Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.CS(O[CH:25]1[CH2:28][N:27]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)(=O)=O>C(#N)C.O1CCCC1>[C:30]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]2[CH2:28][CH:25]([N:10]3[CH2:11][CH2:12][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9]3)[CH2:26]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
Potassium carbonate (26 g) was added to a solution of tert-butyl piperazine-1-carboxylate (7.7 g) in acetonitrile (100 ML), to which a suspension of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (12.05 g) in tetrahydrofuran (30 mL) was added at room temperature, and the mixture was stirred for 4 hours at 100° C., and then concentrated. To the resulting residue was added water, and the mixture was extracted with ethyl acetate twice. The extract was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=3:1→1:2), and the product was washed with tert-butyl methyl ether and collected by filtration to give the title compound (10.68 g) having the following physical data.
Reaction SMILES: [Br:1]Br.C(O)(=O)C.[CH3:7][C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([OH:19])[CH:11]=[CH:10][CH:9]=1>O.C(OCC)(=O)C>[Br:1][C:9]1[CH:10]=[CH:11][C:12]([OH:19])=[C:13]([C:8]=1[CH3:7])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: BrBr
Reactant: CCOC(=O)c1c(C)cccc1O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(O)ccc(Br)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of bromine (5.05 ml, 0.099 mol) and acetic acid (15 ml) is added to a mixture of ethyl 6-methyl-2-hydroxybenzoate (17.05 g, 0.095 mol), and acetic acid (15 ml) at a temperature of 20° C. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with water and ethyl acetate. The organic phase is washed with water twice, concentrated in vacuo and the residue is purified by flash chromatography (petrol ethers:ethyl acetate, 98:2 v/v) yielding the pure product as a yellow oil, 21.7 g, (88.2%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][C@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][C@H:19]1[CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CCCCOc1nc(N)c2c(n1)N(CCCN[C@H]1CCCO1)C(OC)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN[C@H]3CCCO3)c2n1
Yield: 97.1 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9-{3-[(2R)-tetrahydro-2-furanylamino]propyl}-8,9-dihydro-7H-purin-6-amine (3 mg, 8.23 μmol) was stirred with 4M HCl in 1,4 dioxane (0.05 ml, 0.2 mmol) in methanol (2 ml) at 40° C. for 3 hours. The solvent was stripped using the Radleys blowdown apparatus under a stream of nitrogen. The sample was loaded in methanol and purified by SPE (2 g) on an aminopropyl (NH2) cartridge using methanol. The appropriate fractions were combined and dried under a stream of nitrogen to give the title compound as a white solid (2.8 mg).
Reaction SMILES: [Cr]([Cl:5])([O-])(=O)=O.[NH+]1C=CC=CC=1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[C:14]=1[NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:5][C:18]1[CH:17]=[CH:16][C:15]([CH:19]=[O:20])=[C:14]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CC(C)(C)C(=O)Nc1c(Cl)cccc1CO
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.1 %

Procedure:
Pyridinium chlorochromate (1.19 g, 5.5 mmol) was added to a solution of N-(2-chloro-6-(hydroxymethyl) phenyl) pivalamide (884 mg, 3.67 mmol) in CH2Cl2 (100 mL) at 0° C. 5 min later the mixture was allowed stirring at room temperature for 3 hrs. The reaction mixture was passed through a thin pad layer of silica gel with CH2Cl2 (2×100 mL), concentrated on rotary vacuo, and purified on a flash chromatography column eluting with 20˜50% EtOAc/hexanes (1000 mL) to afford the expected product as a white solid (414 mg, 47% yield); 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (s, 9 H), 7.30 (t, J=7.81 Hz, 1H), 7.64 (dd, J=7.93, 1.39 Hz, 1 H), 7.77 (dd, J=7.55, 1.51 Hz, 1 H), 8.25 (s, 1 H), 9.84 (s, 1 H); Mass spec. 240.08 (MH+), Calc. for C12H14ClNO2 239.07.
Reaction SMILES: [I:1]I.[OH:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]2[S:15][CH:16]=[CH:17][C:5]=12>C(Cl)(Cl)Cl>[OH:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]2[S:15][C:16]([I:1])=[CH:17][C:5]=12
Reactant: CCOC(=O)c1cnc2sccc2c1O
Reactant: II
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2sc(I)cc2c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.1 %

Procedure:
Mercuric oxide (7.10 g) and iodine (8.32 g) are added portion-wise to a solution of ethyl 4-hydroxythieno[2,3-b]pyridine-5-carboxylate (J. Heterocyclic Chem. 1977, 14, 807) (5.22 g) in CHCl3 (90 mL). The reaction is stirred at rt for 18 h. The reaction mixture is filtered, and the solid is washed with CHCl3 (400 mL). The organic layer is washed with H2O (200 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange solid is purified by column chromatography (CH2Cl2:heptane, 1:1). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 2.95 g (36%) of ethyl 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylate as a pale yellow solid. Ethyl 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylate (2.64 g) is suspended in 10% NaOH (21 mL) and heated to reflux. The reaction is stirred at reflux for 1 h and then cooled to rt. The reaction mixture is poured into H2O (80 mL). Conc. HCl is added until a precipitate forms, and 2.272 g (94%) of 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylic acid is isolated as a white solid. Carbonyldiimidazole (1.34 g) is added to a solution of 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylic acid (2.041 g) in DMF (58 mL). The reaction is heated to 60° C. and stirred for 18 h. The reaction mixture is cooled to rt, and 4-chlorobenzylamine (1.01 mL, 8.27) is added. The reaction is stirred at rt for 7 h. The reaction mixture is poured into 20% aqueous HOAc (180 mL), and the resulting white solid is filtered off. This material is recrystallized from methanol then toluene to yield 2.095 g (74%) of the title compound as a white solid.
Reaction SMILES: C([C@H]1CC[C@H](OC2C=C3C(=CC=2)N=C(CN2CC(C(O)=O)C2)C=C3C(F)(F)F)CC1)(C)(C)C.C[O:35][C:36]([CH:38]1[CH2:41][N:40]([CH2:42][C:43]2[CH:52]=[C:51]([CH:53]3[CH2:55][CH2:54]3)[C:50]3[C:45](=[CH:46][CH:47]=[C:48]([O:56][C@H:57]4[CH2:62][CH2:61][C@H:60]([C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:59][CH2:58]4)[CH:49]=3)[N:44]=2)[CH2:39]1)=[O:37]>>[C:63]([C@H:60]1[CH2:59][CH2:58][C@H:57]([O:56][C:48]2[CH:49]=[C:50]3[C:45](=[CH:46][CH:47]=2)[N:44]=[C:43]([CH2:42][N:40]2[CH2:39][CH:38]([C:36]([OH:37])=[O:35])[CH2:41]2)[CH:52]=[C:51]3[CH:53]2[CH2:54][CH2:55]2)[CH2:62][CH2:61]1)([CH3:66])([CH3:64])[CH3:65]
Reactant: COC(=O)C1CN(Cc2cc(C3CC3)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C(F)(F)F)c3c2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C4CC4)c3c2)CC1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid using 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid methyl ester as starting material. ESI-MS (M+H+): 437.3; 1H NMR (400 MHz, METHANOL-d4) Shift 7.97 (d, J=9.04 Hz, 1H), 7.70 (d, J=2.76 Hz, 1H), 7.41 (dd, J=2.64, 9.16 Hz, 1H), 7.08 (s, 1H), 4.71 (s, 2H), 4.36-4.59 (m, 5H), 3.70-3.86 (m, 1H), 2.38-2.51 (m, 1H), 2.30 (d, J=10.54 Hz, 2H), 1.85-1.99 (m, 2H), 1.37-1.53 (m, 2H), 1.19-1.34 (m, 4H), 1.05-1.19 (m, 1H), 0.92 (s, 9H), 0.81-0.89 (m, 2H).
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.OC1CC[NH:32]CC1>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:32]
Reactant: OC1CCNCC1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 196.5 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.300 g, 0.770 mmol, 1 eq, Example 56, Step D) was suspended in Dioxane (20 mL) under Ar. 4-Hydroxypiperidine (0.234 g, 2.320 mmol, 3 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.200 g (66%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 393 (M+1); Anal. Calcd for C24H28N2O3.1HCl.0.4H2O: C, 66.09; H, 6.89; N, 6.42; Found: C, 66.18; H, 6.77; N, 6.30.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH3:35])=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH3:35])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: CCCOc1cnc(Cl)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCCOc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-5-propoxy-pyrimidine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.49 min; Mass spectrum (ESI+): m/z=448 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:23]([CH3:29])([CH3:28])[C:24]([O:26]C)=[O:25])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C-]#N.[K+].[Li+].[I-]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:23]([CH3:29])([CH3:28])[C:24]([OH:26])=[O:25])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)C1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCOCC1
Agent: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(C)(C(=O)O)C1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCOCC1
Temperature: 170 °C
Yield: 65.4 %

Procedure:
Methyl 2-(4-(1-(4-fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropanoate (155 mg, 0.40 mmol) was dissolved in 2.5 mL pyridine in a microwave reactor and KCN (104 mg, 1.6 mmol) and LiI (214 mg, 1.6 mmol) were added. The reactor was sealed and heated to 170° C. for 60 minutes. The reaction was purified directly by HPLC to give 2-(4-(1-(4-fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropanoic acid (100 mg, 67%). (M+H)+=383.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[S:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]4[S:27][CH:28]=[C:24]([CH3:23])[CH:25]=4)[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: Cc1csc(B2OC(C)(C)C(C)(C)O2)c1
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: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1csc(-c2cccc(-n3c4c(c5cc(C)ccc53)CN(C)CC4)c2)c1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 4-methylthiophene-2-boronic acid pinacol ester (175 mg, 0.784 mmol) and K2CO3 (162 mg, 1.1 mmol) in DME-water (2:1) was added Pd(PPh3)4 (22 mg, 0.019 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(4-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.78 (d, 1H), 7.6 (m, 2H), 7.3-7.38 (m, 3H), 7.17 (d, 1H), 7.02 (d, 1H), 7.0 (s, 1H), 4.4 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.2 (s, 4H), 3.1 (m, 1H), 2.41 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([OH:14])=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[OH-].[NH4+:34]>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([NH2:34])=[O:14])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [NH4+]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(N)=O)n1Cc1ccccc1Cl

Procedure:
(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid, prepared in Example 1, was treated with thionyl chloride and then ammonium hydroxide, as described in Example 54, to give the title compound; mp 184°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1.C([O-])=O.[NH4+].C(O)C>O.[OH-].[Pd+2].[OH-].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1
Reactant: COc1cc(C#N)nc(-c2ccccn2)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: O=C[O-]
Solvent: O
Solvent: CCO
Product: COc1cc(CN)nc(-c2ccccn2)c1
Temperature: 27 °C
Reaction time: 2 h

Procedure:
A mixture of 4-Methoxy-[2,2′]bipyridinyl-6-carbonitrile (1.0 g, 4.73 mmol), Palladium hydroxide-Pd 20%-50% in water (0.66 g, excess), ammonium formate (1.5 g, excess) and ethanol (60 mL) was stirred at 27° C. for 2 hours. The reaction was then filtered thorough celite, washed with methanol (150 mL) and dichloromethane (150 mL) and the organic phase evaporated to dryness affording C-(4-Methoxy-[2,2′]bipyridinyl-6-yl)-methylamine as an orange oil (0.80 g, 45%, in a ratio 72 to 28 product vs. byproduct).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH2:16])=[O:15])[CH:12]=2)[C:7]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:6]1[CH:22]([OH:25])[CH2:23][CH3:24]>CC(C)=O>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH2:16])=[O:15])[CH:12]=2)[C:7]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:6]1[C:22](=[O:25])[CH2:23][CH3:24]
Reactant: CCC(O)c1c(C(=O)C(C)C)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Solvent: CC(C)=O
Product: CCC(=O)c1c(C(=O)C(C)C)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Yield: 49.2 %

Procedure:
To a solution of 1-(2-chlorobenzyl)-2-(1-hydroxypropyl)-3-isobutyrylindole-6-carboxamide (19 mg) in acetone (3 ml) was added Jone's reagent until the red color existed continuously. The reaction was quenched by 2-propanol, then the mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 1-(2-chlorobenzyl)-3-isobutyryl-2-propionylindole-6-carboxamide (9.3 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:30]=[CH2:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[Br-].[CH2:62]([O:64][C:65](=[O:69])CC[Zn+])[CH3:63]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH2:30][CH2:31][C:65]([O:64][CH2:62][CH3:63])=[O:69])=[N:9][N:10]([C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC[Zn+]
Reactant: C=Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: CCOC(=O)CCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 40 °C
Yield: 33.5 %

Procedure:
An oven-dried, nitrogen cooled 2 ml microwave vial was charged with 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 3a, 103 mg, 0.197 mmol), palladium (II) acetate (2.2 mg, 9.80 μmol) and SPhos (8.2 mg, 0.020 mmol), sealed under an argon atmosphere, charged with (3-ethoxy-3-oxopropyl)zinc(II) bromide (0.5 M in THF, 0.5 ml, 0.250 mmol) and heated to 40° C. for 23 hr. Quenched with MeOH, filtered through celite, concentrated in vacuo and purified via flash chromatography (0-100% EtOAc/Hex). Obtained ethyl 3-(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)propanoate (32.6 mg, 0.066 mmol, 33.3% yield) as a yellow residue. MS ESI calc'd for C30H26ClN3O2 [M+H]+=496, found 496.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1>CO>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH:2][OH:3])=[NH:10])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: NO
Agent: Cl
Solvent: CO
Product: N=C(NO)c1ccc(O)cc1
Yield: 69.4 %

Procedure:
To dry methanol (285 mL) is carefully added K-tert.-butylate (28.28 g, 252 mmol) followed by hydroxylamine hydrochloride (15.0 g, 216 mmol). The suspension is stirred for 30 min before 4-hydroxybenzonitrile (8.58 g, 72 mmol) is added. The mixture is refluxed for 40 h, the solvent is evaporated and the residue is acidified by adding 2 N aq. HCl. The solution is extracted twice with DCM (100 mL). The aq. layer is basified by adding solid NaHCO3. The product precipitates, is filtered off, washed with water and dried to give 4,N-dihydroxy-benzamidine (7.6 g) as a brownish solid; 1H NMR (D6-DMSO): δ 9.57 (s, 1H), 9.33 (s, 1H), 7.48-7.42 (m, 2H), 6.74-6.68 (m, 2H), 5.62 (s, 2H).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][CH:35]([CH2:40][S:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:43])=[O:42])[CH2:36][C:37]([OH:39])=[O:38].CN(C1C=CC=CN=1)C>C(N(CC)CC)C.CN(C=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH:34][CH:35]([CH2:40][S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)(=[O:43])=[O:42])[CH2:36][C:37]([OH:39])=[O:38])=[O:17])=[CH:9][CH:10]=1
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Reactant: NC(CC(=O)O)CS(=O)(=O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NN=Cc1ccc(NC(=O)CCC(=O)NC(CC(=O)O)CS(=O)(=O)c2ccccc2)cc1
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1(3.0 g, 11.3 mmol) was added to dry DMF (200 ml) followed by N-methylmorpholine (1.2 g, 11.3 mmol) and isobutyl chloroformate (1.5 g, 17 mmol) at 25° C. The mixture was stirred for 5 min. 3-Amino-4-phenylsulfonyl butanoic acid (4.0 g, 11.3 mmol) was added followed by triethylamine (2.7 g) and dimethylaminopyridine. After 1 hr, the solvent was removed under reduced pressure and the solid mass was dissolved into a mixture of acetic acid:H2O:H2O2 30% (2:2:1) and stirred at 25° C. for 48 hr. The reaction mixture was concentrated in vacuo and the residue purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to result in 3.5 g of a white solid: 1H NMR (d6-DMSO) 2.25 (m, 2H), 2.53 (m, 4H), 3.55 (m, 2H), 4.33 (m, 1H), 7.44 (m, 5H), 7.79 (s, 4H), 7.99 (d, 1H,J=8.1 Hz), 9.1 (bs, 2H), 9.19 (bs, 2H), 10.42 (s, 1H); MS (FAB) m/z 461.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:26][C:25]([F:28])([F:27])[C:24]([F:30])([F:29])[CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:23][C:24]([F:29])([F:30])[C:25]([F:27])([F:28])[CH2:26]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)N2CC(F)(F)C(F)(F)C2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CC(F)(F)C(F)(F)C2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)ethanamine.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:21])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=2)=[CH:8][CH:7]=1.[OH-].[K+].C(O)(=O)C>CO>[O:21]1[CH2:2][CH:3]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=2)=[CH:8][CH:7]=1
Reactant: OC(CCl)COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[p-(3-chloro-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole (1.92 g.) in methanol (100 ml.) is added crushed potassium hydroxide (1.5 g.). The mixture is stirred 3 hours at room temperature, neutralized with acetic acid and concentrated under reduced pressure (20 mm. Hg.) over steam. The residue is triturated with water (25 ml.), filtered and recrystallized by dissolving in benzene and adding hexane until turbid. A yield of 1.2 g. of 2-[4-(2,3-epoxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained, m.p. 152°-153.5° C.