Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=3)[S:13][C:6]=12.[BH4-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of the nitro compound 8 (1.50 g, 4.05 mmol) and NiCl2.6H2O (2.02 g, 8.52 mmol) in MeOH/THF (45 mL/68 mL) at 0° C. was added NaBH4 (0.618 g, 16.3 mmol) portion wise with vigorous stirring. The reaction mixture was stirred for 30 minutes at 0° C. and concentrated under reduced pressure. The resultant black residue was suspended in 1M HCl (10 mL) and the mixture was basified (pH˜11) with cone. NH4OH. The cloudy suspension was filtered; the solid residue was separated, washed with water and dried under reduced pressure to afford the title compound 9 as a brown solid (0.73 g, 52% yield), which was used in the next step without further purification. MS (m/z): 341.1 (M+H).
Reaction SMILES: O=S(Cl)Cl.[CH:5]1([NH:11][C:12]2([CH2:17]Cl)[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.ClCCN.[CH3:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[N:33]=[C:34]=[O:35]>>[CH:5]1([N:11]2[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:17][O:35][C:34]2=[N:33][C:25]2[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=2[CH3:23])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Reactant: ClCC1(NC2CCCCC2)CCCC1
Agent: NCCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1OCC2(CCCC2)N1C1CCCCC1

Procedure:
1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B1c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. The hydroxyethylamine was reacted with cyclohexanone according to Method B4a, Step 1 to give 6-aza-13-oxadispiro[4.1.5.2]tetradecane. The oxazolidine was reduced according to Method B4a, Step 2 to give 1-(cyclohexylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to 1-(cyclohexylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane.
Reaction SMILES: [C:1]([O:5][C:6]([C:9]([CH2:12][CH2:13]I)([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2].CNC=[O:18].O>CCOCC>[C:1]([O:5][C:6]([C:9]([CH2:12][CH2:13][OH:18])([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2]
Reactant: CNC=O
Reactant: FC(F)(F)OC(F)(F)C(F)(F)CCI
Solvent: O
Solvent: CCOCC
Product: OCCC(F)(F)C(F)(F)OC(F)(F)F
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
A mixture of CF3OCF2CF2CH2CH2I, (92 g, 0.27 mol) and N-methyl-formamide (119 mL), was heated to 150° C. for 26 hours. Then the reaction was cooled to 100° C., followed by the addition of water to separate the crude ester. Ethyl alcohol (30 mL) and p-toluene sulfonic acid (1.03 g) were added to the crude ester, and the reaction was stirred at 70° C. for 15 minutes. Then ethyl formate and ethyl alcohol were distilled out to give a crude product. The crude product was dissolved in ether, washed with aqueous sodium sulfite, water, and brine in turn, then dried over magnesium sulfate. The product was then distilled to give 44 g of CF3OCF2CF2CH2CH2OH (compound B1) in 71% yield.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:18]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1

Procedure:
12.7 Grams (0.0917 mol) of p-hydroxybenzoic acid was added to 150 ml of dichloromethane, and to this suspension was added 10.2 g (0.0917 mol) of triethylamine. The mixture was stirred until a homogeneous solution was formed. 19.7 Grams (0.096 mol) of undecanoyl chloride was added to the solution at such a rate that the dichloromethane was not refluxed. Then, 1.0 g (0.0085 mol) of 4-dimethylaminopyridine was added, and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to the reaction mixture and the mixture was subjected to extraction with ether. The ether was distilled off, and the resultant crude product was washed with hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:19][C:18]2[CH:20]=[CH:21][C:15]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-methoxybenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:36]=[CH:35][C:23]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33]C)=[O:32])[CH2:27][CH2:26]3)=[CH:22][CH:21]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:21]=[CH:22][C:23]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]3)=[CH:35][CH:36]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1
Reactant: COC(=O)C1CCN(Cc2ccc(C3=C/C(=C4\C(=O)Nc5cc(F)c(F)cc54)OC3(C)C)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(CN2CCC(C(=O)O)CC2)cc1
Temperature: 50 °C

Procedure:
To a suspension of methyl 1-{4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylate (50 mg, 0.10 mmol) in MeOH (5 mL), was added 1M NaOH (1 mL). The mixture was heated in 50° C. bath for 1 hour, poured into 50 mL of water and neutralized with 0.5M HCl to pH 7. The precipitates were filtered, washed with water, and dried in vacuo to give 1-{4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylic acid as a yellow solid. Yield: 9 mg, 19%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:12])([C:10]#[CH:11])[CH3:9])[CH:4]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:1][CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]([OH:12])([C:10]#[CH:11])[CH3:9])[CH:4]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CC(C)(O)c1cc(CO)on1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(C)(O)c1cc(COS(=O)(=O)c2ccc(C)cc2)on1
Temperature: 25 °C

Procedure:
To a solution of 2-[5-(hydroxymethyl)isoxazol-3-yl]but-3-yn-2-ol (500 mg, 2.99 mmol) in DCM (5 mL) at 0° C. under an atmosphere of nitrogen was introduced triethylamine (333 mg, 3.29 mmol) and p-toluenesulfonyl chloride (627 mg, 3.29 mmol) in one portion. After warming to RT for 3 hr, the reaction mixture was diluted with DCM (10 mL) and washed with brine (5 mL). The organic extract was dried (Na2SO4), filtered and the filtrate adsorbed onto silica gel in vacuo. Purification by silica gel flash column chromatography (heptane/EtOAc gradient of increasing polarity) furnished the title compound as a colorless oil: 1H NMR (500 MHz, CDCl3) delta 1.84 (3H, s), 2.26 (3H, s), 2.66 (1H, s), 2.86 (1H, br. s), 5.14 (2H, s), 6.41 (1H, s), 7.36 (2H, d, J=8.1 Hz), 7.80 (2H, d, J=8.1 Hz); LC-MS: m/z=+321.9 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][CH:15]1[CH2:19][CH2:18][C:17]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16]1.N1C=CC=CC=1>O>[CH2:16]1[C:17]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:18][CH2:19][CH:15]1[NH:14][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NC1CCC2(CCCCC2)C1
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC1CCC2(CCCCC2)C1)c1cnc2ccccc2n1
Yield: 84.3 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 2-aminospiro(4.5)decane (150 mg, 0.79 mmol), pyridine (5 mL), and water (100 mL) yielding 206 mg (74%) of (236):
Reaction SMILES: [CH3:1][O-].[Na+].[SH:4][C:5]1[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]([C:15]([O:17][CH2:18]C)=[O:16])=[C:8]([C:10]([O:12][CH2:13]C)=[O:11])[N:9]=1.IC>CO>[CH3:1][S:4][C:5]1[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]([C:15]([O:17][CH3:18])=[O:16])=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1nc(S)n(-c2ccccc2)c1C(=O)OCC
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COC(=O)c1nc(SC)n(-c2ccccc2)c1C(=O)OC
Reaction time: 8 h
Yield: 80 %

Procedure:
Sodium methoxide (1.8 g; 0.033 mol) was slowly added to a suspension of diethyl 2-mercapto-1-phenyl-4,5-imidazoledicarboxylate (10 g; 0.031 mol) in absolute methanol (100 mL) then iodomethane (5 g; 0.035 mol) was added. The mixture was allowed to stir overnight, additional iodomethane (5 g; 0.035 mol) was added and the mixture was stirred for 1 hour. The methanol was removed in vacuo and ice-cold water was added to the residue. The mixture was filtered, the collected solid was washed with water and dried to give 7.6 g (80%) of pure dimethyl 2-(methylthio)-1-phenyl-4,5-imidazoledicarboxylate (mp 121°-122° C).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.O=S(Cl)[Cl:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)nc1
Product: O=C(Cl)c1ccc(Cl)nc1

Procedure:
Starting from 250 g 6-chloro-nicotinic acid and 850 ml SOCl2, and using the working conditions as in Ex. 1a, there is obtained 243 g 6-chloronicotinoyl chloride, m.p. 49°-51° C.; b.p. 75° C./0,05 mm.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[O:11]1[C:13]2([CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:12]1>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:12][C:13]2([OH:11])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: C1CC2(CCO1)CO2
Product: Cc1cc(OCC2(O)CCOCC2)cc(C)c1Br

Procedure:
The title compound is prepared from 4-bromo-3,5-dimethylphenol and 1,6-dioxaspiro[2.5]octane following a procedure analogous to that described in Step 3 of Intermediate 2. LC (method 7): tR=1.04 min; Mass spectrum (ESI−): m/z=313 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:5]1[CH:6]=[CH:7][C:2]([O:1][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.9 %

Procedure:
To a solution of 4-hydroxypyridine (4.42 g, 45.8 mmol) and 1-fluoro-4-nitrobenzene (4.89 mL, 45.8 mmol) in anhydrous DMF (50 mL) was added anhydrous K2CO3 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temperature with stirring for 24 h, cooled to room temperature and poured in water (300 mL). The solid that separated was filtered, washed with water and dried well under high vacuum to yield 8.9 g (90%) of desired product, 4-(4-pyridinyloxy)-1-nitrobenzene. 1H NMR (CDCl3, 300 MHz): δ 8.36 (d, 2H, J=9.0 Hz), 8.11 (d, 2H, J=8.1 Hz), 7.83 (d, 2H, J=9.0 Hz), 6.27 (d, 2H, J=7.8 Hz); LCMS (m/z): 217 (MH+).
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].N1C2C(=CC=CN=2)C(=O)C1=O.Cl.[F:25][CH2:26][CH2:27][O:28][NH2:29]>CS(C)=O>[F:25][CH2:26][CH2:27][O:28][N:29]=[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11]
Reactant: NOCCF
Reactant: O=C1Nc2ncccc2C1(Br)Br
Agent: Cl
Agent: O=C1Nc2ncccc2C1=O
Solvent: CS(C)=O
Product: O=C1Nc2ncccc2C1=NOCCF
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A solution of 3,3-dibromo 7-aza oxindole (300 mg, 1.03 mmol) in DMSO (25 mL) was heated at 95° C. under house vacuum for 6.5 hours. The solution containing the corresponding 7-aza isatin was cooled to room temperature, followed by the addition O-(2-fluoro-ethyl)-hydroxylamine hydrochloride (prepared as described by Ishikawa et al J. Antibiot., 2000, 53, 1071) (131 mg, 1.13 mmol). After stirring for 1 hour at room temperature the mixture was quenched with water and extracted with ethyl acetate (6×25 mL). The combined organic phases were washed with brine and dried over MgSO4. The solvent was removed in vacuo and the residue purified by flash column chromatography (gradient, 2% MeOH in methylene chloride to 3%) to give 1H-pyrrolo[2,3-b]pyridine-2,3-dione 3-[O-(2-fluoro-ethyl)-oxime] (200 mg, 93%) as an orange solid that was further purified by trituration from diethyl ether-DCM (1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[H-].[Na+].[CH3:16][O:17][C:18]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][C:29](SC)=[N:30][C:31]=3[C:22]=2[CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH3:16][O:17][C:18]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][C:29]([NH:6][C:5]4[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:30][C:31]=3[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc2c1CCc1cnc(SC)nc1-2
Reactant: COc1cc(N)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1CCc1cnc(Nc3cc(OC)c(OC)c(OC)c3)nc1-2
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
To a solution of 3,4,5-trimethoxyaniline (0.401 g) in tetrahydrofuran at room temperature under nitrogen was added sodium hydride (60% oil dispersion, 0.16 g) in portions over 2-3 minutes. The mixture was stirred for 15 minutes, and then 7-methoxy-2-methylthio-5,6-dihydrobenzo[h]quinazoline (0.258 g) was added, and the mixture was refluxed for 4 hours. The reaction mixture was poured into 300 ml of water, and the resulting yellow precipitate filtered off, washed with pentane, and dried under vacuum, giving 7-methoxy-2-(3,4,5-trimethoxyanilino)-5,6-dihydrobenzo[h]quinazoline (0.3042 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(N)=O
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C(N)=O
Yield: 95 %

Procedure:
1.0 g (4.05 mMol) 6-Chloro-4-o-tolyl-nicotinamide in 9.0 ml 1-methyl-piperazine was heated to 100° C. for 2 hours. The excess N-methyl-piperazine was removed under high vacuum and the residue was filtered on silica gel (eluent: dichloromethane) to yield 1.2 g (95%) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide as a light yellow crystalline foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:30][C:31]([C:33]2[C:42]([NH:43]C(=O)OCC3C=CC=CC=3)=[CH:41][C:40]3[C:35](=[CH:36][C:37]([C:54]4[CH2:55][CH2:56][N:57]([CH3:60])[CH2:58][CH:59]=4)=[CH:38][CH:39]=3)[N:34]=2)=[O:32])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:43][C:42]1[C:33]([C:31]([NH:30][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:24]=2[N:11]2[CH2:12][C@H:13]([CH3:23])[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]2)=[O:32])=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([CH:54]1[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]1)[CH:36]=2
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4=CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4CCN(C)CC4)ccc3cc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 66.6 %

Procedure:
A mixture of benzyl [2-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)pyridin-3-yl]amino}carbonyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl]carbamate (0.013 g, 0.016 mmol) in 1.5 mL of MeOH was hydrogenated in the presence of 10% Pd on carbon (10 mg) under a balloon of hydrogen at room temperature for 1 h. The reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to yield the protected intermediate tert-butyl ((3R,4R,5S)-1-[3-({[3-amino-7-(1-methylpiperidin-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.0075 g, 68%). LCMS calc. for C38H58N7O4Si [M+H]+: m/z=704.4. found: 704.6.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[F:20].[CH3:21]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[F:20][C:3]1[C:2]2[N:1]=[CH:21][O:11][C:10]=2[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]
Reactant: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2F)c1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1F
Reaction time: 1 h
Yield: 1842.8 %

Procedure:
To a solution of 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxy benzoic acid (7.58 g, 27.05 mmol) in trimethyl orthoformate (50 mL) was added p-TsOH (0.23 g, 1.35 mmol). The reaction mixture was stirred for 1 h and treated with water (200 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (7.22 g, 82.7% yield for two steps). 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.14 (m, 1H), 7.05 (m, 2H), 6.86 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])O.[Na+]>C1COCC1>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:32][CH2:31]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCC(O)CC4)cc2)CC3)cc1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
In THF (10 ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (300 mg), and to the mixture was added 4-hydroxypiperidine (235 mg). The mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-[4-(4-hydroxypiperidinomethyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 49) (271 mg) as colorless crystals.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:21])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(COc2ccccc2)[nH]n1
Yield: 54.7 %

Procedure:
Hydrazine hydrate (0.197 mL, 4.06 mmol) was added to a stirring room temperature solution of 40 (1.0163 g, 4.06 mmol) in EtOH (4.1 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 92:4:4 Hexanes:CH2Cl2: 2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.5474 g (54.7%) of 41. 1H (CDCl3, 400 MHz): δ 12.12 (1H, broad s), 7.28 (2H, t, J=7.8 Hz), 7.01-6.94 (3H, m), 6.91 (1H, s), 5.17 (2H, s), 4.36 (2H, q, J=7.0 Hz), 1.36 (3H, t, J=7.1 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 158.11, 129.48, 121.26, 114.71, 107.83, 62.61, 61.31, 14.17 ppm. HPLC: 9.505 min.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[N:9]=[CH:8][C:7]=1[C:21]([NH:23][C:24]1[CH:25]=[N:26][C:27]([C:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=2)=[C:28]([CH3:30])[CH:29]=1)=[O:22].O>N1C=CC=CC=1>[C:1]([N:34]1[CH2:35][CH:36]=[C:31]([C:27]2[N:26]=[CH:25][C:24]([NH:23][C:21]([C:7]3[CH:8]=[N:9][N:10]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=4)[C:6]=3[CH3:5])=[O:22])=[CH:29][C:28]=2[CH3:30])[CH2:32][CH2:33]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1CC=C(c2ncc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cc2C)CC1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Acetyl chloride (50 μl) was added to a solution of 5-methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (300 mg) described in Reference Example 170 in pyridine (3.4 ml), stirred at 40° C. for six hours. Acetyl chloride (50 μl) was added and stirred for two hours, and then, Acetyl chloride (50 μl) was added and stirred for six hours. Water was added to the reaction solution and the precipitated solid was washed with ethanol and water to give the titled compound (283 mg) as a pale yellow solid.