Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.O.[OH-].[Na+]>C1COCC1>[CH3:17][N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][CH2:9][OH:8])[CH2:12][CH2:13]1
Reactant: COC(=O)CC1CCN(C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(CCO)CC1
Reaction time: 4 h

Procedure:
LAH (2.25 g, 59.3 mmol) was slowly added to 150 mL of THF. (1-Methyl-piperidin-4-yl)-acetic acid methyl ester (Step B) in 30 mL of THF was added dropwise to the LAH in THF and the resulting mixture was stirred for 4 h. Water (2.26 mL), 2.26 mL of 15% NaOH and 6.78 mL of water were carefully added and stirring was continued for 30 min. The mixture was filtered through Celite®, the solids were washed with EtOAc and the filtrate was evaporated, giving 2-(1-methyl-piperidin-4-yl)-ethanol as a yellow oil.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[CH:7]=[C:8]([CH:13]2[C:17]([OH:18])=[C:16]([C:19]([CH3:21])=[O:20])[CH2:15][S:14]2)[CH:9]=[CH:10][C:11]=1[CH3:12].S(Cl)(Cl)(=O)=O.O>C(O)(C)C>[CH3:5][C:6]1[CH:7]=[C:8]([C:13]2[S:14][CH:15]=[C:16]([C:19]([CH3:21])=[O:20])[C:17]=2[OH:18])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: CC(=O)C1=C(O)C(c2ccc(C)c(C)c2)SC1
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)c1csc(-c2ccc(C)c(C)c2)c1O
Temperature: -40 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
A chloroform (24 mL) solution of 2-(3,4-dimethylphenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (2.44 g, 9.82 mmol, purity: 72%) was cooled to −40° C., and to this solution, a chloroform (37 mL) solution of sulfuryl chloride (0.79 mL, 1.0 equivalent amount) was dropwise added over a period of 55 minutes, followed by stirring at −40° C. for 60 minutes. The temperature of the solution was raised to 0° C., and water (5 mL) was dropwise added over a period of 1 minute, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a saturated sodium hydrogencarbonate aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. The obtained crude product was suspended in isopropyl alcohol (37 mL) at room temperature, followed by stirring at 0° C. for 30 minutes. The formed crystals were subjected to filtration to give the desired product (0.47 g, yield: 20%) as a yellow solid. Further, the filtrate was isolated and purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1 (v/v)) to give the desired product (0.81 g, yield: 33%) as a yellow solid (1.28 g, yield: 53%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14]C)=[O:13])[CH:8]=[CH:9][CH:10]=1.[OH-].[Na+].Cl>CO>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccc(OCCCl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(OCCCl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-(2-chloro-ethoxy)-phenylacetate (7.0 g, 32.9 mmol) was dissolved in methanol (40 mL) and 6N NaOH (5.5 mL) was added. The mixture was stirred at room temperature overnight then acidified by addition of 6N hydrochloric acid (5.5 mL). A white precipitate formed which was filtered, washed with 1N HCl, water and dried. 3-(3-Chloroethoxy)-phenylacetic acid (6.5 g, 99%). 1H NMR (500 MHz, CDCl3) δ3.55 (s, 2H), 3.75 (t, 2H), 4.15 (t, 2H), 6.78 (dd, 1H), 6.80 (d, 1H), 6.84 (dd, 1H), 7.16 (dd, 1H).
Reaction SMILES: [NH2:1][O:2]C1CCCCO1.[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([OH:29])=O)=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(O)(C(F)(F)F)=O>CN(C=O)C.CO>[OH:2][NH:1][C:27]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([S:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:17])=[O:16])[CH:19]=[CH:20]2)=[O:29]
Reactant: O=C(O)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: NOC1CCCCO1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NO)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
NH2OTHP (0.08 g, 0.72 mmol) was added to a solution of 3 (0.18 g, 0.60 mmol), PyBOP (0.33 g, 0.63 mmol), and triethylamine (0.20 ml, 1.43 mmol) in DMF (1.5 mL). The reaction mixture was stirred at room temperature for 2 h before it was quenched with water and extracted with EtOAc (15 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CH2Cl2:CH3OH=30:1:1% NH3(aq)) to give a white solid, which was treated with TFA (1.70 ml, 22.89 mmol) in the presence of CH3OH (31 mL). The reaction mixture was stirred overnight at room temperature before it was concentrated under reduced pressure to give a white residue. The residue was recrystallized with CH3OH to afford Compound 1 (0.10 g). 1H NMR (500 MHz, CD3OD): δ 6.80 (d, J=3.65 Hz, 1H), 7.49-7.52 (m, 2H), 7.59-7.62 (m, 1H), 7.68 (d, J=8.53 Hz, 1H), 7.75 (d, J=3.72 Hz, 1H), 7.93 (d, J=7.52 Hz, 2H), 7.94-7.97 (m, 1H), 8.04 (d, J=8.53 Hz, 1H); HRMS (EI) for C15H12N2O4S (M+): calcd, 316.0518. found, 316.0518.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]#[N:13])[N:3]=1.[F-:14].[K+].[Cl-].[NH4+]>CS(C)=O>[F:14][C:2]1[N:3]=[C:4]([C:12]#[N:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: [F-]
Reactant: N#Cc1cc(C(F)(F)F)cc(Cl)n1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)cc(F)n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To 9 ml of dimethyl sulfoxide were added 0.9 g of 2-chloro-6-cyano-4-trifluoromethylpyridine, and 0.76 g of potassium fluoride, and the mixture was stirred at 120° C. for 2 hours and 30 minutes. Thereafter, the reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert-butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.7 g of 6-fluoro-4-trifluoromethylpyridine-2-carbonitrile.
Reaction SMILES: [C:1](C1C=CC=CC=1O)(C)(C)C.[Cl:12][C:13]1[CH:37]=[C:36]([CH:38]2[CH2:43]CCC[CH2:39]2)[CH:35]=[CH:34][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH2:24][CH2:25][C@:26]([CH3:33])([C:30]([OH:32])=[O:31])[O:27]2)=[CH:22][CH:21]=1>>[Cl:12][C:13]1[CH:37]=[C:36]([C:38]([CH3:43])([CH3:1])[CH3:39])[CH:35]=[CH:34][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH2:24][CH2:25][C@:26]([CH3:33])([C:30]([OH:32])=[O:31])[O:27]2)=[CH:22][CH:21]=1
Reactant: C[C@]1(C(=O)O)CCc2ccc(OCCCOc3ccc(C4CCCCC4)cc3Cl)cc2O1
Reactant: CC(C)(C)c1ccccc1O
Product: CC(C)(C)c1ccc(OCCCOc2ccc3c(c2)O[C@@](C)(C(=O)O)CC3)c(Cl)c1

Procedure:
The title compound was prepared following the procedures described in Example 5, Step B-E employing tert-butylphenol instead of 4-(2,2,2-trifluoroethoxy)phenol, and (2R)-methyl 2-methyl-7-hydroxychromane-2-carboxylate (Example 23, Step A) instead of ethyl 2-ethyl-7-hydroxychromane-2-carboxylate.
Reaction SMILES: [P:1]([CH:5]([CH3:9])[C:6]([OH:8])=[O:7])([OH:4])([OH:3])=[O:2].[CH3:10]O>>[P:1]([CH:5]([CH3:9])[C:6]([O:8][CH3:10])=[O:7])([OH:4])([OH:3])=[O:2]
Reactant: CC(C(=O)O)P(=O)(O)O
Reactant: CO
Product: COC(=O)C(C)P(=O)(O)O

Procedure:
A solution of 2-phosphonopropionic acid (11.2 g., 0.073 moles) in methanol (150 ml.) is heated at reflux for eighteen hours. The methanol is removed in vacuo. Electrophoresis (0.1 N NH4HCO3, 2000 V, 20 minutes, 7.5 cm) indicates complete conversion to the desired product, methyl 2-phosphonopropionate; yield quantitative.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([NH:21]C(OC(C)(C)C)=O)=[CH:18][CH:19]=2)[C:14]([CH3:29])=[CH:13][C:12]1([CH3:31])[CH3:30])(=[O:10])[CH3:9].[Al+3].[Cl-].[Cl-].[Cl-]>>[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([NH2:21])=[CH:18][CH:19]=2)[C:14]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([CH3:29])[CH2:13][C:12]1([CH3:30])[CH3:31])(=[O:10])[CH3:9]
Reactant: CC(=O)N1c2ccc(NC(=O)OC(C)(C)C)cc2C(C)=CC1(C)C
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1c2ccc(N)cc2C(C)(c2ccc(F)cc2)CC1(C)C

Procedure:
Friedel-Crafts alkylation of fluorobenzene (2 ml) with 1-acetyl-6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (25 mg) in the presence of AlCl3 (35 mg) was performed according to the method described in example 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:23][CH:22]3[CH:18]([CH2:19][NH:20][CH2:21]3)[CH2:17]2)=[O:15])=[CH:4][CH:3]=1.CN(C=O)C.Cl[C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[CH3:37][C:32]1[N:31]=[C:30]([N:20]2[CH2:19][CH:18]3[CH:22]([CH2:23][N:16]([C:14]([C:9]4[N:10]=[C:11]([CH3:13])[S:12][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:15])[CH2:17]3)[CH2:21]2)[CH:35]=[C:34]([CH3:36])[N:33]=1
Reactant: Cc1nc(C(=O)N2CC3CNCC3C2)c(-c2ccc(F)cc2)s1
Reactant: Cc1cc(Cl)nc(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CC3CN(C(=O)c4nc(C)sc4-c4ccc(F)cc4)CC3C2)nc(C)n1
Temperature: 100 °C
Yield: 61.4 %

Procedure:
To a solution of Intermediate 48 (15.8 mg, 0.048 mmol) was added DMF (0.4 mL), 4-chloro-2,6-dimethylpyrimidine (8.2 mg, 0.057 mmol) and cesium carbonate (38.8 mg, 0.119 mmol). The mixture was heated to 100° C. for 18 hours, diluted with water and extracte with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by reverse phase HPLC to give the title compound (12.9 mg, 62%). MS (ESI): mass calculated for C23H24FN5OS, 437.5; m/z found [M+H]+438.2. 1H NMR (400 MHz, CDCl3): 7.51-7.41 (m, 2H), 7.06-6.95 (m, 2H), 6.29 (s, 1H), 3.892-3.76 (m, 2H), 3.73-3.51 (m, 3H), 3.44 (dd, J=11.6, 5.0 Hz, 1H), 3.32 (dd, J=11.6, 4.5 Hz, 1H), 3.10 (dd, J=11.3, 5.3 Hz, 1H), 3.02-2.80 (m, 2H), 2.70 (s, 3H), 2.31 (d, J=20.0 Hz, 6H).
Reaction SMILES: [CH3:1][NH2:2].CS(O[CH2:8][CH:9]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)(=O)=O.C(Cl)Cl.N>CS(C)=O.C(Cl)(Cl)Cl.CO.C(Cl)Cl>[CH3:15][C:12]1([CH3:16])[O:13][CH2:14][CH:9]([CH2:8][NH:2][CH3:1])[CH2:10][O:11]1
Reactant: CC1(C)OCC(COS(C)(=O)=O)CO1
Reactant: CN
Agent: N
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNCC1COC(C)(C)OC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
Methylamine solution (3 mL, 34.8 mmol) was added to a solution of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (0.9 g, 4.01 mmol, prepared as per B. Xu et al. J. Med. Chem. 2002, 45, 5694) in DMSO (7 mL) and stirred at 75° C. overnight. The reaction was diluted with CHCl3 and the CHCl3 washed with water (×2), dried and concentrated in vacuo to afford approximately 670 mg of crude product. The crude material was columned on silica eluting with DCM, 20% MeOH/DCM, and 20% 7N NH3 in MeOH/DCM to afford (2,2-dimethyl-1,3-dioxan-5-yl)-N-methylmethanamine (330 mg, 52% yield) as an oily residue. 13C NMR (CD3OD) δ 99.7, 64.4 (2×CH2), 52.3, 36.9, 36.0, 26.0, 23.5.
Reaction SMILES: CO.[O:3]=[C:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:6]([C:7](=[O:31])[CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:5]1.Cl>O1CCCC1>[O:3]=[C:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:6]([C:7](=[O:31])[CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:5]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC(=O)[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC(=O)[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
The 3,6-dioxo-5α sterol was prepared by acid-catalyzed isomerization of the 5β sterol. To methanol (250 ml) was added the 3,6-dioxo-5β sterol 1017 (9.6 g, 24 mmol) and tetrahydrofuran (25 ml) to dissolve the sterol completely. Concentrated hydrochloric acid (12.5 ml) was added, and the reaction was allowed to proceed overnight. The solvent was then remove under vacuum to yield 9.6 g (100% yield) of methyl 3,6-dioxo-5α-cholan-24-oate 1018 (see Organic Preparations and Procedures Int. 19(2-3), 1987, 197-208; authors used base-catalyzed isomerization using sodium methoxide rather than HCl).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH2:19]([O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)=[CH:28][CH:29]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOc1ccc(N)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: CCCCOc1ccc(Nc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-butoxy-phenylamine to give N1-(4-butoxy-phenyl)-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 388(MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]2[CH:22]=1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH:21][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=3)[CH:18]=[CH:17][N:16]2[CH:22]=1
Reactant: O=C(O)c1cccnc1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(N)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(NC(=O)c3cccnc3)cc2n1
Yield: 14 %

Procedure:
As described for Example 48, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-7-ylamine (92 mg, 0.32 mmol) was converted, using nicotinic acid instead of cyclopropanecarboxylic acid, to the title compound (19.4 mg, 14%) which was obtained as an off-white solid. MS: m/e=396.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[CH:22][C:23]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:25])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)O)cc2)CC1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)N3CCOCC3)cc2)CC1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a stirred solution of 3-[4-(1-t-butyloxycarbonyl piperidin-4-yloxy)phenyl]prop-2-ene-1-oic acid (38 grams, 0.109 moles, obtained in above step) and triethylamine (38.4 mL, 0.273 moles) in dichloromethane (500 mL) was added ethylchloroformate (13.6 mL, 0.142 moles) at 0° C. The reaction mass was further stirred for 2 hours at 0-5° C. Morpholine (19.2 mL, 0.219 moles) was added to above mass at 0-5° C. and the resulting mixture were stirred for 2 hours. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the mass was quenched by adding water (100 mL). Layers were separated and the organic layer was washed with brine solution (100 mL) and dried over sodium sulphate. The organic phase was concentrated under vacuum to obtain the crude residue, which was further purified by flash chromatography using methanol:triethylamine:chloroform in the ratio of 1:1:98 to afford the title compound (34 grams).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C@@H:11]([C:16]([O:29][CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[N:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C@@H:11]([C:16]([O:29][CH3:30])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([O:14][CH3:15])=[O:13])[N:4]=1
Reactant: COC(=O)[C@@H](Oc1nc(C)cc(C=O)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](Oc1nc(C)cc(CO)n1)C(OC)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 5.8 %

Procedure:
To a solution of the crude compound from Example 10 (76 mmol) in methanol (170 mL) is added sodium borohydride (1.93 g, 51 mmol) portion-wise and the reaction stirred for 3 hr. The reaction is quenched with ice-water (50 mL) and the methanol is removed under reduced pressure on a rotary evaporator. The residual aqueous phase is extracted with ethyl acetate (2×100 mL) to yield crude product (25 g). This crude product is purified by column chromatography on silica gel eluted with ethyl acetate/hexane to yield the title compound (1.8 g, 8.6%). MS m/z 409.1 (M+.+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:10]([Cl:11])=[CH:9][C:8]([N+:12]([O-])=O)=[CH:7][C:4]=1[C:5]#[N:6].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.[Zn]>[NH2:2][C:3]1[C:10]([Cl:11])=[CH:9][C:8]([NH2:12])=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: N#Cc1cc([N+](=O)[O-])cc(Cl)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(N)cc(Cl)c1N
Reaction time: 2 h
Yield: 99 %

Procedure:
Aqueous hydrochloric acid (12 M, 5.3 mL) was added slowly to a mixture of zinc dust (2.01 g) and 2-amino-3-chloro-5-nitro-benzonitrile (0.50 g) in tetrahydrofuran (40 mL). The reaction mixture was stirred for 2 hours, neutralized with saturated aqueous sodium carbonate (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo to furnish 0.42 g (99% yield) of the title compound as a red solid. 1H NMR (500 MHz, DMSO-d6): 4.89 (s, 2H), 5.13 (s, 2H), 6.64 (d, 1H), 6.89 (d, 1H).
Reaction SMILES: C(OCC)C.C([Li])CCC.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[CH:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]>O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[OH:19])[CH:13]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1cccnc1)c1cccc2ccccc12
Temperature: -120 °C
Reaction time: 0.75 h

Procedure:
To a 500 ml 3-neck flask round bottom flask equipped with an addition funnel, septum, thermometer and an argon inlet is added 100 ml of anhydrous diethyl ether and 62.5 ml of 1.6 molar butyllithium solution (in hexane). The system is cooled to -120° C. and 15.90 gm of 3-bromopyridine in 50 ml of tetrahydrofuran is added over 2 hours. After addition of the 3-bromopyridine, the system is stirred for an additional 45 minutes. At this time, 15.60 gm of 1-formylnaphthalene in 50 ml of tetrahydrofuran is added to the system while still maintaining a temperature of -120° C. The system is kept at -120° C. for an additional 3 hours after addition of the 1-formylnaphthalene and afterwards is allowed to come to room temperature. After 10 hours at room temperature, the system is quenched with saturated ammonium chloride (in water). The system is adjusted to pH 2 with HCl solution. The solution is extracted with diethyl ether. The aqueous solution is made basic with a 5% NaOH solution. The product is extracted with methylene chloride and dried over sodium sulfate. The methylene chloride is removed by stripping and the residue is triturated with hexane to give the 3-pyridyl-1-naphthylcarbinol.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[C:18]([CH3:20])[NH:17][N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:21]([N:6]1[C:5]2[CH:25]=[CH:26][C:2]([C:31]3[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]=[C:18]([CH3:20])[NH:17][N:16]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: Cc1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n[nH]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n[nH]1
Temperature: 100 °C
Yield: 24.8 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(5-methyl-1H-1,2,4-triazol-3-yl)-phenyl]-1H-benzimidazole (78 mg, 0.19 mmol) in DMF (3 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (50 mg, 0.226 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (20 mg, 0.028 mmol) and 2M aq. Na2CO3 (0.4 mL, 0.8 mmol). The reaction mixture is heated under Argon at 100° C. for 10 hours. The residue is diluted with EtOAc, washed with brine, dried under Na2SO4, is filtered and is concentrated. The residue is loaded to a silica gel column. The column is eluted with 0-8% 7M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford the title compound (20 mg, 25%) as a off-white solid. LCMS (ESMS): m/z 425.79 (M++1)
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][NH:12][CH:13]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]1>[OH-].[Na+]>[CH3:11][N:12]([CH:13]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]1)[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CNC1CCN(C)C1
Reactant: Clc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(N(C)c2nc3ccccc3[nH]2)C1
Temperature: 120 °C
Yield: 39.5 %

Procedure:
A mixture of 2-chlorobenzimidazole (25 g, 0.165 mol) and 3-methylamino-1-methylpyrrolidine (72 g, 0.63 mol) was heated at 120° C. with an oil bath for 18 hr. After cooling, 500 ml of 2.5N NaOH solution was added and the mixture extracted twice with 100 ml portions of methylene chloride. The methylene chloride extracts were combined and washed successively with 2×100 ml portions of 2.5N NaOH solution and 3×100 ml portions of water. The methylene chloride solution was dried (Na2SO4) and concentrated to obtain 15 g of product (40% yield).