylbenzoyl chloride (83.6 mg, 0.4 mmol) in pyridine (5 mL) was refluxed for 4 h and then cooled. The solution was diluted by water and the precipitate was collected by filtration, and then dried to yield 129 mg (93%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[CH2:7][OH:8]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1Cl
Temperature: 25 °C

Procedure:
To a solution 5-bromo-2-chlorobenzoic acid (100 g, 425 mmol) in tetrahydrofuran (500 mL) at 0 r was added borane dimethyl sulfide complex (170 mL, 170 mmol). The resulting mixture was stirred with gradual warming to ambient temperature over 15 h, re-cooled to 0° C., and quenched with MeOH. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to yield the titiled compound as a white solid, which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NCCCOc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCOc1ccncc1)c1cccnc1
Yield: 88.7 %

Procedure:
To a solution of 700 mg (4.60 mmol) of 4-(3-aminopropyloxy)pyridine and 1.54 ml (11.0 mmol) of triethylamine in 30 ml of methylene chloride, 830 mg (4.66 mmol) of nicotinoyl chloride hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10 to 1:5) to obtain 1.05 g of the desired compound (yield: 85.8%, colorless crystals).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][CH:7]1[CH2:11][CH2:10][C:9](=O)[C@@H:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CO>[NH2:5][C:9]1[CH2:10][CH2:11][C@@H:7]([CH3:6])[C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)[C@H]1C(=O)CCC1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)C1=C(N)CC[C@H]1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.8 %

Procedure:
Ammonium acetate (240 g, 3114 mmol) was added to a solution of (R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (106.0 g, 622.8 mmol) in MeOH (1.2 L). The reaction mixture was stirred at room temperature under nitrogen for 20 hours, and the reaction was complete as determined by TLC and HPLC. The reaction mixture was concentrated to remove MeOH. The resulting residue was dissolved in DCM, washed with H2O (2×), brine (1 X), dried (Na2SO4), filtered, and concentrated to give (R)-ethyl 2-amino-5-methylcyclopent-1-enecarboxylate (102 g, 97% yield) as an oil. LC/MS (APCI+) m/z 170 [M+H]+.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[CH2:13]([O:15][P:16](Cl)([O:18][CH2:19][CH3:20])=[S:17])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[P:16](=[S:17])([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:2]1[CH2:3][CH2:4][CH2:5][S:1]1)([O:18][CH2:19][CH3:20])[O:15][CH2:13][CH3:14]
Reactant: CCOP(=S)(Cl)OCC
Reactant: Oc1ccccc1C1CCCS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=S)(OCC)Oc1ccccc1C1CCCS1

Procedure:
A mixture of 3 g. of 2-(tetrahydro-2-thienyl) phenol, 4 g. of diethylchlorothiophosphate, 50 ml. of methyl ethyl ketone and 10 g. of anhydrous potassium carbonate was refluxed for 5 hours. Thereafter, the solids were recovered by filtration and the solvent was removed. The residue was treated with ether and water resulting in the formation of a two-layer liquid. The water layer was removed and the ether layer was washed twice with water. The ether layer resulting therefrom was dried over magnesium sulfate and the solvent removed.