Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N:11]([O-])=O.[Na+].O.O.[Cl:17][Sn]Cl>Cl>[ClH:17].[NH:1]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[NH2:11]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(C(=O)O)c1
Reaction time: 1 h

Procedure:
To a solution (200 mL) of m-amino benzoic acid (200 g, 1.46 mol) in concentrated HCl was added an aqueous solution (250 mL) of NaNO2 (102 g, 1.46 mol) at 0° C. The reaction mixture was stirred for 1 h and a solution of SnCl2.2H2O (662 g, 2.92 mol) in concentrated HCl (2 L) was then added at 0° C., and the reaction stirred for an additional 2h at RT. The precipitate was filtered and washed with ethanol and ether to yield 3-hydrazino-benzoic acid hydrochloride as a white solid.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4](O)[CH:3]=1.[Cl-:14].[Cl-:15].[Ca+2].C(Cl)Cl>O(Cl)Cl.[P+5].O>[Cl:14][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:15])[CH:3]=1
Reactant: [Cl-]
Reactant: CCOC(=O)c1cnc(O)cc1O
Agent: ClOCl
Agent: [Ca+2]
Agent: [P+5]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
(Wallace, E., et. al., ibid.) A stirred suspension of compound ii (1.40 g, 7.67 mmol) in phosphorus (V) oxychloride (15 mL) was heated to 110° C. for 2.5 h with a guard tube (CaCl2) fitted. The reaction mixture was cooled to room temperature, reduced in vacuo and the resulting dark brown residue taken up in a small volume of DCM (˜5 mL) and transferred dropwise onto a slurry of ice in water (250 mL) whilst stirring vigorously. The aqueous mixture was extracted with EtOAc (3×100 mL), the organic extracts combined, dried (MgSO4) and evaporated to dryness to afford the crude product as an orange gum. Column chromatography (SiO2), eluting with 15:1 Hexanes-EtOAc, afforded compound iii. (1.33 g, 6.14 mmol, 79%) as a colourless oil; [M+H]+ m/z=220.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]([CH2:17]Br)[CH2:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]([CH2:17][N:29]3[CH2:30][CH2:31][C:26]([CH2:25][C:24]4[CH:23]=[CH:22][C:21]([CH3:20])=[CH:34][CH:33]=4)([OH:32])[CH2:27][CH2:28]3)[CH2:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Solvent: Cc1ccccc1
Product: Cc1ccc(CC2(O)CCN(CC3Cc4cc(OCc5ccccc5)ccc4O3)CC2)cc1
Temperature: 110 °C
Yield: 88.2 %

Procedure:
(RS)-5-Benzyloxy-2-bromomethyl-2,3-dihydro-benzofuran (840 mg, 2.63 mmol) and 4-(4-methyl-benzyl)-piperidin-4-ol (1.08 g, 5.26 mmol) were suspended in toluene (20 ml) and heated to 110° C. for 17 hr. The mixture was filtered and evaporated to afford an orange oil which was chromatographed over SiO2 (Merck 230-400 mesh) with MeOH—CH2Cl2 (3:97) to afford (RS)-1-(5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol as a yellow oil (1.03 g, 2.32 mmol, 88%), MS: m/e=444.5 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[NH2:9][C:4]1[N:3]=[C:2]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: Cc1cc(Cl)nc(N)n1
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: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cc(C)nc(N)n3)cc2s1
Temperature: 90 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a suspension of tetrakis(triphenylphosphine)palladium (0) (0.115 g, 0.0999 mmol), 4-chloro-6-methylpyrimidin-2-amine (0.142 g, 0.999 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.318 g, 0.999 mmol) under nitrogen was added sodium carbonate (1 mL, 2M in water, 2 mmol) and then 1,4-dioxane (6 mL). The flask was heated in a pre-heated (90° C.) bath and stirred under an inert atmosphere overnight. The mixture was allowed to cool to ambient temperature and concentrated. The crude material was diluted with DCM and washed with brine. The organic layer was dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0-10% MeOH in DCM) to give N-(6-(2-amino-6-methylpyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (200 mg, 67%) as a brown solid. MS (ESI pos. ion) m/z: 300 (MH+). Calculated exact mass for C14H13N5OS: 299.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH2:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)[CH3:25]>>[CH2:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:31])=[CH:28][CH:27]=1)[CH3:25]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: CCc1ccc(C(=O)O)cc1
Product: CCc1ccc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)cc1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Ethyl-benzoic acid.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[NH4+:37].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:37][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][C:18]3([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:6]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCc1nc2cnc3cccnc3c2n1CC1(O)CCCCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a solution of 1-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol (1.43 g, 4.41 mmol) in chloroform (20 mL) at rt was added m-chloroperbenzoic acid (m-CPBA, 70%, 2.17 g, 8.82 mmol). After 1.5 h, the solution was was cooled to 0° C. and concentrated ammonium hydroxide (5 mL) was added. After 3 min, p-toluenesulfonyl chloride (TsCl, 0.920 g, 4.85 mmol) was added in portions. After 1 h, the reaction mixture was filtered and the filter cake was washed with chloroform. The filtrate was washed with saturated aqueous sodium bicarbonate (50 mL) and dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an orange foam which was purified twice by HPFC (silica gel, gradient elution with 0-25% CMA/CHCl3 where CMA is a solution comprised of 80% CHCl3, 18% MeOH, and 2% conc. NH4OH; followed by 0-30% CMA/CHCl3). The appropriate fractions were concentrated and triturated with acetonitrile. The solid was isolated by filtration and dried at 100° C. under vacuum to yield 1-[(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol (567 mg, 38%) as a white powder, mp 209.0-211.0° C. Anal. Calcd for C19H25N5O.0.2H2O C, 66.35; H, 7.47; N, 20.36. Found: C, 66.62; H, 7.34; N, 20.05.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][CH2:37][CH:38]([NH2:40])[CH3:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:40][CH:38]([CH3:39])[CH2:37][O:36][CH3:35])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: COCC(C)N
Product: COCC(C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(methyloxy)-2-propanamine using methods similar to Example 563 to provide a white solid: 1H NMR (CDCl3) δ 10.17 (1H, d, J=8 Hz), 8.54 (1H, s), 8.27 (1H, s), 7.23 (2H, dd, J=5, 8 Hz), 6.98 (2H, t, J=8 Hz), 4.31-4.43 (3H, m), 4.15 (2H, s), 3.53 (2H, b), 3.47 (2H, d, J=5 Hz), 3.40 (3H, s), 3.36 (2H, b), 2.35 (2H, b), 1.75 (4H, b), 1.30 (3H, d, J=7 Hz); ES+ MS: 511 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[C:4]([F:17])[CH:3]=1.[C:18]([CH2:20][C:21](OCC)=[O:22])#[N:19].N1CCCCC1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:21](=[O:22])[C:20]([C:18]#[N:19])=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[N:9]2)=[C:4]([F:17])[CH:3]=1
Reactant: O=C(C=NNc1ccc(Cl)cc1F)C(F)(F)F
Reactant: CCOC(=O)CC#N
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: N#Cc1c(C(F)(F)F)cnn(-c2ccc(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
After 1.0 g of 3, 3, 3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluorophenylhydrazone) was dissolved in 10 mL of pyridine, 0.8 mL of ethyl cyanoacetate and 0.5 mL of piperidine were added to the pyridine solution, which was followed by stirring for 3 days at room temperature. After pouring into water, the reaction solution was extracted with ethyl acetate. After the organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate/hexane =4/1), and thin-layer chromatography (eluent: ethyl acetate/hexane =5/1) to afford 0.28g of 2-(4-chloro-2-fluorophenyl)-4-cyano-5-trifluoromethylpyridazin-3-one (The present compound 1-1).
Reaction SMILES: C(OC([N:8]([CH:46]1[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[C:25]([CH3:38])=[N:26][N:27]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=5)[C:28]=4[CH3:29])=[CH:22][N:21](C(OC(C)(C)C)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][CH:10]=1)=O)(C)(C)C>CO.CCOCC.Cl>[F:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:23]2[C:17]3[C:18](=[N:19][CH:20]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([NH:8][CH:46]5[CH2:47][CH2:48][NH:49][CH2:50][CH2:51]5)=[CH:14][CH:13]=4)[CH:16]=3)[NH:21][CH:22]=2)[C:25]([CH3:38])=[N:26]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1cn(C(=O)OC(C)(C)C)c2ncc(-c3ccc(N(C(=O)OC(C)(C)C)C4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(NC4CCNCC4)cc3)cc12
Yield: 20.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 5-(4-((tert-butoxycarbonyl)(1-(tert-butoxycarbonyl)piperidin-4-yl)amino)phenyl)-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (25 mg, 0.050 mmol) was deprotected in methanol/ether HCl (3/2 ml). This afforded 5 mg (31.2% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.70 (s, 1H), 8.59 (s, 1H), 7.80 (s, 1H), 7.72-7.70 (d, 2H), 7.46-7.40 (m, 1H), 7.02-7.18 (d, 2H), 7.12-7.09 (m, 2H), 7.02-7.00 (d, 1H), 5.51 (s, 2H), 3.85-3.80 (m, 1H), 3.52-3.47 (d, 2H), 3.20-3.10 (t, 2H), 2.33-2.13 (m, 8H), 2.13-1.83 (m, 2H). MS: m/z=494.9 (M+1), HPLC: 95.22% in method B.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Cl:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)(=O)C.[CH3:20]I.[H-].[Na+].CO.CN([CH:29]=[O:30])C>O>[Cl:19][C:18]1[C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:29](=[O:30])[CH3:20])[C:8]=2[CH:7]=[CH:6][C:5]=1[O:4][CH3:1]
Reactant: CC(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1Cl)Sc1ccccc1N2C(C)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-chloro-3-acetoxy-10H-phenothiazine (see Example 4) in DMF (10 mls) was added methyl iodide (0.34 ml) and sodium hydride (114 mg). The reaction mixture was stirred at ambient temperature for 12 hours. Methanol and water were then added and the resulting mixture extracted with EtOAc. The organic phases were then collected, dried and evaporated. The resulting residue was purified by chromatography on silica gel (HPLC) to give 0.56 g of 4-chloro-3-methoxy-10-acetyl-10H-phenothiazine (m.p. 136° C.).
Reaction SMILES: N1CCCCC1.[CH2:7]([O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][CH3:21])[C:8]#[C:9][CH3:10].C([CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:33])=[O:32])=[O:27])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH2:7]([O:11][C:12]1[CH:19]=[CH:18][C:15](/[CH:16]=[CH:25]/[C:26]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])=[CH:14][C:13]=1[O:20][CH3:21])[C:8]#[C:9][CH3:10]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CC#CCOc1ccc(C=O)cc1OC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 56.3 %

Procedure:
Piperidine (0.34 mL, 3.4 mmol) was added to a suspension of 4-(but-2-ynyloxy)-3-methoxybenzaldehyde (0.70 g, 3.4 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.70 g, 3.4 mmol) in toluene (10 mL) and treated according to Procedure 2, acidifying with 20% AcOH. (E)-2-{[3-(4-(But-2-ynyloxy)-3-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid (0.70 g, 61%) was obtained as a yellow crystalline solid; mp 194-195° C.; δH (400 MHz, DMSO-d6) 1.82 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.77 (s, 2H, OCH2), 6.79 (d, J=15.6 Hz, 1H, CH═CHCO), 7.02 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.14 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.23 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.33 (s, 1H, NH), 13.59 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 3.2, 55.7, 56.4, 74.6, 83.9, 110.7, 113.3, 116.8, 120.3, 120.4, 122.3, 122.8, 127.9, 131.2, 134.0, 141.1, 141.6, 148.6, 149.3, 164.2, 169.5; HRMS (ESI) calculated for C21H19NO6 [M+Na]+ 388.1155. found 388.1158; vmax 753, 1253, 1506, 1584, 1659, 2917, 3239, 3516 cm−1.
Reaction SMILES: [BH4-].[Na+].[N+:3]([CH:6]=[CH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)([O-:5])=[O:4].C(O)(=O)C>O1CCOCC1.C(O)C>[N+:3]([CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])C=Cc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc2ccccc2c1
Temperature: 0 °C
Yield: 6.7 %

Procedure:
To a suspension of sodium borohydride (4 g) in a mixture of dioxane (85 ml) and ethanol (30 ml) was added dropwise a solution of 2-(2-nitroethenyl)naphthalene (100 g) in dioxane (90 ml) over 30 minutes. The flask was cooled with a cold water bath during addition. Stirring was maintained for an additional 11/2 hours. Ice (100 ml) and 50% aqueous acetic acid (12 ml) were added and the mixture was stirred for 2 hours at room temperature, concentrated in vacuo and extracted with methylene chloride. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo to yield an oil which was crystallized from acetic acid to give the title compound (6.79 g) as a yellow solid, m.p. 59-60° C.
Reaction SMILES: [OH-].[Na+].C1COCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])=[CH2:30])=[CH:25][C:24]=3[C:32]3[CH:33]=[CH:34][C:35]([C:38]([NH:40][CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])=[O:39])=[N:36][CH:37]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl>CO>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])=[CH2:30])=[CH:25][C:24]=3[C:32]3[CH:33]=[CH:34][C:35]([C:38]([NH:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:39])=[N:36][CH:37]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: C=C(C)c1ccc(CNc2ccc(-c3ccc(F)cc3)cc2)c(-c2ccc(C(=O)NCCC(=O)OCC)nc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)c1ccc(CNc2ccc(-c3ccc(F)cc3)cc2)c(-c2ccc(C(=O)NCCC(=O)O)nc2)c1
Temperature: 25 °C

Procedure:
A 3M aqueous NaOH solution (0.32 mL, 0.97 mmol) was added to a THF (1.0 mL) and MeOH (1.5 mL) solution of ethyl 3-(5-(2-(((4′-fluoro-[1,1′-biphenyl]-4-yl)amino)methyl)-5-(prop-1-en-2-yl)phenyl)picolinamido)propanoate (87 mg, 0.16 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to give the title compound.
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].O1CCCC1>C(O)C.[C].[Pd]>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COC(=O)c1cccc(C=CC#N)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cccc(CCC#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of the above-mentioned crude product of methyl 3-(2-cyanoethenyl)benzoate in ethanol (45 mL)/tetrahydrofuran (15 mL) was added 10% palladium-carbon (648 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 2 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→75/25), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (2.03 g, 88%) as a colorless oil.
Reaction SMILES: ClC1C=C(C2C=C(C([N:22]3C[CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=O)OC=2C2C=CC(F)=CC=2)C=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42](O)=[O:43])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42]([N:22]3[CH2:23][C:24](=[O:28])[NH:25][CH2:26]3)=[O:43])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)cc3)o2)CCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)c(-c3ccc(F)c(Cl)c3)o2)CN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 6 starting with the compound from Example 21A and the compound from Example 35A. 1.1 equivalents of the compound from Example 35A are used. 203 mg (60% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH3:12])=[O:4].[CH2:13](O)[CH:14]([OH:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][C:3]1([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=2[CH3:12])[O:16][CH:14]([CH3:15])[CH2:13][O:4]1
Reactant: CC(O)CO
Reactant: Cc1ccc(C)c(C(=O)CCl)c1
Solvent: Cc1ccccc1C
Product: Cc1ccc(C)c(C2(CCl)OCC(C)O2)c1
Reaction time: 1.5 h

Procedure:
A mixture of 36.5 g [0.2 mol] of 2-chloro-1-(2,5-dimethylphenyl)ethanone, 22.8 g [0.3 mol] of propylene glycol, 3.6 g [0.02 mol] of p-TsOH hydrate and 150 ml of xylene is heated to boiling with a water trap for about 1.5 hours. Part of the xylene is then distilled off, and the reaction mixture is extracted at room temperature twice with 100 ml of water each time. The organic phase is dried over sodium sulfate and concentrated in vacuo, and volatiles are distilled off up to about 50° C./0.2 mbar. 39.65 g of an orange-colored oil remain with, according to GC, 93.0% product (76.7% of theory).
Reaction SMILES: [CH2:1]([N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[Cl:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(O)C>[Cl-:13].[OH:8][CH2:7][CH2:6][N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCl
Reactant: CCCCN(CCO)CCCC
Solvent: CCO
Product: CCCC[N+](CCO)(CCCC)CCCC
Product: [Cl-]
Yield: 100 %

Procedure:
70 mmol of 2-(dibutylamino) ethanol, 75 mmol of 1-chlorobutane, and 50 g of ethanol were mixed under N2 atmosphere, and made to react at 80 degrees C. for 8 hours under reflux condition. The ethanol and extra 1-chlorobutane were distilled away therefrom by reducing pressure to produce 70 mmol of (2-hydroxyethyl)tributylammonium chloride.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N:13]([O-])=O.[Na+].C(O)C.O>C(O)(=O)C.[Zn]>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([O:11][CH3:12])[C:10]([NH2:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: COc1cc2cccc(Br)n2n1
Agent: [Na+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1nn2c(Br)cccc2c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.3 %

Procedure:
After dissolving 7-bromo-2-methoxypyrazolo[1,5-a]pyridine (1 g) in acetic acid (10 mL), an aqueous solution (5 mL) containing sodium nitrite (334 mg) was added and the mixture was stirred at room temperature for 20 minutes. After adding ethanol (60 mL) and water (30 mL) to the reaction mixture, zinc powder (1 g) was added and the mixture was heated and stirred at 60° C. for 30 minutes. The insoluble residue was filtered out, water was added, and extraction was performed with ethyl acetate. After washing the organic layer with brine, drying it over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (750 mg) was obtained from the n-hexane:ethyl acetate (3:1) fraction as brown crystals.