Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:8][C:9]=1[N:10]([C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]1)=[O:30])[CH:11]1[CH2:16][CH2:15][CH:14]([O:17]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:13][CH2:12]1)=[O:4].O.[Li+].[OH-]>O1CCOCC1>[OH:17][CH:14]1[CH2:15][CH2:16][CH:11]([N:10]([C:29]([CH:31]2[CH2:32][CH2:33][CH:34]([CH3:37])[CH2:35][CH2:36]2)=[O:30])[C:9]2[CH:8]=[C:7]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:12][CH2:13]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.5 %

Procedure:
3-{(4-Methyl-cyclohexanecarbonyl)-[4-(4-nitro-benzoyloxy)-cyclohexyl]-amino}-5-phenyl-thiophene-2-carboxylic acid methyl ester (44 mg, 0.073 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (1 ml) and then LiOH 1N (365 ul, 0.365 mmol) was added. After 4 hours of stirring at room temperature, solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 15 mg (47%) of 3-[(4-Hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19](Cl)([CH:20]=[N:21][OH:22])[CH2:18][C:17]=1[CH3:26].C(=O)([O-])O.[K+]>O1CCCC1>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:11]([F:14])([F:12])[F:13])[O:22][N:21]=2)=[CH:18][C:17]=1[CH3:26]
Reactant: CC1=C(Br)C=CC(Cl)(C=NO)C1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Yield: 90.5 %

Procedure:
In a solution of 22.7 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene produced in Step 1 of Synthetic Example 3 and 26.0 g of 4-bromo-1-chloro-3-methylbenzaldoxime in 120 ml of tetrahydrofuran, 15.7 g of potassium hydrogen carbonate was added, and stirred under reflux with heat for 5 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off, then the solvent was distilled off under reduced pressure. 150 ml of water was added in the residue, stirred at room temperature for 18 hours, and precipitated crystal was filtered off and dried to obtain 38.6 g of the aimed product as white crystal.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1.C(Cl)(Cl)Cl>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:61][C:58]2[S:59][C:60]3[C:52]([CH:47]4[CH2:48][O:49][CH2:50][CH2:51][O:46]4)=[CH:53][CH:54]=[C:55]([O:62][CH3:63])[C:56]=3[N:57]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc(N(C)C)cc3)nc12

Procedure:
From 4-dimethylaminobenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+22.6° (c=0.45, CHCl3), ES-MS m/e (%): 414 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([C:14]3[CH:19]=[C:18]([C:20]#N)[CH:17]=[CH:16][N:15]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-:22].[Na+].Cl.[OH2:25]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([C:14]3[CH:19]=[C:18]([C:20]([OH:25])=[O:22])[CH:17]=[CH:16][N:15]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nc(-c3ccc(Cl)cc3)cc2O)c1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccnc(-n2nc(-c3ccc(Cl)cc3)cc2O)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 2-[3-(4-chlorophenyl)-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile (250 mg, 0.85 mmol) in EtOH (10 mL) and water (5 mL) was added NaOH (168 mg, 4.2 mmol) at r.t. The reaction mixture was stirred at 90° C. for 2 h. Removed EtOH, acidified with 1N HCl to pH 5, filtered, washed with ethyl acetate (5 mL) to give the title compound (200 mg, 75%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 6.20 (1H, s), 7.50 (2H, d, J=8.4 Hz), 7.76 (1H, d, J=4.0 Hz), 7.91 (2H, d, J=8.4 Hz), 8.26 (1H, s), 8.65 (1H, d, J=5.2 Hz), 12.20 (1H, brs), 13.96 (1H, brs). [M+H] Calc'd for C15H10ClN3O3, 316; Found, 316.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=2Br)=[O:15])[CH2:9]1)C1C=CC=CC=1.BrC1C=C(F)C=C(F)C=1N.C[O:37][C:38]([C:40]1CN(CC2C=CC=CC=2)CCC=1)=[O:39]>C1(C)C=CC=CC=1.C(#N)C.C(N(CC)CC)C>[C:38]([OH:39])(=[O:37])[CH3:40].[F:24][C:20]1[CH:19]=[C:18]2[C:10]3([CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[C:14](=[O:15])[NH:16][C:17]2=[C:22]([F:23])[CH:21]=1
Reactant: O=C(Nc1c(F)cc(F)cc1Br)C1=CCCN(Cc2ccccc2)C1
Reactant: COC(=O)C1=CCCN(Cc2ccccc2)C1
Agent: Nc1c(F)cc(F)cc1Br
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)O
Product: O=C1Nc2c(F)cc(F)cc2C12CCCNC2

Procedure:
1-Benzyl-N-(2-bromo-4,6-difluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxamide. The title compound was prepared from 2-bromo-4,6-difluoroaniline and 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester as described in EXAMPLE 1. Rf 0.53 (toluene/acetonitrile/tri-ethyl amine 10:10:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:24]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7]1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115.3 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (200 mg, 0.81 mmol) and potassium carbonate (214 mg, 2.02 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 25° C. for 30 min. The reaction was then treated with 1-iodobutane (0.14 mL, 1.21 mmol) and heated at 60° C. for 5 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (2×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-(1-butyl-6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (283.7 mg) as an orange oil which was used without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:15][CH2:16][OH:17])[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:15][CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:30](=[O:31])[C:29]3[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:27]([C:26]([F:25])([F:40])[F:41])[CH:28]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CNCCO1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCO[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
5.60 g (20.3 mmol) of 2-[(2R)-2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol (specification of U.S. Pat. No. 6,159,967, EXAMPLE 51(d)) was dissolved in methylene chloride (60 mL) and 2.83 mL (24.3 mmol) of triethylamine was added thereto. 5.60 g (20.3 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride and 248 mg (2.03 mmol) of 4-dimethylaminopyridine were added to the mixture under ice-cooling and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture and the methylene chloride layer was washed with water and a saturated NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/1) to obtain 5.68 g (yield: 54%) of 2-{(2R)-2-(3,4-dichlorophenyl)-4-[3,5-bis(trifluoromethyl)benzoyl]morpholin-2-yl}ethanol.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][NH:12][CH2:13][CH2:14][C:3]1=2.[C:15](#[N:18])[CH:16]=[CH2:17]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CC(O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][N:12]([CH2:17][CH2:16][C:15]#[N:18])[CH2:13][CH2:14][C:3]1=2
Reactant: C=CC#N
Reactant: Cn1c2c(c3ccccc31)CNCC2
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: CC(C)O
Product: Cn1c2c(c3ccccc31)CN(CCC#N)CC2
Yield: 86.6 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indole (0.07 mol), acrylonitrile (0.14 mol) and Aliquat 336 (3 drops) in 2-propanol (150 ml) was stirred and refluxed for 30 minutes. The reaction mixture was cooled on an ice-bath and the resulting precipitate was filtered off, washed with diisopropyl ether (50 ml) and dried, yielding 14.5 g (87%) of 1,3,4,5-tetrahydro-5-methyl-2H-pyrido[4,3-b]indole-2-propanenitrile (intermediate 15).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12].C(OCC)(=O)C.Cl>CO.O>[OH:3][CH:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12]
Reactant: CC(C)(CCCCCC(=O)CCCCCC(C)(C)C(=O)O)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CCCCCC(O)CCCCCC(C)(C)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 59.8 %

Procedure:
Under nitrogen atmosphere, sodium borohydride (0.06 g, 1.6 mmol) was added to a stirred solution of 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid (1.18 g, 3.4 mmol) in methanol (50 mL) at 0° C. The reaction progress was monitored by thin layer chromatography (silica; hexanes:ethyl acetate=50:50). Additional sodium borohydride was added after 1 h (0.48 g, 13 mmol). After 8 h, the reaction mixture was hydrolyzed with water (50 mL) and acidified with concentrated hydrochloric acid (3 mL) to pH 1. The solution was diluted with water (50 mL) and extracted with dichloromethane (4×25 mL). The combined organic layers were washed with saturated sodium chloride solution (2×30 mL), dried over magnesium sulfate, concentrated in vacuo, and dried in high vacuo to give 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (0.7 g, 60%) as a very viscous oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.42 (br. s, 3H), 3.59 (br. s, 1H), 1.65-1.00 (m, 20H), 1.18 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 184.5, 71.8, 42.1, 40.5, 37.0, 29.8, 25.2, 25.1, 24.9, 24.8. HRMS (FAB): Calcd. for C19H37O5 (MH+): 345.2635, found: 345.2646. HPLC: 83.8% purity.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=1)=[O:7].[CH3:17][O:18][C:19](=[O:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30]Br)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:17][O:18][C:19](=[O:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][N:2]([CH2:3][CH2:4][NH:5][C:6]([C:8]2[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=2)=[O:7])[CH3:1])=[CH:24][CH:23]=1
Reactant: CNCCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: COC(=O)COc1ccc(CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CCCN(C)CCNC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 25 °C

Procedure:
To a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid (2-methylamino-ethyl)-amide (Intermediate E) (0.97 g, 2.7 mmol) and [4-(3-Bromo-propyl)-phenoxy]-acetic acid methyl ester (Intermediate Q) (2.33 g, 8.12 mmol) in acetone (30 mL) is added sodium carbonate (0.86 g, 8.12 mmol), and the reaction is heated at reflux for 4 days. After this time, the reaction is allowed to cool to RT, filtered, and concentrated in vacuo. The residue is purified by reverse phase chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% TFA) to yield {4-[3-({2-[(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-methyl-amino)-propyl]-phenoxy}-acetic acid methyl ester. [M+H]+ 451.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH:21]([CH3:23])[CH3:22])[C:9](=[O:20])/[CH:10]=[CH:11]\[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH:21]([CH3:22])[CH3:23])[C:9](=[O:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)/C=C\c1cccc(C#N)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)CCc1cccc(C#N)c1
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
Palladium on carbon (740 mg of 10% wt/wt Pd/C) was added to a degassed solution of [(R)-(Z)-4-(3-cyano-phenyl)-1-isopropyl-2-oxo-but-3-enyl]-carbamic acid tert-butyl ester (7.4 g, 22.5 mmol, 1 equiv) in methanol (200 mL) at room temperature. The reaction mixture was thoroughly degassed and backfilled with hydrogen gas from a balloon. Hydrogenation proceeded at atmospheric pressure for 2.5 h. The (degassed) reaction mixture was then diluted with diethyl ether (300 mL), filtered through Celite, and washed with additional ether (2×100 mL). Upon concentration in vacuo, the residue was purified by flash column chromatography (20% ethyl acetate-hexanes) to provide the ketone product as a white solid (5.9 g, 79%). ESMS [M+H]+: 331.2. 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 2H), 7.46 (m, 1H), 7.41 (m, 1H), 5.07 (m, 1H), 4.24 (m, 1H), 2.98 (m, 2H), 2.86 (m, 2H), 2.11 (m, 1H), 1.45 (s, 9H), 0.98 (d, 3H, J=6.76 Hz), 0.74 (d, 3H, 6.78 Hz), [α]D=+24.74 (c=0.95, CH3OH).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:28]#[N:29])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=3[Cl:27])[CH2:16][CH2:17][CH2:18][N:11]21.[BH4-].[Na+]>O1CCCC1.CC(O)C.O>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=4[Cl:27])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:28]([NH2:29])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C#N)c12
Reactant: CC[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Yield: 106.5 %

Procedure:
Ethylmagnesium bromide (3 M solution in diethyl ether, 4.50 mL, 13.5 mmol) was added to a stirred suspension of 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbonitrile (530 mg, 1.35 mmol) in tetrahydrofuran (14 mL) at room temperature. After the resultant mixture was refluxed for 3 hr, a suspension of sodium tetrahydroborate (1.02 g, 27.0 mmol) in 2-propanol (14 mL) was added at room temperature. The resultant mixture was stirred at 50° C. for 30 min, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (609 mg), which was used for the next step without further purification. To a mixture of crude 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (120 mg) and triethylamine (0.0742 mL, 0.532 mmol) in tetrahydrofuran (2.7 mL) was added acetic anhydride (0.0302 mL, 0.319 mol) at 0° C. The resultant mixture was stirred at room temperature for 10 min, diluted with aqueous sodium bicarbonate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-100% ethyl acetate/n-hexane gradient mixture and preparative HPLC eluting with a 10-40% acetonitrile/water gradient mixture to give the two title compounds as colorless solids.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([Cl:23])=O)=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>>[ClH:23].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]=[C:21]([C:20]3[CH:24]=[CH:25][C:17]([C:14](=[O:16])[CH3:15])=[CH:18][CH:19]=3)[O:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(C(=N)NO)CC1
Reactant: CC(=O)c1ccc(C(=O)Cl)cc1
Product: CC(=O)c1ccc(-c2nc(C3CCN(C(C)C)CC3)no2)cc1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 56, starting from 1-isopropyl-N-hydroxypiperidine-4-carboxamidine and 4-acetylbenzoyl chloride.
Reaction SMILES: [Li][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:8]1([P:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH4+].[Cl-]>C1COCC1>[C:25]1([P:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][CH:22]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:21]=[CH:20]3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: [Li]c1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2cccc3cccnc23)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C1=CC(c2ccccc2)Nc2c1cccc2P(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
PhLi (0.56 mL, 1.8M in di-n-butyl ether, 1 mmol) was added to a stirred solution of 8-diphenylphoshinoquinoline (1) (156 mg, 0.5 mmol) in dry THF (5 mL) at −78° C. and the solution was stirred at 0° C. for 10 minutes. The solution was then cooled to −78° C., saturated aqueous NH4Cl solution (10 mL) was added and the mixture was warmed to room temperature. Products were extracted with EtOAc, washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated to give 4 (196 mg) quantitatively as a yellow oil. 1H NMR (400.13 MHz, CDCl3) δ 7.4-7.3 (m, 15H, Ph-H), 6.92 (d, 1H, J=7.2 Hz, C5—H), 6.69 (ddd, 1H, J=7.2, 6.0, 1.2 Hz, C7—H), 6.54 (t, 1H, J=7.2 Hz, C6—H), 6.38 (d, 1H, J=9.6 Hz, C4—H), 5.64 (dd, 1H, J=10.0, 4.0 Hz, C3—H), 5.44 (bs, 1H, N1—H), 5.15 (d, 1H, J=7.2 Hz, C2—H) ppm; 13C NMR (100.61 MHz, CDCl3) δ 146.5 (d, J=19.2 Hz), 145.1, 135.4 (d, J=8.1 Hz), 135.3 (d, J=7.1 Hz), 134.5, 133.7 (d, J=18.2 Hz), 133.6 (d, J=19.2 Hz), 133.4 (d, J=19.2 Hz), 127.3, 128.7-128.3 (m), 127.1, 126.0, 125.2, 124.5, 119.1, 117.1, 116.1 (d, J=8.1 Hz), 57.6 ppm; 31P NMR (161.97 MHz, CDCl3) δ-23.8 ppm.
Reaction SMILES: [N:1]1(C(=O)C)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(=O)n1ncc2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: c1cnc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
Pyrazolo[4,3-b]pyridin-1-yl-ethanone (973 mg, 6.04 mmol) was dissolved in THF/MeOH (1:1, 16 mL) and 10% NaOH (1.8 mL) was added. The reaction mixture was stirred at room temperature for 30 min then neutralized with 1.0 M HCl, diluted with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated to afford 687 mg (96%) of 1H-pyrazolo[4,3-b]pyridine as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.29 (br. s., 1H), 8.50 (d, J=4.5 Hz, 1H), 8.27 (s, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.34 (dd, J=8.7, 4.5 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]#[C:13][Si](C)(C)C)[CH:9]=[CH:10][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CO.O.CCOC(C)=O>[F:1][CH:2]([F:18])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[CH:13])[CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cccc(OCCC(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C#Cc1cccc(OCCC(F)F)c1
Reaction time: 1.5 h

Procedure:
To a solution of ((3-(3,3-difluoropropoxy)phenyl)ethynyl)trimethylsilane (2.1 g, 7.82 mmol) from the previous step in MeOH (19.5 mL) was added K2CO3 (10.81 g, 78.2 mmol) at room temperature. The reaction mixture was stirred for 1.5 h after which it was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc once. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a brown oil. The oil was absorbed onto Celite (8 g). Flash chromatography (SiO2, 1% EtOAc 99% Hexanes to 3% EtOAc 97% Hexanes) provided 1.31 g, 85%, of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:10](=[O:20])[CH2:9][CH2:8]2.[O:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C>C(O)(=O)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[CH2:18][CH2:19]1)[C:10](=[O:20])[CH2:9][CH2:8]2
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC1CCNCC1)C(=O)CC2
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC1CCN(C3CCOCC3)CC1)C(=O)CC2
Reaction time: 8 h
Yield: 30 %

Procedure:
To 5-(8-methoxy-1-piperidin-4-ylmethyl-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione (20 μmol, 1.0 eq.) was added a DMF (200 μl) solution of tetrahydropyran-4-one (24 μmol, 1.2 eq.) and acetic acid (10 μl). MP-sodium triacetoxy borohydride was added further. After this solution was shaken for several minutes, DIEA (30 μl) was added and a reaction was carried out at 60° C. overnight. The resin was removed by filtration and washed with methylene chloride. The solvent was distilled off with nitrogen gas, and the residue was purified by HPLC (UV-trigger, column:CAPCELL PAK C18, UG 120 S-5, 20 mm×50 mm, 0.05% trifluoroacetic acid-H2O, 0.05% trifluoroacetic acid-CH3CN). The structure was confirmed by LC-MS, and freeze-drying was conducted, giving 5-{8-methoxy-1-[1-(tetrahydropyran-4-yl)piperidin-4-yl]methyl-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione in 30% yield.