Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:26][N:25]=3)=[CH:18][CH:17]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6].CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:54][C:55]([F:58])([F:57])[F:56])(=O)=O>CC#N>[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:32][CH2:33][N:34]([CH2:54][C:55]([F:58])([F:57])[F:56])[CH2:35][CH2:36]4)=[CH:26][N:25]=3)=[CH:20][CH:21]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCN(CC(F)(F)F)CC4)cn3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a stirred solution of N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride (50 mg, 0.091 mmol) from Step 4 of Example 17 in 3 mL of CH3CN was added DIEA (32 mL, 0.18 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (21 mg, 0.18 mmol). The resulting mixture was then stirred at rt for 1 h, heated at 85° C. for 1 h. CH3CN was then evaporated under reduced pressure and the residue was taken up in 2 mL of DMF. To the reaction mixture was then added DIEA (32 μL, 0.18 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (21 mg, 0.18 mmol), and heated at 85° C. for 2 h. LC-MS indicated that the reaction was complete. Purification by reverse phase HPLC yielded N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yloxy)picolinamide (40 mg, 74%) as a white solid. LC-MS (ESI) m/z 597 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.59 (s, 1H), 8.77 (s, 1H), 8.36 (d, J=2.83 Hz, 1H), 8.08 (d, J=8.85 Hz, 1H), 7.81 (d, J=8.85 Hz, 2H), 7.67 (dd, J=2.83, 8.85 Hz, 1H), 7.42 (d, J=8.85 Hz, 2H), 6.79 (s, 1H), 4.73 (s, 2H), 4.65 (td, J=3.93, 8.15 Hz, 1H), 4.57 (s, 2H), 3.23 (q, J=10.24 Hz, 2H), 2.80-2.96 (m, 2H), 2.62 (t, J=9.42 Hz, 2H), 1.97 (br. s., 2H), 1.60-1.76 (m, 2H), 1.34 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13](C2C=CC=CC=2O)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:25]12[CH:31](SCC3C(C(OC)=O)=C(OC)C(Br)=CC=3)[CH:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2>>[CH:25]12[CH:31]([S:13]([CH2:12][C:9]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:23][CH3:24])[C:2]([Br:1])=[CH:11][CH:10]=3)(=[O:14])=[O:15])[CH:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2
Reactant: COC(=O)c1c(CSC2C3CCC2CC3)ccc(Br)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2O)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)C2C3CCC2CC3)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 138, starting from methyl 6-(bicyclo[2.2.1]heptan-7-ylthiomethyl)-3-bromo-2-methoxybenzoate (Intermediate 182).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([CH2:32][OH:33])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:34]>CN(C)C=O.C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([CH:32]=[O:33])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:34]
Reactant: Cc1cc(CO)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C=O)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
To a solution of 3-[2-chloro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-phenyl]-5-hydroxymethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (15 mg) in N,N-dimethylformamide (1 mL) was added manganese(IV) oxide (0.3 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) to give the title compound (12 mg).
Reaction SMILES: N1C=CC(C(O)=O)=C1.[CH3:9][C:10]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[C:13]([CH3:19])[NH:12][C:11]=1C(OCC)=O.[OH-].[K+].C(O)(=O)C>C(O)C>[CH3:19][C:13]1[NH:12][CH:11]=[C:10]([CH3:9])[C:14]=1[C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: CCOC(=O)c1[nH]c(C)c(C(C)(C)C)c1C
Agent: O=C(O)c1cc[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c[nH]c(C)c1C(C)(C)C
Temperature: 180 °C

Procedure:
A procedure reported for the decarboxylation of derivatives of pyrrole-3-carboxylic acid was adapted from Clue, J. Org. Chem. 19:266, 1954. A solution of ethyl 3,5-dimethyl-4-tert-butylpyrrole-2-carboxylate 4g (3.0 g, 0.01 mol) and potassium hydroxide (6.0 g, 0.11 mol) in ethanol (50 ml) was heated at 80° C. for 4 h, combined with ice water (200 ml), and made slightlyacidic by the addition of acetic acid to bring about the precipitation of crude 3,5-dimethyl-4-tert-butylpyrrole-2-carboxylic acid 4 (W=CH3, X=C(CH3)3, R=CO2H). The crude acid was combined with ethanolamine (5 g), heated at 180° C. for 1 h, and diluted with ice water (100 ml) to bring about the precipitation of2,4-dimethyl-3-tert-butylpyrrole 5g as a colorless solid, 1.6 g (79%), mp 70°-71° C. (lit. 69°-71° C.) after drying in avacuum for 24 h; 1H NMR (CDCl3): δ 7.60 (br, 1H), 6.30 (s,1H), 2.25 (s, 3H), 2.15 (s, 3H), 1.28 (s, 9H). By the phosphoric acid method the pyrrole ester 4g was converted to 2,4-dimethylpyrrole 5a.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[CH:3][C:2]=1[CH3:8].C([Li])CCC.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17]>C1COCC1>[CH2:16]([O:15][C:14](=[O:18])[CH2:8][C:2]1[CH:3]=[CH:4][C:5]([CH3:7])=[CH:6][N:1]=1)[CH3:17]
Reactant: Cc1ccc(C)nc1
Reactant: CCOC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(C)cn1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-lutidine (540 mg, 5.05 mM) in 10 ml of THF at -10° C. was added 2.5M n-butyllithium solution (2.0 ml, 5.00 mM). The resulting mixture was stirred for 30 minutes while allowing the temperature to rise to 0° C. The reaction was cooled to -50° C. and diethyl carbonate (0.61 ml, 5.00 mM) was added and the reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated NH4Cl solution and extracted into EtOAc. The resulting organic layer was washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The residue was chromatographed on silica gel using 30% EtOAc/hexanes as the eluant to yield the title compound (43).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[N:11][N:10]([CH3:13])[C:9](=[O:14])[CH:8]=1.[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:21][O:22][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([CH:23]3[CH2:24][CH2:25][N:26]([CH2:3][CH2:4][CH2:5][NH:6][C:7]4[CH:12]=[N:11][N:10]([CH3:13])[C:9](=[O:14])[CH:8]=4)[CH2:27][CH2:28]3)=[N:21][O:22][C:18]=2[CH:17]=1
Reactant: Cn1ncc(NCCCCl)cc1=O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cn1ncc(NCCCN2CCC(c3noc4cc(F)ccc34)CC2)cc1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.1 %

Procedure:
4.12 g (17.3 millimoles) of 5-(3-chloropropylamino)-2-methyl-2H-pyridazine-3-one-hydrochloride, 100 ml of acetonitrile, 4.29 g (19.5 millimoles) of 6-fluoro-3-piperidine-4-yl-1,2-benzisoxazole, 7.24 g of potassium carbonate and 0.39 g of potassium iodide are admixed. The reaction mixture is heated to boiling under stirring for 24 hours, cooled to room temperature and filtered. To the product 100 ml of water are added and the aqueous phase is extracted five times with 90 ml of dichloro methane each. The united organic phases are washed with a saturated sodium chloride solution; dried over magnesium sulfate and filtered over activated charcoal. The organic filtrate is evaporated in vacuo. The residue is suspended in diethyl ether and filtered. The crude product is recrystallized from acetonitrile. Thus 4.14 g of the desired compound are obtained. Yield 62.2%. M.p.: 163–165° C.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]>CN(C=O)C.[Cu]>[CH3:8][C:7]1[C:6]([CH3:9])=[CH:5][CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1ccc([N+](=O)[O-])c(I)c1C
Agent: [Cu]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(-c2c([N+](=O)[O-])ccc(C)c2C)c1C
Yield: 9.6 %

Procedure:
In 20 ml of a DMF solvent, 5.5 g (20 mmol) of 2-iodo-3,4-dimethyl-1-nitrobenzene and 10 g (155 mmol) of copper powder were heated at 150° C. for 48 hours. After the completion of the reaction, copper powder was removed by filtration and thereafter, the resultant was extracted using ethyl acetate, dried/concentrated, and then purified by column chromatography (ethyl acetate:hexane=1:10) to obtain 2.9 g (0.96 mmol) of 2,3,2′,3′-tetramethyl-6,6′-dinitrobiphenyl (34) (yield was 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:14]=2[CH3:22])[S:11][CH:12]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(O)(=O)C.C(OCC)(=O)C>[CH3:22][C:14]1[CH:15]=[CH:16][C:17]([NH:19][C:23](=[O:25])[CH3:24])=[CH:18][C:13]=1[C:10]1[S:11][CH:12]=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccncc1-c1csc(-c2cc([N+](=O)[O-])ccc2C)n1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C)c(-c2nc(-c3cnccc3C)cs2)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
4-Methyl-3-[2-(2-methyl-5-nitrophenyl)-1,3-thiazol-4-yl]pyridine (100 mg) and reduced iron (180 mg) were suspended in acetic acid (2 ml)-acetic anhydride (0.04 ml) and the mixture was stirred at 70° C. for 4 hrs. The reaction mixture was diluted with ethyl acetate and the insoluble material was filtered off. The organic layer was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was separated and concentrated by drying. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1–0:1) for purification. Recrystallization from ethyl acetate gave the title compound (43 mg) as colorless powder crystals.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([C:6]2[C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[O:3][C:2]=2[CH3:1])=[O:20])=[CH:13][CH:14]=1
Reactant: Cc1cc2ccccc2o1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)c2c(C)oc3ccccc23)cc1

Procedure:
2-Methylbenzofuran (7.25 g., 0.055 mol.) was acylated with 15.7 g. (0.092 mol.) of p-anisoyl chloride according to the procedure described in Example 1 to give 3-(4-methoxybenzoyl)-2-methylbenzofuran. Demethylation as previously described gives 3-(4-hydroxybenzoyl)-2-methylbenzofuran.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=2)=[CH:4][CH:3]=1.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])[CH:18]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1CC1
Reactant: Nc1ccc2nc(NC3CCc4ccc(F)cc43)ccc2c1
Product: O=C(Nc1ccc2nc(NC3CCc4ccc(F)cc43)ccc2c1)C1CC1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(6-fluoro-indan-1-yl)-quinoline-2,6-diamine and cyclopropanecarboxylic acid; MS: m/e=362.4 (M+H−).
Reaction SMILES: [CH:1](=[C:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5].II>>[CH2:1]([C:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC=C1CCCC1=O
Agent: II
Product: CCCCCC1=CCCC1=O
Yield: 78 %

Procedure:
In a 100 ml four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were placed 2-pentylidenecyclopentanone (50 g) synthesized in Reference Example 4 and iodine (5 mg), followed by 3 hours of the reaction at 180° C. The crude product (50 g) was distilled without any treatment using a Claisen distillation apparatus to obtain 39 g of 2-pentyl-2-cyclopentenone (boiling point: 105° C./933 Pa; GC purity: 98.3%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][C@@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=1)[C@@H:9]1[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:28][C:24]1[C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)=[C:22]([C@@H:8]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
(R)-tert-butyl 2-((S)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (202 mg, 0.42 mmol) was dissolved in 20% TFA in CH2Cl2 (8 mL) and stirred for about 1 h at rt. The mixture was neutralized with satd aq NaHCO3 and the product was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give N-(2-((S)-(6-fluoro-3′-methylbiphenyl-2-yl)((R)-morpholin-2-yl)methoxy)ethyl)acetamide (130 mg, 82%). 1H NMR (300 MHz, CDCl3): δ=1.98 (s, 3 H), 2.39 (s, 3 H), 2.90˜3.3 (m, 6 H), 3.31˜3.41 (m, 2 H), 3.6˜4.0 (m, 3 H), 4.33 (d, 1 H), 6.56˜6.57 (s, 1 H), 6.97˜7.14 (m, 3 H), 7.27˜7.40 (m, 4 H), 9.40˜9.55 (s, 1H). MS (E/Z): 387 (M+H+).
Reaction SMILES: [OH-].[Li+].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[CH2:5][CH2:4]1.C1COCC1.O.Cl>CS(C)=O>[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(OCCN2CCOCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Lithium hydroxide (hydrated) (0.59 g, 14.1 mmol) was added to a solution of methyl 4-(2-morpholinoethoxy)benzoate 193 (1.25 g, 4.7 mmol) in a 1:1 mixture of THF-water (20 mL). The reaction mixture was stirred at rt overnight then acidified with 1N HCl to pH 2, solvent was evaporated and the residue was lyophilized to provide crude 194 (1.66 g, >>100% Yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 7.88 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 4.53 (m, 2H), 3.89 (m, 4H), 3.53 (m, 2H), 3.26 to 3.14 (m, 4H). MS: 251.12 (calc), 252.1 (obs).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH2:6][N:5]([C:8]3[C:9]([Cl:18])=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([NH2:14])[CH:13]=3)[CH2:4]2)[CH2:2]1>[Ni].CCOC(C)=O>[CH2:1]1[C:3]2([CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[CH:10][C:9]=3[Cl:18])[CH2:4]2)[CH2:2]1
Reactant: Nc1cc(N2CCC3(CC3)C2)c(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(N2CCC3(CC3)C2)cc1N
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 5-(5-aza-spiro[2.4]hept-5-yl)-4-chloro-2-nitro-phenylamine (550 mg, 2.1 mmol), EtOAc (20 mL) and Ra—Ni (150 mg) was stirred for 21 h at RT under a hydrogen atmosphere (3 bar). After addition of further catalyst the hydrogenation was continued at rt for 7 h. The catalyst was removed by filtration. The filtrate was acidified with 1.25 M HCl in EtOH (6 mL) and concentrated to give the sub-title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:3]=1.Cl.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29]2[N:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[CH2:23]1>>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([NH:28][CH:24]2[CH2:25][CH2:26][CH2:27][N:22]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[N:3]=3)[CH2:23]2)=[N:34][CH:33]=1)#[N:36]
Reactant: N#Cc1c(C(F)(F)F)cc(-c2ccc(F)cc2)nc1Cl
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Agent: Cl
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)c3C#N)C2)nc1

Procedure:
Analogously to the preparation of Example 20, 60 mg (0.2 mmol) of 2-chloro-6-(4-fluorophenyl)-4-(trifluoromethyl)pyridine-3-carbonitrile and 59.5 mg (0.24 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 10A) were used to obtain, after separation by means of preparative HPLC (method 13), 61 mg (66% of theory) of the product in solid form.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][OH:22])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+].O1CCCC1>CO.C(#N)C>[NH2:29][CH:12]([C:10]1[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][OH:22])[CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCCC(CO)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCCC(CO)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[3-(hydroxymethyl)piperidin-1-yl]quinolin-7-yl}ethanone (0.0235 g, 0.0737 mmol) and ammonium acetate (0.0568 g, 0.737 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.184 mL, 0.184 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H23ClN3O (M+H)+: m/z=320.2; Found: 320.2.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[Ca].[OH-:10].[Na+].[OH-]>>[C:1]([OH:8])(=[O:7])[CH:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:10]
Reactant: [OH-]
Reactant: O=C([O-])/C=C\C(=O)[O-]
Agent: [Ca]
Agent: [Na+]
Product: O=C(O)CC(O)C(=O)O

Procedure:
A preferred procedure to be followed when using calcium carbonate as a calcium source, i.e., as a calcium starting-material, in the instant process is as follows; preformed malic acid, sodium hydroxide, a maleate reactant selected from maleic anhydride, maleic acid and mixtures thereof, and a calcium reactant selected from calcium carbonate and mixtures thereof with calcium hydroxide are reacted according to the immediately consecutive steps: (i) mixing calcium carbonate, water, malic acid and a proportion of said maleate reactant, allowing complete evolution of carbon dioxide and forming an acidic mixture; (ii) adding sodium hydroxide or a mixture thereof with calcium hydroxide, to the acidic mixture of step (i), forming a sodium cation-containing alkaline mixture; (iii) in a period of duration about 1 hour or less, adding the remainder of said maleate reactant to the stirred sodium cation-containing alkaline mixture of step (ii), at temperatures in the range from about 75° C. to about 110° C., having at the end of the step (iii) addition a net hydroxide excess MOH ; (iv) in a period of duration about 1 hour or less, cooling the mixture formed in step (iii) to a temperature in the range from about 35° C. to about 45° C.; (v) at said temperature in the range from about 35° C. to about 45° C., continuing to react the mixture of step (iv); the duration of step (v) being from about 48 hours to about 240 hours, whereby a crude product having a HPLC yield of at least 80% 2,2'-oxodisuccinate is secured; and (vi) diluting the product of step (v) with water and precipitating calcium carbonate therefrom; thereby arresting the step (iv) reaction and depleting the level of calcium; provided that in step (iii) and (iv) together; the total time at any temperature above about 100° C. does not exceed about 15 minutes; the total time at any temperature above about 90° C. does not exceed about 30 minutes; the total time at any temperature above about 80° C. does not exceed about 2 hours; the total time at any temperature above about 70° C. does not exceed about 6 hours; and the total time at any temperature above about 65° C. does not exceed about 12 hours; and provided that for each mole of preformed malic acid reacted, the total molar amount of maleate reactant is about 1.1 to about 1.6 moles; the total molar amount of calcium reactant, is from about 0.9 to about 1.65 moles; the total molar amount of sodium hydroxide, is from about 0.92 to about 3.7 moles; the net hydroxide excess in step (iii), MOH, is from about 0.02 to about 0.3 moles; and further provided that for each mole of preformed malic acid reacted (i.e., charged in the reactor), the total net amount of water added in steps (i), (ii) and (iii) together, allowing for evaporation losses, is no less than about 189 grams and no more than about 282 grams.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]1)=[O:14])[CH2:6][CH2:5]2.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH:21]1([N:18]2[CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][N:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([N:25]5[CH:29]=[CH:28][CH:27]=[N:26]5)[CH:3]=4)[CH2:8]3)[CH2:16][CH2:17]2)[CH2:24][CH2:23][CH2:22]1
Reactant: c1cn[nH]c1
Reactant: O=C(CN1CCc2cc(Br)ccc2C1)N1CCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CN1CCc2cc(-n3cccn3)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 120 °C

Procedure:
A mixture of 6-bromo-2-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinoline (120 mg, 0.307 mmol), pyrazole (31 mg, 0.46 mmol), Cu2O (4 mg, 0.03 mmol), salicylaldoxime (16 mg, 0.12 mmol) and Cs2CO3 (300 mg, 0.92 mmol) in CH3CN (8 mL) is degassed by argon and heated at 120° C. in a sealed tube overnight. EtOAc (10 mL) is added and the mixture is filtered. The organic layer is washed with brine (10 mL) and dried. Purification of the residue by PTLC gives title compound as a light yellow solid. MS (M+1): 380.2; 1H NMR (δ, CDCl3): 7.88 (d, 1H), 7.70 (d, 1H), 7.47 (d, 1H), 7.41 (dd, 1H), 7.08 (d, 1H), 6.45 (dd, 1H), 3.71 (s, 2H), 3.65 (t, 4H), 3.38 (s, 2H), 2.96 (t, 2H), 2.81 (t, 2H), 2.63-2.72 (m, 1H), 2.28 (q, 4H), 1.64-2.08 (m, 6H).