Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:58]=[CH:57][C:7]([O:8][P:9]2([O:47][C:48]3[CH:53]=[CH:52][C:51]([N+:54]([O-])=O)=[CH:50][CH:49]=3)[N:14]=[P:13]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=3)([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[N:12]=[P:11]([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:10]=2)=[CH:6][CH:5]=1)([O-])=O.NC1C=CC=CC=1.[H][H]>[Pt]=O.C1CCCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][P:9]2([O:47][C:48]3[CH:49]=[CH:50][C:51]([NH2:54])=[CH:52][CH:53]=3)[N:14]=[P:13]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=3)([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[N:12]=[P:11]([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:10]=2)=[CH:57][CH:58]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OP2(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccc([N+](=O)[O-])cc3)(Oc3ccc([N+](=O)[O-])cc3)=NP(c3ccccc3)(c3ccccc3)=N2)cc1
Agent: O=[Pt]
Solvent: Nc1ccccc1
Solvent: C1CCCCC1
Product: Nc1ccc(OP2(Oc3ccc(N)cc3)=NP(Oc3ccc(N)cc3)(Oc3ccc(N)cc3)=NP(c3ccccc3)(c3ccccc3)=N2)cc1
Yield: 78 %

Procedure:
2,2,4,4-Tetra(p-nitrophenoxy)-6,6-diphenylcyclotriphosphazene (16.01 g, 0.021 moles), platinum oxide catalyst (0.09 g, 0.0004 moles), and 50 mls aniline are added to a 500 ml Fischer-Porter reaction vessel. The reaction is heated to 50° C. at 50-60 psi of hydrogen pressure for 65 hours. The reaction mixture is then cooled and concentrated to about 25 mls under vacuum. The concentrate is poured into 250 mls cyclohexane, and a brown coagulate forms. The solvent is decanted off and the residue is poured into hot cyclohexane and allowed to cool until stirring becomes difficult. The solvent is decanted off and the residue chilled for about 20 minutes. Recrystallization from o-dichlorobenzene yields a pale brown precipitate, which is boiled in cyclohexane for two hours. A solid is recovered (10.8 g, 78% yield). 31P NMR (THF), δ21.3(triplet), 10.1(doublet).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]1[CH:18]=[C:17]2[C:13]([C:14]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:25]/[N:24]=[C:6](/[NH2:7])\[C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]4([CH2:20][CH2:21][CH2:22][CH2:23]4)[C:15](=[O:19])[NH:16]3)=[CH:12][CH:11]=2)[CH:4]=1
Reactant: Cc1ccc(C#N)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(/C(N)=N\O)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 85 °C
Reaction time: 6 h
Yield: 89.4 %

Procedure:
A stirred mixture of 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzonitrile (preparation 54b, 0.06 g, 0.20 mmol), hydroxylamine (0.02 g, 0.24 mmol) and sodium acetate (0.02 g, 0.27 mmol) in ethanol (0.60 mL) and water (0.10 mL) were heated to 85° C. in a sealed tube. After 6 hours, the mixture was cooled and concentrated in vacuo. Water was added to the residue and the resultant precipitate was filtered to give the title compound (0.06 g, 19%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([OH:18])[C:16]=1[OH:17])[CH:12]=[O:13]>>[CH2:2]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:16]=1[O:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:12]=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=Cc1cc(O)c(O)c(O)c1
Reactant: CCCCCCBr
Product: CCCCCCOc1cc(C=O)cc(OCCCCCC)c1OCCCCCC

Procedure:
The title compound was prepared according to the method described in Example 9 above from 1-bromohexan and 3,4,5-trihydroxy-benzaldehyde.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[N:7]=[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CS(C)=O>[C:17]1([C:8]2[O:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]([CH2:5][C:1]#[N:2])[N:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [C-]#N
Reactant: ClCc1nc(-c2ccccc2)oc1-c1ccccc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1nc(-c2ccccc2)oc1-c1ccccc1
Temperature: 45 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
To a suspension of potassium cyanide (67.1 mg, 0.999 mmol) in DMSO (2 mL) was added dropwise at RT a solution of 4-(chloromethyl)-2,5-diphenyloxazole (245 mg, 908 μmol) in DMSO (3 mL) over a period of 5 min. The reaction mixture was stirred at RT for 2 h and at 45° C. for another 3 h. The reaction mixture was cooled to RT, poured into water (25 mL) and extracted with ethyl acetate (2×75 mL). The organic phases were washed with water (2×20 mL) and brine (1×20 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 245 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow solid (189 mg, 726 μmol, 79.9%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=O)[CH3:12])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][N:10]=[C:11]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)NCCc1ccc(Br)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2ccc(Br)cc21

Procedure:
In close analogy to the procedure described above, N-[2-(4-bromo-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)=[C:4]([F:14])[CH:3]=1.O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[C:6]2[C:5]([CH2:9][CH2:10][C:11]2=[O:13])=[C:4]([F:14])[CH:3]=1
Reactant: O=C(O)CCc1cc(F)c(Br)cc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1CCc2c(F)cc(Br)c(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(4-bromo-2,5-difluorophenyl)propanoic acid (1.10 g) in DCM (20 mL) was added SOCl2 (2.45 g). The mixture was stirred at room temperature for 18 hours. The solvent was removed by evaporation under reduced pressure. The residue was dried under high vacuum to give a crude solid. To the residue was added AlCl3 (2.76 g) and the mixture heated to 130° C. The mixture was stirred at 130° C. for 2 hours and then cooled to room temperature. The resulting mixture was treated with ice water and then extracted with ethyl acetate (50 mL×3). The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (5:1) to give the subtitle compound as a light yellow solid. MS ESI+: m/z=247 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.Br[C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]([CH:30]([F:41])[C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[C:28]([CH:42]4[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]4)[C:27]4[CH:26]([O:50]CC5C=CC(OC)=CC=5)[CH2:25][C:24]([CH3:61])([CH3:60])[CH2:23][C:22]=4[N:21]=3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1>>[F:49][C:45]1([F:48])[CH2:44][CH2:43][CH:42]([C:28]2[C:27]3[CH:26]([OH:50])[CH2:25][C:24]([CH3:60])([CH3:61])[CH2:23][C:22]=3[N:21]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:11]4[N:12]=[CH:13][C:8]([N:1]5[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]5)=[CH:9][N:10]=4)[CH2:19][CH2:18]3)[C:29]=2[CH:30]([F:41])[C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:40])[F:39])=[CH:35][CH:36]=2)[CH2:47][CH2:46]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: O[C@H]1CCNC1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(N5CC[C@H](O)C5)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Reference Example 13 were performed except for using (3S)-3-pyrrolidinol instead of isonipecotic acid ethyl ester, and from 100 mg (0.120 mmol) of (−)-2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 11, 56 mg of the title compound was obtained as a white solid (yield: 65%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:20])CCOC>C(Cl)Cl>[C:1]([F:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: O=C(F)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of benzoyl chloride (141 mg, 1 mmol) in CH2Cl2 (5.0 mL) was added to bis(methoxyethyl)aminosulfur trifluoride (567 mg, 3.0 mmol ) under N2 and stirred for 16 h at room temperature. After work-up as above benzoyl fluoride (124 mg, quantitative yield) was obtained. The product was identified by g.c.m.s. M+=124
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:31]([O:33][C:34](Cl)=[O:35])[CH3:32]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:34]([O:33][CH2:31][CH3:32])=[O:35])[CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(-c2ccccc2)cn1S(=O)(=O)c1ccc2c(c1)CCN2
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
4-Phenyl-1-(indoline-5-sulfonyl)-2-imidazolone (150 mg, 0.44 mmol) prepared in Preparation 3 was dissolved in 10 m of dichloromethane and then pyridine (39 μ, 0.484 mmol) and ethylchloroformate (46 μ, 0.484 mmol) were added thereto one after another. After the reaction mixture was stirred for one hour at room temperature, it was diluted with dichloromethane and washed twice with brine. The organic layer thus obtained was dried over anhydrous magnesium sulfate, concentrated to an oily state under reduced pressure, and then purified by silica gel column chromatography (eluent:dichloromethane/methanol=15/1, v/v) to afford 173 mg of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH:30]([CH3:34])[NH:29][CH2:28][CH2:27]3)=[CH:18][N:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:24]([C:19]5[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=5)[CH:25]=4)[CH:30]3[CH3:34])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ncc(-c2ccc3c(c2)CCNC3C)c(OC)n1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1ncc(-c2ccc3c(c2)CCN(C(=O)c2cc4ncc(Br)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[C:10]([O:13][CH2:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([O:29][C:30](=[O:32])[CH3:31])[C@H:17]([N:33]2[C:41]3[C:36](=[C:37]([CH3:42])[CH:38]=[CH:39][CH:40]=3)[C:35]([CH2:43][C:44]3[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[CH2:52][CH2:53][N:54]4[CH2:59][C:58]5([CH2:64][CH2:63][NH:62][CH2:61][CH2:60]5)[CH2:57][CH2:56][CH2:55]4)=[CH:46][CH:45]=3)=[CH:34]2)[O:16]1)(=[O:12])[CH3:11].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:77]([O:81][C:82]([NH:84][CH2:85][C:86](O)=[O:87])=[O:83])([CH3:80])([CH3:79])[CH3:78]>ClCCl>[C:10]([O:13][CH2:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([O:29][C:30](=[O:32])[CH3:31])[C@H:17]([N:33]2[C:41]3[C:36](=[C:37]([CH3:42])[CH:38]=[CH:39][CH:40]=3)[C:35]([CH2:43][C:44]3[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[CH2:52][CH2:53][N:54]4[CH2:59][C:58]5([CH2:60][CH2:61][N:62]([C:86](=[O:87])[CH2:85][NH:84][C:82]([O:81][C:77]([CH3:79])([CH3:78])[CH3:80])=[O:83])[CH2:63][CH2:64]5)[CH2:57][CH2:56][CH2:55]4)=[CH:46][CH:45]=3)=[CH:34]2)[O:16]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCN4CCCC5(CCNCC5)C4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCN4CCCC5(CCN(C(=O)CNC(=O)OC(C)(C)C)CC5)C4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 450 %

Procedure:
Add 4N HCl in 1,4-dioxane (112 5 mmol) to a solution of tert-butyl 4-[(E)-4-[4-[[4-methyl-1-[(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]indol-3-yl]methyl]phenyl]but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate (22.5 mmol) in dichloromethane (200 mL) at room temperature. Stir for 3 hours, then concentrate under reduced pressure to yield crude [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[(E)-4-(4,9-diazaspiro[5.5]undecan-4-yl)but-1-enyl]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate dihydrochloride (22.5 mmol): MS (m/z): 758.0 (M+H). Add triethylamine (112 5 mmol) to a solution of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[(E)-4-(4,9-diazaspiro[5.5]undecan-4-yl)but-1-enyl]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate dihydrochloride (22 5 mmol) in dichloromethane (200 mL). In a separate flask, add CDI (28.1 mmol) portion wise to a solution of 2-(tert-butoxycarbonylamino)acetic acid (27 mmol) in dichloromethane (50 mL). After stirring for 45 minutes at room temperature, add the solution to the previously prepared amine solution and stir at room temperature for 1 hour. Wash with a concentrated sodium bicarbonate solution (200 mL) and brine (200 ml). Dry the organics over sodium sulfate, filter, and concentrate under reduced pressure to yield crude title compound (21.6 g, 22.5 mmol): MS (m/z): 915.2 (M+H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[CH:37][C:36]([O:39][C:40]3[C:45]([C:46](=O)[C:47]([O:49][CH3:50])=[O:48])=[CH:44][CH:43]=[CH:42][N:41]=3)=[N:35]2)=[CH:30][CH:29]=1.O>CN(C)C=O>[CH3:2][O:3][CH:4]=[C:46]([C:45]1[C:40]([O:39][C:36]2[CH:37]=[CH:38][N:34]([C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)[N:35]=2)=[N:41][CH:42]=[CH:43][CH:44]=1)[C:47]([O:49][CH3:50])=[O:48]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=O)c1cccnc1Oc1ccn(-c2ccc(Cl)cc2)n1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC=C(C(=O)OC)c1cccnc1Oc1ccn(-c2ccc(Cl)cc2)n1
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
At room temperature, a mixture of 1.86 g (5.4 mmol) of methoxymethyltriphenylphosphonium chloride and 0.98 g (5.4 mmol) of sodium methoxide solution (30% strength in methanol) in 15 ml of dimethylformamide was stirred for 10 minutes. Subsequently, the reaction mixture was admixed with 1.0 g (2.72 mmol) of methyl [2-(1-(4-chlorophenyl)-3-pyrazolyloxy)pyridin-3-yl]glyoxylate (Example 1a.) dissolved in 5 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 2 hours and then hydrolyzed with 20 ml of water. The aqueous phase was subsequently extracted with methyl tert-butyl ether. The combined organic phases were dried over sodium sulfate and the solvent was subsequently removed under reduced pressure. 0.6 g (57%) of the title compound was obtained in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][N:9]1[CH3:19].O1CCCC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[CH:10][N:9]1[CH3:19]
Reactant: CCOC(=O)c1cn(C)n(-c2ccccc2Cl)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c(=O)n1-c1ccccc1Cl
Yield: 92 %

Procedure:
In the same manner as in Reference Example 65 and using ethyl 2-(2-chlorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2.8 g, 9.9 mmol), tetrahydrofuran (6 mL), methanol (5 mL) and 4N aqueous sodium hydroxide solution (8 mL) as starting materials, the title compound (2.3 g, 91%) was obtained as a white solid.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13](/[CH:19]=[CH:20]/[C:21]([O:23]C)=[O:22])=[C:12]([CH3:25])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CC#N.O>[NH:1]([C:8]1[N:9]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]2[N:11]=[C:12]([CH3:25])[C:13](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:14][C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1cc2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1nc2c(cc1/C=C/C(=O)O)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
To a suspension of 2-anilino-6-[(E)-3-methoxy-3-oxo-1-propenyl]-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (10 mg, 0.025 mmol) in CH3CN (2.0 mL) was added 1N NaOH (2.0 mL). The suspension was stirred at room temperature for 18 h. The mixture was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo to afford (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoic acid (6.2 mg, 63%): LCMS RT: 2.37 min, MH+: 398.3, Rf=0.51 (EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccs1
Reactant: Clc1cc(I)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cc(-c2cccs2)ccn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A round-bottomed flask was charged with 2-chloro-4-iodopyridine (600 mg, 2.5 mmol), thiophen-2-ylboronic acid (385 mg, 3.0 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (176 mg, 0.251 mmol), THF (9 mL) and 2M aqueous sodium carbonate (3.0 mL, 6.0 mmol). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature then diluted with 20 mL water and extracted with 100 mL EtOAc (2×). The combined organic layers were washed with 20 mL water and 20 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on ˜2 g SiO2 and chromatographed over 24 g SiO2 with EtOAc/hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated to give 430 mg (88%) of 2-chloro-4-thiophen-2-yl-pyridine as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]2[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]=2[CH:16]=1>CCOCC>[C:17]([C:8]1[C:9]2[O:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:16]=[C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CN=C=O
Reactant: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Solvent: CCOCC
Product: CNC(=O)Nc1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
Methylisocyanate (0.14 mL, 2.28 mmol) is added dropwise to a solution of 5-amino-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (500 mg, 2.28 mmol) in Et2O (5 mL). A solid forms over 0.5 h and the reaction is quenched with H2O (10 mL) after 1 h. The reaction is extracted with Et2O (3×10 mL) and the organic layers dried (MgSO4) and evaporated to a tan solid (550 mg). This solid is recrystallized from EtOAc to give the product as white prisms (350 mg, 56%), mp=193°-194° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]([OH:13])[CH2:11]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:10]1[O:13][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To the mixture of (2R,3S)-3-(t-butoxycarbonyl)amino-4-phenyl-butane-1,2-diol (44 g) and 400 ml of pyridine, 60 g (2 equivalents) of p-TsCl was added and the solution was stirred at 0° C. for 4 hours. After pH of the solution was adjusted 10 with 25% NaOH and it was stirred at 0° C. for 3 hours. 400 ml of methylene chloride was added to the solution and it was washed by 400 ml of 1N HCl, 400 ml of 5% aq.NaHCO3 and 400 ml of water and was distillated under reduced pressure. A white crystal compound of (2R,3S)-3-(t-butoxycarbonyl)amino-1,2-epoxy-4-phenylbutane was obtained using a column chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=1)[CH3:2].[NH2:31][C:32]1[CH:33]=[C:34]([C:43]([F:46])([F:45])[F:44])[C:35]([C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])=[N:36][CH:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:31][C:32]2[CH:37]=[N:36][C:35]([C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])=[C:34]([C:43]([F:46])([F:44])[F:45])[CH:33]=2)=[O:29])=[C:22]([F:30])[CH:21]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Reactant: CC(C)(CO)c1ncc(N)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cnc(C(C)(C)CO)c(C(F)(F)F)c2)c(F)c1
Yield: 26.2 %

Procedure:
A solution of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (50 mg, 0.122 mmol), 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropan-1-ol (28.5 mg, 0.122 mmol), HATU (92 mg, 0.243 mmol) and DIEA (0.064 mL, 0.365 mmol) in DCM (10 mL) was stirred at 25° C. After LCMS analysis showed the starting material was consumed, the mixture was washed with H2O. The organic layer was washed with brine and dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative TLC (DCM/MeOH=20/1) to yield 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (20 mg, 0.032 mmol, 26% yield): 1H NMR (400 MHz, CD3OD) δ 8.95 (br. s., 1H), 8.50 (s, 1H), 7.99 (s, 1H), 7.43-7.39 (m, 3H), 7.30-7.24 (m, 2H), 6.95-6.91 (m, 2H), 6.48 (s, 1H), 5.30 (s, 2H), 4.16-4.11 (m, 2H), 3.87-3.79 (m, 6H), 1.40-1.38 (m, 9H); ES-LCMS m/z: 628.3 (M+H).