Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH2:2]([C:4]1[N:13]=[C:12]([CH2:14][CH3:15])[CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:54]([O:56]CC)=O)[C:8](=[O:53])[N:9]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]=[N:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:33]=2)=[CH:19][CH:18]=1)[CH3:3]>CO.ClCCl>[CH2:2]([C:4]1[N:13]=[C:12]([CH2:14][CH3:15])[CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:54]([NH2:1])=[O:56])[C:8](=[O:53])[N:9]2[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]=[N:31][N:32]([C:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:33]=2)=[CH:21][CH:22]=1)[CH3:3]
Reactant: CCOC(=O)c1cc2c(CC)nc(CC)cc2n(Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c1=O
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: CCc1cc2c(cc(C(N)=O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Reaction time: 72 h

Procedure:
Concentrated aqueous ammonia solution (d 0.88 ) was added dropwise to a solution of ethyl 5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxylate (600 mg) in a mixture of methanol (7 ml) and dichloromethane (1.5 ml) until the solution became cloudy. Dichloromethane (2 ml) was added to give a clear solution and the mixture was stirred for 3 days. Volatile material was then removed by evaporation to give 5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxamide as a solid (500 mg), which was used without further purification or characterisation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>CN(C)C=O>[CH3:32][S:33]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(NS(C)(=O)=O)cc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide (0.035 g, 0.103 mmol), pyridine (0.017 mL, 0.207 mmol) and catalytic N,N-dimethylaminopyridine in dimethylformamide (0.7 mL) was cooled to 0° C. Methanesulfonyl chloride (0.014 g, 0.126 mmol) was added and the reaction solution was allowed to stir at room temperature for 2 hours. The reaction mixture was concentrated and purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.74 (s, 1H), 8.54 (s, 1H), 8.26 (t, J=5.6 Hz, 1H), 7.74-7.78 (m, 2H), 7.63-7.66 (m, 2H), 7.32 (d, J=8.1 Hz, 1H), 7.14-7.20 (m, 2H), 4.73-4.76 (m, 4H), 3.15-3.25 (m, 2H), 2.98 (s, 3H), 1.45-1.62 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 417 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18].O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:15][C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])=[C:4]([CH:9]=1)[C:3]([OH:23])=[O:2])(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1OCC(F)(F)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(OCC(F)(F)C(F)(F)F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To 5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acid methyl ester (414 mg) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (72 mg) in water (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After such time 1.72 mL of 1N aqueous hydrochloric acid solution was added. The reaction mixture was then concentrated in vacuo, and the resulting precipitate was then washed several times with water to yield the title compound as a white solid (367 mg). MS (m/e): 347.1 (M−H, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=C(O)/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 78.4 %

Procedure:
As in Example 115, (E)-5,5-bis(4-fluorophenyl)-2,4-pentadienoic acid (23.75 g) and 4-nitrophenol (12.7 g) in dichloromethane (250 mL) was treated with 1,3-dicyclohexylcarbodiimide (17.12 g). The mixture was stirred at 0°-5° C. for 60 minutes and then at room temperature for 1 hour. After the usual work up, the crude product was crystallized from 2-propanol to give 26.5 g of (E)-5,5-bis (4-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester mp 112°-114° C. Recrystallization of a portion from the same solvent yielded the analytical sample, mp 112.5°-114° C. Anal. Calculated for C23H15F2NO4 :C, 67.81; H, 3.71; N, 3.44; F, 9.33 Found: C, 67.76; H, 3.77; N, 3.48; F, 9.11.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30]([OH:32])=O)=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH2:42]([NH2:45])[CH:43]=[CH2:44]>C1COCC1>[CH2:42]([NH:45][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C:9]([CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:10][C:11]=2[CH:29]=1)=[O:32])[CH:43]=[CH2:44]
Reactant: C=CCN
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: C=CCNC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of allylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 482.2 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[C:16]([C:17]#[N:18])=[CH:15][C:14]([C:19](=[O:21])[CH3:20])=[C:13]([CH3:22])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)(Cl)Cl>C(O)C.C(O)(=O)C>[CH2:3]([O:10][C:11]1[C:16]([C:17]#[N:18])=[CH:15][C:14]([CH:19]([OH:21])[CH3:20])=[C:13]([CH3:22])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1cc(C#N)c(OCc2ccccc2)nc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1nc(OCc2ccccc2)c(C#N)cc1C(C)O

Procedure:
Sodium borohydride (0.35 g, 0.0092 mol) was added at room temperature to 2-benzyloxy-5-acetyl-6-methylpyridin-3-carbonitrile (2.44 g, 0.0092 mol) in ethanol (60 mL). After 2 hours chloroform was added plus a few drops of acetic acid. After washing with water and brine, the chloroform solution was evaporated to give product which was not purified further.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH:9]12[CH2:16][C:15](=O)[CH2:14][CH:13]1[CH2:12][C:11](=O)[CH2:10]2>>[OH:7][C:4]1[CH:5]=[CH:6][C:1]([C:11]2([C:1]3[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=3)[CH2:12][CH:13]3[CH:9]([CH2:16][C:15]([C:1]4[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=4)([C:1]4[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=4)[CH2:14]3)[CH2:10]2)=[CH:2][CH:3]=1
Reactant: O=C1CC2CC(=O)CC2C1
Reactant: O=C1CCC(=O)CC1
Product: Oc1ccc(C2(c3ccc(O)cc3)CC3CC(c4ccc(O)cc4)(c4ccc(O)cc4)CC3C2)cc1

Procedure:
Compound [I-c] was synthesized in the same manner as in Synthesis Example (5) except that 1,4-cyclohexanedione was replaced by 27.6 g (0.2 mole) of bicyclo[3.3.0]octane-3,7-dione (m.p. 85° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>>[N:1]1([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1ccc(I)cc1
Reactant: c1ccc2[nH]ccc2c1
Product: N#Cc1ccc(-n2ccc3ccccc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 4-iodobenzonitrile: ESMS m/e: 219.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([O-:27])=[O:26])[CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH2:13][N+:14]([O-:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C(N(C)C)=N.[CH2:43]=[O:44]>C(#N)C.C([O-])(O)=O.[Na+]>[C:31]([O:30][C:28]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH:13]([N+:14]([O-:16])=[O:15])[CH2:43][OH:44])[C:25]([O:27][CH2:12][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:26])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](C[N+](=O)[O-])c1cccc(F)c1F)C(=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@@H](c1cccc(F)c1F)C(CO)[N+](=O)[O-])C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of (5S)—N,N-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro-D-norleucinate (2.30 g, 3.975 mmol) and 1,1,3,3-tetramethylguanidine (46 mg, 0.40 mmol) in acetonitrile (20 mL) was added formaldehyde (0.15 mL, 37% aqueous solution). After stirring for 60 min, more formaldehyde (0.050 mL, 37% aqueous solution) was added. After stirring for an additional 60 min the mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (25%→75% ethyl acetate/hexanes) to give the title compound (1.44 g,). MS 409.1 (M+1−2Boc).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[Cl-].[CH3:8]OC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH2:41][CH2:42][CH3:43])[CH:36]=[C:35]2[CH2:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][C:46]=1[O:55][CH3:56])=O.Cl>O1CCCC1>[CH3:8][O:4][CH:2]=[CH:1][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH2:41][CH2:42][CH3:43])[CH:36]=[C:35]2[CH2:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][C:46]=1[O:55][CH3:56]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=COC)ccc21
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
A solution of potassium tert-butoxide (0.92 g) in dry tetrahydrofuran (10 ml) was added to a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (2.8 g) in tetrahydrofuran (30 ml) under a nitrogen atmosphere, at ice-bath temperature. After 15 min, a solution of methyl 4-(5-formyl-1-propylindol-3-ylmethyl)-3-methoxybenzoate (2.0 g) in tetrahydrofuran (20 ml) was added dropwise. After 30 min, the mixture was poured onto water, and acidified with 1M hydrochloric acid. The mixture was extracted with ethyl acetate (twice), and the extract washed with water, and brine, then dried (MgSO4) and evaporated. The residue was dissolved in methylene chloride, ether was added to give a precipitate, and the isolated precipitate was purified by flash chromatography, eluting with 85:15 hexane:ethyl acetate, to give methyl 4-[5-(2-methoxyvinyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (1.2 g, 56%) as an oil; partial NMR (300 MHz, DMSO-d6): 0.80(t, 3H, CH3), 1.70(m, 2H, CH2), 3.60 and 3.70(2xs, 3H, OCH3, E and Z isomers), 3.83(s, 3H, OCH3), 3.90(s, 3H, OCH3), 4.03(m, 4H, NCH2, ArCH2Ar').
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:23]2[CH:22]=[C:21]([N:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20]([O:37][CH3:38])=[CH:19][C:18]=2[O:17][C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH:15]=2)([OH:3])=[O:2].[C:44](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C)C(=O)C>[CH3:44][O:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:23]2[CH:22]=[C:21]([N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:20]([O:37][CH3:38])=[CH:19][C:18]=2[O:17][C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([N:39]([CH2:40][CH3:41])[CH2:42][CH3:43])[CH:15]=2)=[O:3]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc(OC)c(N(c3ccccc3)c3ccccc3)cc1C2c1ccccc1C(=O)O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN(CC)c1ccc2c(c1)Oc1cc(OC)c(N(c3ccccc3)c3ccccc3)cc1C2c1ccccc1C(=O)OC
Reaction time: 1 h

Procedure:
The carboxylic acid thus obtained and 10 parts of potassium carbonate were mixed in 200 cc of N,N-dimethylacetamide, to which 6.5 parts of dimethyl sulfate was added dropwise at 45° C. followed by stirring at the same temperature for one hour. The resulting reaction mixture was poured into 2 λ of water. Then, the deposited crystals were filtered off and recrystallized with methanol-ethylacetate to obtain 25.7 parts of 9- ( 2-methoxycarbonylphenyl ) -2-diphenylamino-3-methoxy-6-diethylaminoxanthene having a melting point of 117° to 119° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:28][NH2:29])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[CH3:25]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH2:28][C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:26])([F:27])[CH3:25])=[C:16]([Cl:15])[CH:17]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(F)(F)COc1ncc(CN)cc1Cl
Product: CC(F)(F)COc1ncc(CN2Cc3c(ccnc3Cl)C2=O)cc1Cl
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (925 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (945 mg, 3.39 mmol, Step-1 of Intermediate-1) and (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanamine (730 mg, 3.08 mmol, Amine-86) in a similar manner to Intermediate-2.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[C:8]([C@@H:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)[CH3:3]>CC(C)=O.O=[Mn]=O>[C:2]([C:4]1[CH:9]=[C:8]([C@@H:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=[O:1])[CH3:3]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C(C)O)c1
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C(C)=O)c1
Reaction time: 18 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid {(S)-1-[2-(1-hydroxy-ethyl)-pyridin-4-yl]-propyl}-amide (71 mg, 0.17 mmol) in acetone (4 mL) was added MnO2 (147 mg, 1.69 mmol). After 18 hours, the reaction was monitored by HPLC-MS indicating a 1:3 mixture of product to starting material. The mixture was filtered through diatomaceous earth rinsing with acetone (200 mL) and the filtrate was concentrated in vacuo. The residue was diluted with acetone (4 mL) and MnO2 (147 mg, 1.69 mmol) was added. After 5 hours, the reaction was filtered through diatomaceous earth, rinsed with acetone and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with using a gradient of 10-100% EtOAc in heptane to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-acetyl-pyridin-4-yl)-propyl]amide as a white solid.
Reaction SMILES: O.[OH-].[Ba+2].[OH-].C(O)C.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[O:18][CH2:19][CH2:20][NH:21]C(=O)C>C(OCC)(=O)C>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[O:18][CH2:19][CH2:20][NH2:21]
Reactant: CC(=O)NCCOc1ccc2ccccc2c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCCOc1ccc2ccccc2c1
Temperature: 50 °C
Yield: 103.2 %

Procedure:
A 3-neck round bottom flask was charged with water (50 mL) and barium hydroxide (12.27 g, 71.61 mmol) while stirring. The resulting slurry was charged with ethanol (50 mL) and finally N-(2-(naphthalen-2-yloxy)ethyl)acetamide (10.0 g, 35.80 mmol) as prepared above. The resulting mixture was heated to reflux for 18 h. The reaction was monitored by TLC. The reaction was then allowed to cool to 50° C., then charged with water (50 mL) followed by ethyl acetate (100 mL). The mixture was then stirred for 15 min. The mixture was then filtered and thelayers were separated. The upper organic layer was washed with saturated sodium chloride (50 mL) and dried over sodium sulfate and concentrate to afford 2-(2-naphthyloxy)ethylamine as an amber oil (6.92 g, 47%).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]([CH:34]1[CH2:36][CH2:35]1)([CH:31]1[CH2:33][CH2:32]1)[C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH:16]=[C:17]([CH3:19])[CH:18]=2)=[CH:9][CH:8]=1.C1COCC1.C(O)(=O)C>C([O-])(O)=O.[Na+].O>[CH:31]1([C:6]([CH:34]2[CH2:36][CH2:35]2)([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:14]=[C:15]([NH:20][C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=4)[CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:11][N:12]=2)[NH:5][C:2]([NH2:3])=[O:1])[CH2:33][CH2:32]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(N)(C3CC3)C3CC3)nc2)c1
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(NC(N)=O)(C3CC3)C3CC3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium cyanate (71.1 mg, 0.876 mmol) was added to a mixture of N-(3-{6-[amino(dicyclopropyl)methyl]pyridin-3-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (257 mg, 0.584 mmol), THF (4.00 mL), acetic acid (0.050 ml, 0.876 mmol), and water (2.00 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous NaHCO3 (20.0 mL) and extracted with ethyl acetate (50.0 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% methanol in ethyl acetate) and the isolated material was then triturated with ethyl acetate (4.00 mL) and methanol (0.50 mL) to yield 1-{dicyclopropyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]methyl}urea. MS APCI calc'd for C25H26F3N6O [M+H]+ 483. found 483. 1H NMR (500 MHz, CD3OD) δ11.08 (s, 1H), 9.65 (d, J=5.3 Hz, 1H), 9.49 (d, 1H), 8.74 (s, 1H), 8.68 (d, J=11.2 Hz, 1H), 8.47-8.19 (m, 2H), 8.08 (d, J=5.2 Hz, 1H), 7.98 (s, 1H), 6.87 (s, 1H), 6.24 (s, 2H), 3.16 (s, 4H), 2.26 (s, 2H), 1.26 (d, J=25.7 Hz, 3H), 1.10 (d, J=6.0 Hz, 4H).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3](C(OCC)=O)[CH2:2]1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH:15]=O.[NH2:22][C:23]1[CH:27]=[CH:26][NH:25][N:24]=1>>[ClH:12].[C:2]([C:3]1[CH:15]([C:14]2[C:13]([Cl:12])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])[C:27]2[C:23](=[N:24][NH:25][CH:26]=2)[NH:22][C:9]=1[CH:9]1[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1)#[N:1]
Reactant: CCOC(=O)C1CCCNC1
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1c(Cl)cccc1Cl
Product: Cl
Product: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared from ethyl nipecotate, 2,6-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(Cl)Cl>[CH3:21][S:22]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)(=[O:24])=[O:23]
Reactant: NCCSc1cccc2nccn12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCSc1cccc2nccn12
Yield: 78.1 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (9.63 g, 49.8 mmoles) and triethylamine (7.64 ml) in methylene chloride (150 ml) was added methanesulfonyl chloride (3.85 ml, 49.7 mmoles) with stirring under ice-cooling and was stirred under ice-cooling for 1 hour. The reaction solution was poured into water and stirred. Then, the crystals precipitated were filtered off, washed with water and dried to obtain 10.53 g of the desired product (77.9%, colorless crystals).
Reaction SMILES: [CH2:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O[CH2:26][CH:27]=[CH:28][CH2:29]OC(=O)C)(=O)C>O1CCCC1.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>[CH2:12]([N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:26][CH:27]=[CH:28][CH2:29][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:29][CH2:28][CH2:27][CH3:26])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCNCCCCCCCCCC
Reactant: CC(=O)OCC=CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCN(CC=CCN(CCCCCCCCCC)CCCCCCCCCC)CCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of di-n-decylamine (10.9 g, 36.6 mmol) and 2-butene-1,4-diol diacetate (3.15 g, 18.3 mmol) in tetrahydrofuran (THF) (150 ml) is treated with tetrakis(triphenylphosphine)palladium (0) (1.0 g, 0.9 mmol) and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to a oil that is redissolved in THF (500 ml) and treated with 20% aqueous sodium hydroxide (250 ml). The mixture is stirred for one hour, concentrated, and extracted with ether. The ether extracts are dried and concentrated giving an orange oil which is purified by medium pressure chromatography (silica gel; 25% ethyl acetate in hexanes). The title compound is isolated as 5.8 g (49% yield) of a clear oil.