Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1)#[N:23]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:21][C:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)=[O:32])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: Cc1ccc(C(N)c2ccccc2N2CCCCC2)cc1
Product: Cc1ccc(C(NC(=O)Cc2ccc(C#N)cc2)c2ccccc2N2CCCCC2)cc1

Procedure:
Prepared from α-(4-methyl-phenyl)-2-piperidino-benzylamine and 4-cyano-phenylacetic acid analogously to Example 55.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][P:12]([CH2:19][O:20]S(C1C=CC(Cl)=CC=1)(=O)=O)(=[O:18])[O:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:34][CH:33]=1>>[C:43]([O:42][C:41]([NH:40][CH2:39][CH2:38][C:35]1[CH:34]=[CH:33][C:32]([O:20][CH2:19][P:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:18])[O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:37][CH:36]=1)=[O:47])([CH3:46])([CH3:44])[CH3:45]
Reactant: CCCCOP(=O)(CCCOCc1ccccc1)COS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Product: CCCCOP(=O)(CCCOCc1ccccc1)COc1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared from 3-benzyloxypropyl-(4-chlorobenzenesulfonyloxymethyl)phosphinic acid, n-butyl ester and 2-(4-hydroxyphenyl)ethylcarbamic acid, t-butyl ester according to the procedure described in Procedure 24. The crude product was purified by chromatography, eluting with dichloromethane containing 3% methanol, to give an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].Cl.O1CCO[CH2:15][CH2:14]1>C(O)C>[CH2:14]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-4-chlorobenzoic acid (5.0 g, 21 mmol) in 150 mL absolute ethanol was added 15 mL of 4N HCl/dioxane. The mixture was heated to reflux for 24 hours then cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and H2O, and the separated organic phase was washed sequentially with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO-d6) δ 8.22 (d, 1H), 7.94 (dd, 1H), 7.80 (d, 1H), 4.33 (q, 2H), 1.33 (t, 3H); MS (DCI+) m/z 263 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]3[N:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(C(CC)CNC1N=CC=CC=1[C:29](OCC)=[O:30])C>>[C:1]12([CH2:11][N:12]3[C:13]4[N:21]=[CH:20][CH:19]=[CH:18][C:14]=4[C:15](=[O:17])[O:16][C:29]3=[O:30])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: O=C(O)c1cccnc1NCC12CC3CC(CC(C3)C1)C2
Product: O=c1oc(=O)n(CC23CC4CC(CC(C4)C2)C3)c2ncccc12

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 34A for the product of Example 3A (0.025 g, 20%). 1H NMR (300 MHz, CDCl3) δ 1.74 (m, 12H), 2.04 (s, 3H), 3.65 (d, J=5.88 Hz, 2H), 6.91 (dd, J=7.72, 5.52 Hz, 1H), 8.51 (d, J=4.78 Hz, 1H), 8.77 (d, J=7.72 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[C:5]([CH2:11][CH3:12])=[C:4]([I:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1.S(Cl)([Cl:28])=O>>[I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[C:5]([CH2:11][CH3:12])=[C:4]([I:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([Cl:28])=[O:21])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1c(I)c(CC)c(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Product: CCc1c(I)c(CC)c(I)c(-c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)c1I

Procedure:
2′,4′,6′-triiodo-3′,5′-bis(ethyl)-3-nitrobiphenyl-4-carboxylic acid (18) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3′,5′-bis(ethyl)-3-nitrobiphenyl-4-carbonyl chloride (19).
Reaction SMILES: [N+]([C:4]1[CH:31]=[CH:30][C:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[S:10][C:6]=2[CH:5]=1)([O-])=O.N.[CH3:33][OH:34]>[Pd]>[CH3:33][O:34][C:4]1[CH:31]=[CH:30][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[N:15][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4ccc([N+](=O)[O-])cc4s3)cn2)CC1
Agent: [Pd]
Agent: N
Product: COc1ccc2nc(-c3ccc(N4CCNCC4)nc3)sc2c1
Reaction time: 8 h

Procedure:
tert-Butyl 4-[5-(6-nitro-1,3-benzothiazol-2-yl)pyridin-2-yl]piperazine-1-carboxylate (90 mg, 0.2 mmol) was dissolved in methanol (8 mL). After addition of 7M NH3 in methanol (2 mL), palladium on carbon (10%, 10 mg) was added and the flask was evacuated and filled with hydrogen gas. The reaction mixture was shaken under an atmosphere of hydrogen overnight. The mixture was thereafter filtered through diatomaceous earth and evaporated in vacuo. The crude product was purified by flash column chromatography (heptane:ethyl acetate; 70:30 to 35:65), to give the title compound (38 mg) as a solid. MS m/z (M+H) 412.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:24][C:23]([C:25]([O:27]C)=[O:26])=[CH:22][C:9]=3[N:10]([CH2:18][C:19](O)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.B(Br)(Br)Br>CN(C=O)C.C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[S:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][C:9]=3[N:10]([CH2:18][C:19]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:20])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccccc1)n2CC(=O)O
Reactant: C1COCCN1
Agent: BrB(Br)Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccccc1)n2CC(=O)N1CCOCC1
Reaction time: 0.07 h
Yield: 43 %

Procedure:
Following the procedure described above for 6-cyclohexyl-4-[2-(dimethylamino)-2-oxoethyl]-5-phenyl-4N-thieno[3,2-b]pyrrole-2-carboxylic acid (step 3), treatment of a solution (0.08 M) of [6-cyclohexyl-2-(methoxycarbonyl)-5-phenyl-4H-thieno[3,2-b]pyrrol-4-yl]acetic acid in DMF with morpholine (1.1 eq.), DIEA (3 eq.) and HATU (1.1 eq.) followed by treatment of a solution (0.1 M) of the resulting residue in DCM with BBr3 (1 M solution in DCM, 3 eq.) gave a residue that was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 5 micron, 19×150 mm; flow: 17 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 60% A isocratic for 4 min, linear to 50% A in 2 min, linear to 40% in 2 min then isocratic for 2 min, linear to 35% A in 2 min isocratic for 1 min then linear to 30% A isocratic for 1 min then linear to 0% A in 3 min) to afford the title compound (43%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:27][CH2:28]CS([O-])(=O)=O)[CH2:12][CH2:11][N:10]([C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[N:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[C:44]1([C:50]2([C:56]([OH:58])=O)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[N:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:27][CH2:28][N:53]3[CH2:52][CH2:51][C:50]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([C:56]([NH2:35])=[O:58])[CH2:55][CH2:54]3)[CH2:12][CH2:11][N:10]([C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(F)cc3)C2)cc(OC)c1OC
Agent: Cl
Agent: NC(=O)N1CCOCC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(F)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using 2-[3-(4-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid morpholine-amide hydrochloride to give the title compound: Rf =0.57 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][O:9][CH2:10][CH:11]=C)[CH:2]=C.F[P-](F)(F)(F)(F)F>C1(C)C=CC=CC=1>[O:9]1[CH2:10][CH:11]=[C:7]([C:6]2[CH2:5][O:4][CH2:1][CH:2]=2)[CH2:8]1
Reactant: C=CCOCC#CCOCC=C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Product: C1=C(C2=CCOC2)COC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
A mixture of 1,4-bis(allyloxy)-2-butyne (157 mg, 1.02 mmol) and (p-cymene)RuCl(PCy3)(═C═C═CPh2)+PF6− (22 mg) in toluene (5 mL) is stirred for 3 h under argon at 80° C. The solvent is evaporated and the residue purified by flash chromatography using diethylether/pentane (1/4) as eluent. This affords the title compound as white solid (110 mg, 86%). 1H NMR (200 MHz, CDCl3): δ=4.70 (br. S, 8H), 5.59 (s, 2H). 13C NMR (50 MHz, CDCl3): δ=74.7, 76.0, 122.5, 131.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH2:18][CH2:19]Cl)[CH:3]=1.[C-:21]#[N:22].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH2:18][CH2:19][C:21]#[N:22])[CH:3]=1
Reactant: ClCCCc1cc(Cl)ccc1OCCc1ccccc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: N#CCCCc1cc(Cl)ccc1OCCc1ccccc1
Yield: 98.7 %

Procedure:
To a solution of 1.62 g of crude 4-chloro-2-(3-chloropropyl)-1-(2-phenylethoxy)benzene in 20 ml of acetonitrile, were added 681 mg of potassium cyanide and 138 mg of 18-crown-6 and heated under reflux for 11 hours. After cooling, the solvent was evaporated under reduced pressure and ethyl acetate and water were added to the residue thus obtained. Then the ethyl acetate layer was collected, washed thrice with water and a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, 1.55 g of crude 4-[5-chloro-2-(2-phenylethoxy)phenyl]butyronitrile was obtained. This compound was not purified any more but used in the subsequent reaction.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24](=[S:26])[NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[CH2:28][C:29](=O)[CH3:30]>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24]5[S:26][CH:28]=[C:29]([CH3:30])[N:25]=5)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)CCl
Reactant: NC(=S)C1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Product: Cc1csc(C2(c3ccc(OC4CCN(C5CCC5)CC4)cc3)CCOCC2)n1
Yield: 83 %

Procedure:
The title compound (155 mg, 83%) was prepared from 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carbothioamide and chloroacetone similarly to the procedure used for example 136. 1H NMR (400 MHz, CDCl3) δ 1.64-1.71 (m, 2H), 1.78-1.81 (m, 2H), 1.88-2.04 (m, 6H), 2.10-2.20 (m, 2H), 2.31-2.38 (m, 2H), 2.42 (s, 3H), 2.61-2.64 (m, 4H), 2.74 (m, 1H), 3.71 (t, 2H), 3.81-3.85 (m, 2H), 4.28 (m, 1H), 6.75 (s, 1H), 6.83 (d, 2H), 7.23 (d, 2H). HRMS ESI+ m/z 413.2257 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2ccc3cc(O)ccc3c2)cc1F
Agent: BrB(Br)Br
Product: Oc1ccc2cc(-c3ccc(O)c(F)c3)ccc2c1

Procedure:
The title compound was prepared by-reacting 6-(3-fluoro-4-methoxyphenyl)-2-naphthol (600 mg, 2.24 mmol) with boron tribromide (6.27 mL of 1.0 M solution in CH2Cl2, 6.27 mmol) according to method D to yield 385 mg (68%) of a yellowish solid: mp 216–219 ° C.; 1H NMR (DMDO-d6): δ 7.03–7.13 (3H, m), 7.43 (1H, dd, J=8.37 Hz, J=1.77 Hz), 7.58 (1H, dd, J=12.92 Hz, J=2.13 Hz), 7.68 (1H, dd, J=8.68 Hz, J=1.61 Hz), 7.74 (1H, d, J=8.68 Hz), 8.03 (1H, s), 9.79 (1H, s), 9.98 (1H, s); MS (ESI) m/z 253 (M−H)−. Anal. for C16H11FO2.0.13H2O:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][N:20](C(=O)C)[CH2:19][CH2:18]3)[N:11]=2)=[CH:2]1.[OH-].[Na+]>C(O)(=O)C>[NH:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:12]2[N:11]=[C:10]([C:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:1][CH:2]=3)[CH:15]=[CH:14][N:13]=2)[CH2:18][CH2:19]1
Reactant: CC(=O)N1CCC(Nc2nccc(-c3c[nH]c4ncccc34)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1cnc2[nH]cc(-c3ccnc(NC4CCNCC4)n3)c2c1
Temperature: 100 °C
Yield: 188.6 %

Procedure:
To a flask was added compound 64 (20 mg) and 1 M aqueous NaOH (1 mL). The mixture was heated to 100° C. for 3 hrs. After being neutralized with acetic acid, the solution was concentrated and the residule was purified by reverse phase HPLC to afford 33 mg (71%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.85 (m, 1 H), 8.60 (s, 1 H), 8.35 (d, 1 H), 8.10 (d, 1 H), 7.35 (m, 2 H), 4.40 (m, 1 H), 3.50 (m, 2 H), 3.30 (m, 2 H), 2.40 (m, 2 H), 1.95 (m, 2 H). MS (ESI) m/z: 295 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][CH:17]([NH2:19])[CH3:18]>C1COCC1>[CH:17]([NH:19][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1)([CH3:18])[CH3:16]
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: COc1ccc2nc(NC(C)C)c(C=O)cc2c1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 99.2 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.50 g, 6.77 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added propan-2-amine (5.76 mL, 67.7 mmol) and the reaction mixture was stirred for 12.5 h at 160° C. and finally 45 min at 180° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 1 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with saturated NaHCO3 aqueous solution before extraction with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum to give 2-(isopropylamino)-6-methoxyquinoline-3-carbaldehyde SLA 28186 as an orange solid (1.64 g, 99% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[F:16][C:17]1([F:24])[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[F:16][C:17]1([F:24])[CH2:22][CH2:21][C:20]2([NH:1][C:2]3[CH:6]=[C:5]([C:7]4[CH:8]=[N:9][NH:10][C:11]=4[CH3:12])[S:4][C:3]=3[C:13](=[O:14])[NH:15]2)[CH2:19][CH2:18]1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Reactant: O=C1CCC(F)(F)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCC(F)(F)CC1)N2
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl) thiophene-2-carboxamide (100 mg, 0.45 mmol), 4,4-difluorocyclohexanone (181 mg, 1.35 mmol), CSA (10 mg, 0.045 mmol), MgSO4 (108 mg, 0.90 mmol) and DMA (1 mL) was stirred at 80° C. for 2 h. The mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc to give the title compound (59 mg, 39%) as a pale yellow solid:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C:12]1[C:16]2[CH:17]=[N:18][C:19]([NH:21][C:22]([NH:24][C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])=[O:23])=[CH:20][C:15]=2[NH:14][N:13]=1.[B-](F)(F)(F)[F:34].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O.NN>CC(N(C)C)=O.CO.CCO>[NH2:3][C:12]1[C:16]2[CH:17]=[N:18][C:19]([NH:21][C:22]([NH:24][C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])=[O:23])=[C:20]([F:34])[C:15]=2[NH:14][N:13]=1
Reactant: C[C@@H](NC(=O)Nc1cc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2cn1)c1ccccc1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: NN
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CO
Product: C[C@@H](NC(=O)Nc1ncc2c(N)n[nH]c2c1F)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(R)-1-(3-(1,3-Dioxoisoindolin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (114 mg, 0.267 mmol) was dissolved in DMA (1 mL) and methanol (1 mL), charged with powdered Selectfluor® (108 mg, 0.305 mmol), and stirred at room temperature for 20 h. The solvents were concentrated in vacuo and the residue was purified by flash chromatography (3-15% MeOH/DCM). The crude mixture obtained was then dissolved in EtOH (3 mL), charged with hydrazine hydrate (0.130 mL, 2.67 mmol), and heated to 85° C. for 30 min. The solvents were concentrated in vacuo and the residue was purified by mass-triggered reverse phase HPLC followed by purification via flash chromatography (2-10% MeOH/DCM) to give (R)-1-(3-amino-7-fluoro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C15H15FN6O [M+1]+ 315. found 315. 1H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.42-7.34 (m, 4H), 7.27 (m, 1H) 5.07 (q, J=6.7 Hz, 1H), 1.58 (d, J=7.0 Hz, 4H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[NH:9][CH:10]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>O1CCCC1>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][C:6]1[C:7]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[NH:9][CH:10]=1
Reactant: N#CCCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCCCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution of 0.94 g (3.08 mmol) of 4-(3-cyanopropyl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in step 67(i) above] in 50 ml of tetrahydrofuran was added dropwise to a suspension of 468 mg (12.32 mmol) of lithium aluminum hydride in 100 ml of tetrahydrofuran at room temperature with stirring. The resulting mixture was stirred at 60° C. for 3 hours. After cooling to room temperature, 0.47 ml of a 15% aqueous solution of sodium hydroxide and 20 ml of water were successively added gradually to the reaction mixture. The resulting mixture was filtered and the filtrate thus obtained was concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 25:1 by volume mixture of ethyl acetate and isopropylamine as the eluant to give 410 mg (yield 43%) of the title compound as a pale red powder.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([NH2:11])[CH:3]=1.Cl.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1Cl>C(O)(C)C>[ClH:13].[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[NH:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[CH:3]1
Reactant: Cc1cn(N)c2ccccc12
Reactant: Clc1ccncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: Cc1cn(Nc2ccncc2Cl)c2ccccc12

Procedure:
The title compound was prepared from 3-methyl-1H-indol-1-amine and 3,4-dichloropyridine hydrochloride in isopropanol at 80° C. for 5 hours in substantially the same manner as in Example 17. Recrystallized from ethanol, m.p. 278°-280° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[CH:6]([OH:15])[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C1C=CC=CC=1.C(Cl)(=[O:33])C=C>C(Cl)Cl>[C:17]([OH:19])(=[O:33])[CH:16]=[CH2:5].[CH3:20][O:19][C:17]1[CH:16]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:18]=1)[CH:6]([OH:15])[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(=O)Cl
Agent: COc1cc(OC)cc(C(O)C(=O)c2ccccc2)c1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: C=CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of 0.8 g (2.94 mmoles) of 3',5'-dimethoxybenzoin prepared in (3) above and 1.13 ml dimethylaniline in 10 ml methylene chloride, under nitrogen, was slowly added a solution of 1.5 ml (18 mmoles) acryloyl chloride in 10 ml of mehtylene chloride. After the addition was complete, the mixture was stirred overnight at room temperature, diluted with methylene chloride, washed twice with 75 ml 5% aqueous HCl, once with 100 ml H2O, once with 100 ml 5% aqueous NaHCO3, once with 100 ml H2O, once with 100 ml saturated Na2SO4 and dried over anhydrous Na2SO4. The solvent was filtered and stripped off to yield an oil that crystallized to give 0.6 g (63%) of compound. Recrystalization from benzene/hexane (1/1) gave colorless crystals, mp 88°-89° C. Infrared, NMR, and mass spectrometric analyses showed that the above compound was obtained.