Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:15].[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]([C:18]1[N:22]([CH3:23])[C:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]3[CH2:14][CH2:13]3)(=[O:10])=[O:9])=[CH:4][C:3]=2[F:15])=[CH:20][CH:19]=1)#[N:17]
Reactant: O=S(=O)(NC1CC1)c1ccc(Br)c(F)c1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NC2CC2)cc1F
Reaction time: 16 h
Yield: 13.8 %

Procedure:
According to general procedure B, 4-bromo-N-cyclopropyl-3-fluorobenzenesulfonamide (175 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-3-fluorobenzenesulfonamide (26 mg, 14%) was provided after purification. MS (ESI) m/z 319. HPLC purity 100.0% at 210-370 nm, 8.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][C:21]=1B(O)O.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:17])=[C:2]([C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH:26]=[O:27])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1=[O:14])[CH3:13]
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC)cc21
Temperature: 80 °C
Yield: 98.8 %

Procedure:
A round bottom flask was charged with 6.0 g of Compound 1A (20.3 mmol), 5.5 g of 2-methoxy-5-formylphenylboronic acid (30.4 mmol) and tetrakis(triphenylphosphine)palladium(0), (1.17 g, 0.10 mmol). The flask was sealed and 100 mL of toluene and 30 mL of ethanol was added. The resulting solution was stirred to dissolve the reactants and then 21 mL of 2M K2CO3 was added via syringe. The reaction mixture was heated to 80° C. for 4 hours. After cooling, the reaction mixture was partitioned between ethyl acetate (200 mL) and water (75 mL). The water layer was further extracted (2×100 mL) and the combined organic layers were washed with water (50 mL) followed by brine (50 mL), dried over magnesium sulfate, filtered and excess solvent removed on the rotary evaporator. The crude product was purified by flash chromatography (EtOAc/Hexanes; gradient 20% to 40%) to give 7.05 g (99%) of product Compound 1B as a foamy solid. MS (electrospray): mass calculated for C22H25NO3, 351.18; m/z found 352.4, [M+H]+. 1HNMR (300 MHz, CDCl3): 9.94 (s, 1H), 7.93 (dd, J=2.1, 8.6 Hz, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.85 (s, 1H), 4.01 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 2.52 (s, 2H), 2.10 (s, 3H), 1.33 (s, 6H), 1.23 (t, J=6.9 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1ccccc1
Yield: 34.6 %

Procedure:
Using the general method of Example 186 except that chloroform was used as the solvent, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) was reacted with benzoyl chloride (972 mg, 5.55 mmol) to provide 700 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}benzamide as a white solid, m.p. 183.0-186.0° C. Analysis: Calculated for C23H25N5O2.0.5 H2O: % C, 66.97; % H, 6.35; % N, 16.98. Found: % C, 67.16; % H, 6.18; % N, 17.07.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][C:11](=[N:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:10]2[CH3:22])=[CH:5][C:4]=1[S:24](=[O:27])(=[O:26])[NH2:25].C(OC(C)C)(C)C>C(O)C>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:22])[C:11](=[N:14][C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[S:12][CH:13]=2)=[CH:5][C:4]=1[S:24](=[O:26])(=[O:27])[NH2:25]
Reactant: Cc1ccc(N=C2SCC(O)(c3ccc(Cl)c(S(N)(=O)=O)c3)N2C)cc1
Agent: Br
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: Cc1ccc(N=c2scc(-c3ccc(Cl)c(S(N)(=O)=O)c3)n2C)cc1
Temperature: 25 °C

Procedure:
0.02 mole (9.8 g) of 4-(4-chloro-3-sulfamoylphenyl)-3-methyl-2-(4-methylphenyl-imino)-thiazolidin-4-ol hydrobromide are boiled in 120 ml of ethanol for 2 hours under reflux. After cooling to room temperature, 200 ml of diisopropyl ether are added and the crystals are filtered off. Melting point 265° C. (with decomposition).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([NH2:18])[N:15]=[C:16](Cl)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:21]=1[NH2:22].FC(F)(F)C(O)=O>FC(F)(F)CO>[CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([NH2:18])[N:15]=[C:16]([NH:22][C:21]3[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=3[CH3:19])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(Nc2nc(N)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 100 °C
Yield: 90 %

Procedure:
To a suspension of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (200 mg, 0.78 mmol) and 2,4,6-trimethylaniline (0.44 mL, 3.08 mmol) in 2,2,2-trifluoroethanol (4 mL) was added trifluoroacetic acid (0.48 mL, 6.24 mmol). The resulting solution was heated at 100° C. for 2 days and cooled to room temperature. The reaction was concentrated to brown oil and diluted with CH2Cl2 (30 mL). The organic solution was washed with aqueous NaHCO3 solution (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (CH2Cl2:MeOH=95:5) yielded 251 mg (90%) of 7-benzyl-N4-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:11][O:12][CH3:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH2:14])[CH2:10][CH2:11][O:12][CH3:13])=[CH:7][CH:8]=1
Reactant: COCCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COCCC(N)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
Hydrogen chloride (4M in 1,4-dioxane, 0.667 mL, 2.67 mmol) was added to tert-butyl 1-(4-chlorophenyl)-3-methoxypropylcarbamate (Intermediate 99) (80 mg, 0.27 mmol) in a mixture of DCM (5 mL) and methanol (2 mL) at 22° C. The resulting solution was stirred at 22° C. for 5 hours. The mixture was concentrated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness to afford 1-(4-chlorophenyl)-3-methoxypropan-1-amine (47.0 mg, 88%) as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[CH:3]=1.S(OC)(O[CH3:27])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:27][O:1][C:2]1[C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cc(O)c2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reaction time: 6 h

Procedure:
A suspension of 1-hydroxy-3-methoxyestra-1,3,5(10)-trien-17-one (2.5 g, 8.3 mM), dimethyl sulfate (1.3 g, 10.3 mM) and potassium carbonate (1.2 g) in 250 ml of anhydrous acetone is refluxed with vigorous stirring for 6 hrs. An additional 0.5 g of dimethyl sulfate is added and the suspension refluxed for 14 hrs. The reaction mixture is filtered while warm and the solids washed well with acetone. The combined acetone filtrates are evaporated in vacuo and the residue is recrystallized from methanol-H2O. Two recrystallizations give 1,3-dimethoxyestra-1,3,5(10)-trien-17-one, yield 1.91 g (73%); m.p. 132°-133°.
Reaction SMILES: COC1C=C(C(O)CCC2C=CC(C(F)(F)F)=CC=2)C=CC=1OC.CS(Cl)(=O)=O.CCN(CC)CC.Cl.[CH3:38][O:39][C:40](=[O:49])[C@H:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)N>C(OCC)C.O.C1COCC1>[CH3:38][O:39][C:40](=[O:49])[CH2:41][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: COc1ccc(C(O)CCc2ccc(C(F)(F)F)cc2)cc1OC
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2.74 g (80 mmol) 1-(3,4-dimethoxy-phenyl)-3-(4-trifluoromethyl-phenyl)-propan-1-ol, 1.1 g (9.6 mmol) methanesulfonylchloride and 2.44 g (24 mmol) NEt3 in 60 mL diethyl ether was stirred at 0° C. for 1 h. 3.25 g (16 mmol) (S)-2-phenylglycine methyl ester hydrochloride, and 2.44 g (24 mmol) NEt3 and 30 mL THF was added. The mixture was stirred at 0° C. for 1 h and 16 h at room temperature. Water was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water, dried with MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were evaporated to dryness to yield 0.97 g (S)-[(S or R)-1-(3,4-dimethoxy-phenyl)-3-(4-trifluoromethyl-phenyl)-propylamino]-phenyl-acetic acid methyl ester (MS (m/e): 488.0 (MH+)) as yellow oil and 0.91 g (S)-[(R or S)-1-(3,4-Dimethoxy-phenyl)-3-(4-trifluoromethyl-phenyl)-propylamino]-phenyl-acetic acid methyl ester (MS (m/e): 488.0 (MH+)) as yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][OH:9])[CH2:6][C:5]([CH3:11])([CH3:10])[C:4]1=[O:12])[CH3:2].Cl([O-])=[O:14].[Na+].OP([O-])(O)=O.[Na+].CC1(C)N([O])C(C)(C)CCC1.Cl[O-].[Na+].ClCl.S([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[CH2:1]([N:3]1[C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[CH2:6][C@H:7]1[C:8]([OH:14])=[O:9])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CCN1C(=O)C(C)(C)CC1CO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: ClCl
Agent: O=P([O-])(O)O
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)C[C@H]1C(=O)O
Temperature: 40 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
1-Ethyl-5-(hydroxymethyl)-3,3-dimethyl-2-pyrrolidinone (0.366 g, 2.1 mmol), sodium chlorite (0.387 g, 4.3 mmol), and a 1M aqueous sodium phosphate monobasic buffer solution (2.46 ml, 2.46 mmol) were combined in acetonitrile (3 ml) and heated to 40° C. A few crystals of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical) and approximately 1 drop of bleach (sodium hypochlorite solution, available chlorine >12%) were then added to the mixture and stirring continued at 40° C. for 4 hrs. The mixture was then poured onto ice containing 1% w/w sodium sulphite and the resulting mixture was extracted with ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulphate and concentrated to give 1-ethyl-4,4-dimethyl-5-oxoproline (0.392 g) as a white solid which was used without additional purification. LC/MS [M+H]+=186.
Reaction SMILES: C1COCC1.[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:22]([C:24](=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])#[N:23]>C1(C)C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:24]([C:22]#[N:23])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C#N)=Cc1ccccc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C(Cc1ccc(OCc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
835 mg of Mg are suspended in 5 ml of abs. THF. A solution of 2.0 g of 4-benzyloxybenzyl chloride in 5 ml of abs. tetrahydrofuran is subsequently added dropwise. When the addition is complete, the cloudy solution is stirred at room temperature for a further 1 hour, a solution of 1.73 g of ethyl 2-cyano-3-phenylacrylate in 10 ml of abs. toluene is subsequently added, and the mixture is refluxed for 16 hours. The solvent is removed, and conventional work-up gives ethyl 4-(4-benzyloxyphenyl)-2-cyano-3-phenylbutyrate (“AA”).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14]>CCCCCC>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[N:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NN=C1C2CC3CC(C2)CC1C3

Procedure:
A hexane solution containing 2-adamantanone (2 g) and tert-butyl carbazate (1.76 g) was heated to reflux for 3 hours. When the solution cooled, the title compound crystallized and was filtered (3.28 g). M.p. 175-177°
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.Cl.Cl.[NH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:1].[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([N:23]3[CH2:24][CH2:25][CH2:26][CH:21]([NH2:20])[CH2:22]3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Reactant: NC1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC1CCCN(c2ccc(-c3ccc(C(F)(F)F)cc3)nn2)C1
Temperature: 120 °C
Yield: 27.5 %

Procedure:
3-Chloro-6-(4-trifluoromethylphenyl)pyridazine (0.2 g, 0.77 mmol), 3-aminopiperidine dihydrochloride (0.27 g, 1.54 mmol) and potassium carbonate (0.53 g, 3.87 mmol) were mixed in acetone (4 mL) in a 20 mL microwave vessel. The reaction mixture was heated in a microwave oven for 2 h at 120° C. The reaction mixture was filtered and the precipitate was washed with MeOH. The combined organic phases were evaporated. The crude oil was purified on a silicagel column (0.04-0.063 mesh) using dichloromethane/MeOH (9:1) as eluent. This afforded 110 mg of a oil that was dissolved in MeOH and acidified with concentrated HCl (5 mL). The mixture was evaporated and the residue was dissolved in MeOH (1 mL) and ether (100 mL) was added with stirring. The mixture was evaporated to give 76 mg (25%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].[BH4-].[Na+].Cl>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]([OH:25])[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: COc1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(O)c2cc(C#N)c3ccc4ccccc4n23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 3-cyano-(4-methoxy-benzoyl)-pyrrolo[1,2-a]quinoline (5.2 mg, 0.0159 mmol) in 5 mL of methanol at room temperature was added sodium borohydride (5.3 mg, 0.14 mmol) and it was stirred overnight at room temperature. Upon the completion of the reaction, 2 drops of aqueous 1N HCl was added and the reaction mixture was evaporated to near dryness. The residue was dissolved in 15 mL of ethyl acetate, washed with water, saturated NaCl and the organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude was purified by chromatography (30% ethyl acetate/hexane) to yield the title compound (5.1 mg, 97%). 1H NMR (CDCl3): 8.69 (d, J=8.40 Hz, 1H), 7.77 (dd, J=7.80, 1.80 Hz, 1H), 7.57 (m, 2H), 7.47 (m, 1H), 7.38 (m, 3H), 6.95 (dt, J=8.42, 2.12 Hz, 2H), 6.59 (s, 1H), 6.51 (d, J=4.2 Hz, 1H), 3.84 (s, 3H), 2.64 (d, J=4.8, 1H).
Reaction SMILES: C([Li])CCC.O1CCCC1.[Cl:11][C:12]1[CH:29]=[CH:28][C:15]2[S:16][CH:17]=[C:18]([CH2:19][N:20]([CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])[CH3:21])[C:14]=2[CH:13]=1.[C:30](=[O:32])=[O:31]>CO>[Cl:11][C:12]1[CH:29]=[CH:28][C:15]2[S:16][C:17]([C:30]([OH:32])=[O:31])=[C:18]([CH2:19][N:20]([CH2:22][CH:23]([O:24][CH3:25])[O:26][CH3:27])[CH3:21])[C:14]=2[CH:13]=1
Reactant: COC(CN(C)Cc1csc2ccc(Cl)cc12)OC
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: COC(CN(C)Cc1c(C(=O)O)sc2ccc(Cl)cc12)OC
Temperature: -30 °C
Yield: 54 %

Procedure:
Butyllithium in tetrahydrofuran (2.6M, 0.04 mol) was added slowly to a solution of 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]benzo[b]thiophene (10 g, 0.033 mol) in freshly distilled tetrahydrofuran (100 ml) stirred at -30° C. under argon. The mixture was stirred for 30 minutes, treated with dry carbon dioxide for 5 minutes and allowed to warm to 25° C. The mixture was treated with methanol, poured into ice water and extracted with ethyl ether. The aqueous phase was adjusted to pH 7.5 and extracted with methylene chloride. The organic phase was washed with water, dried with magnesium sulfate and concentrated to give 6.0 g (54%) of 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]benzo[b]thiophene-2-carboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=2)[N:20]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([OH:13])[CH2:8][CH2:9][N:10]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]([F:25])([F:27])[F:26])=[N:22][N:23]=3)[N:20]=2)[CH2:11][CH2:12]1
Reactant: OC1(c2ccccn2)CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: OC1(c2ccccn2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 77 %

Procedure:
A mixture of 4-(pyridin-2-yl)piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-pyridin-2-yl-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 77% yield.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:12]3[NH:31][C:15]4=[N:16][C:17]([N:20]5[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([O:28]CC)=[O:27])[CH2:21]5)=[CH:18][CH:19]=[C:14]4[N:13]=3)[CH2:11][CH2:10]2)[CH:8]=1>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:12]3[NH:31][C:15]4=[N:16][C:17]([N:20]5[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([OH:28])=[O:27])[CH2:21]5)=[CH:18][CH:19]=[C:14]4[N:13]=3)[CH2:10][CH2:11]2)[CH:8]=1
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Reaction time: 3 h
Yield: 83.4 %

Procedure:
Lithium hydroxide (500 mg, 10.20 mmol) was added to a solution of (R)-ethyl 1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (900 mg, 2.17 mmol) in tetrahydrofuran/water (1:1, 10 mL) at room temperature. The reaction mixture was stirred for 3 h. The solvent was removed under reduced pressure and to the residue was added water. The pH of the mixture was adjusted to 6 using an aqueous solution of hydrochloric acid (1N). The mixture was extracted with ethyl acetate and the organics were dried over sodium sulfate, filtered and concentrated to afford (R)-1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (700 mg). MS (ES+) (M+H) 387.1; LCMS retention time 1.971 min (Method N1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[C:10]3[C:15](=[C:16](Br)[CH:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)[CH:2]=1.[N+:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[C:10]3[C:15](=[C:16]([C:26]4[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=4)[CH:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)[CH:2]=1
Reactant: Brc1cc(Cc2cccnc2)cc2cccnc12
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: O=[N+]([O-])c1cccc(-c2cc(Cc3cccnc3)cc3cccnc23)c1

Procedure:
6-(3-pyridylmethyl)-8-bromoquinoline and 3-nitrobenzene boronic acid can be combined to form 6-(3-pyridylmethyl)-8-(3-nitrophenyl)quinoline,
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=1)[CH3:25]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:29]([C:36]([F:37])([F:38])[F:39])[CH:28]=1)[CH3:25]
Reactant: CCOc1ccc(B(O)O)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: CCOc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
Tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) was dissolved in DME (7.8 mL). Ba(OH)2 8H2O (236.6 mg, 0.75 mmol) in H2O (2.6 mL) was added. 4-ethoxy-2-trifluoromethylphenyl boronic acid (140 mg, 0.6 mmol) was added followed by Pd(PPh3)4 (12 mg, 0.01 mmol). The reaction flask was degassed and refluxed under a nitrogen atmosphere for 18 hrs. After cooling to RT, the reaction was concentrated in vacuo. Water (10 mL) and EtOAc (10 mL) were added. The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (2×10 mL), dried over MgSO4 and concentrated in vacuo and after chromatographic purification (30% EtOAc/Hexane) to afford the title compound (140 mg, 57%). 1H NMR (CDCl3, 300 MHz) δ 7.20 (d, 2H, J=5.9 Hz), 7.19 (s, 1H), 7.01 (dd, 1H, J=6.2, 2.2 Hz), 6.85 (s, 1H), 6.81 (s, 1H), 4.05–4.10 (m, 3H), 3.82–3.94 (m, 1H), 3.64–3.68 (m, 1H), 3.22–3.44 (m, 4H), 2.84–3.10 (m, 3H), 1.80–1.90 (m, 2H), 1.42–1.47 (m, 12H) ppm. MS-ApCI: 489 [M+H+].