Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]1=O)=O)C.C(OC(C1CC[N:28](CC2C=CC=CC=2)CC1=O)=O)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CCN(CC)CC>[OH-].[OH-].[Pd+2].CCO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]2[CH:7]([NH:28][CH2:4]2)[CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: [Pd+2]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reaction time: 24 h
Yield: 94.25 %

Procedure:
3-Oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester. A mixture of 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester (11.31 g, 38 mmol), di-t-butyl dicarbonate (8.78 g, 40.2 mmol), Et3N (5.4 mL, 38.7 mmol) and Pd(OH)2 on carbon (20% on dry basis-Pearlman's catalyst) (1.3 g) were taken into EtOH (110 mL). The mixture was hydrogenated at 60 psi for 24 h in a Parr bottle. The catalyst was removed by filtration and the filtrate was concentrated to dryness to tan solid. Crude residue was shaken well with hexane (100 mL) and filtered. The filtrate was concentrated to yield the title compound (9.70 g, 94.25%). MS (ESI) mass calcd. for C13H21NO5, 271.32; 1H NMR (400 MHz, CDCl3) 4.24 (q, J=7.1, 2H), 4.03 (s br, 2H), 3.49 (t, J=5.6, 2H), 2.32 (m, 3H), 1.47 (s, 9H), 1.31 (t, J=7.1, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([CH:14]=[CH:15][N:16]=3)[CH2:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[N:10]([CH:14]=[CH:15][N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2=CCCn3ccnc32)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Clc1ccc(-c2cccn3ccnc23)cc1

Procedure:
Combine 30 g (0.12 mol) of the product from Example 1 with 150 g of "activated" manganese dioxide in 500 ml of methylene chloride, and heat to reflux for 6 hr. Filter off the solids and remove the solvent in vacuo. The residue is crystallized from ether to provide the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:47][C:48]1[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][N:49]=1.[CH2:55]([O:57][C:58]([CH:60]1[CH2:65][CH2:64][N:63]([C:66]2[S:67][C:68]([C:71]3[CH:76]=[CH:75][CH:74]=[C:73](Br)[N:72]=3)=[CH:69][N:70]=2)[CH2:62][CH2:61]1)=[O:59])[CH3:56].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:54][C:52]1[CH:51]=[CH:50][N:49]=[C:48]([NH:47][C:73]2[N:72]=[C:71]([C:68]3[S:67][C:66]([N:63]4[CH2:62][CH2:61][CH:60]([C:58]([O:57][CH2:55][CH3:56])=[O:59])[CH2:65][CH2:64]4)=[N:70][CH:69]=3)[CH:76]=[CH:75][CH:74]=2)[CH:53]=1
Reactant: CCOC(=O)C1CCN(c2ncc(-c3cccc(Br)n3)s2)CC1
Reactant: Cc1ccnc(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ncc(-c3cccc(Nc4cc(C)ccn4)n3)s2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (434 mg, 0.70 mmol) and palladium acetate (117 mg, 0.52 mmol) was dissolve in toluene (15 ml), and after 2-amino-4-picoline (395 mg, 3.65 mmol) and a toluene (15 ml) solution of ethyl 1-[5-(6-bromopyridin-2-yl)thiazol-2-yl]piperidine-4-carboxylate obtained by Step 2 (1.38 g, 3.48 mmol) were sequentially added, cesium carbonate (1.70 g, 5.22 mmol) was added and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution and extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over anhydrous sodium sulfate and the residue obtained by vacuum concentration was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1 to 1:10) and the title compound (817 mg, 55%) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:6][CH2:5]2)=[N:8]1
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 78.6 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H indazole (3.2 g, 0.016 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.0 g, 0.016 mol) K2CO3 (2.2) and acetonitrile (100 ml) was stirred and refluxed for 6hours. The reaction was poured into water and the resulting yellow solid that formed was collected to afford 5.3 g of product. The compound was recrystallized from acetonitrile and then from ethyl acetate to yield 3.0 g (45%) of a slightly yellow solid of 1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidiyl]butoxy]-3-methoxyphenyl]ethanone, m.p.=133°-135° C.
Reaction SMILES: O/[N:2]=[CH:3]/[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14].N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCOCC1.O>[C:3]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14])#[N:2]
Reactant: COC(=O)c1[nH]c2ccccc2c1/C=N/O
Agent: CS(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1[nH]c2ccccc2c1C#N
Temperature: 60 °C
Yield: 76 %

Procedure:
To a mixture of methyl 3-[(E)-(hydroxyimino)methyl]-1H-indole-2-carboxylate (from Key Organics, 1.0 g, 4.6 mmol) and pyridine (7.4 mL, 92 mmol) in 1,4-dioxane (20 mL) was added methanesulfonyl chloride (1.4 mL, 18 mmol). The reaction was heated at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-5% MeOH/dichloromethane) to give the desired product (0.7 g, 76%). LCMS calculated for C11H9N2O2(M+H)+: m/z=201.1. Found: 201.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[C:8]([NH2:16])[CH:7]=1)=[O:5])[CH3:2].[CH:17](=O)[CH3:18]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:15])[F:14])=[C:8]([NH:16][CH2:17][CH3:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)c(N)c1
Reactant: CC=O
Agent: [Pd]
Solvent: CCO
Product: CCNc1cc(C(=O)OCC)ccc1C(F)(F)F

Procedure:
To 0.466 g. of 2-amino-α,α,α-trifluoro-p-toluic acid ethyl ester (prepared according to the procedure described in Example 2) predissolved in 20 ml. of anhydrous ethanol is added 5 ml. of 31% aqueous acetaldehyde and 46 mg. of 10% palladium on carbon. The resultant mixture is then hydrogenated at 60° for 18 hours. The reaction mixture is then cooled, filtered, the solvent removed, and the resultant oil is chromatographed on preparative thin layer plates to yield 2-ethylamino-α,α,α-trifluoro-p-toluic acid ethyl ester (N-ethyl-4-trifluoromethylanthranilic acid ethyl ester).
Reaction SMILES: [Cs].C(OC=C)(=[O:4])C.[C:8]([O:21][CH:22]=[CH2:23])(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCCCC>O>[C:22]1(=[O:4])[O:21][C:8](=[O:20])[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:23]12
Reactant: C=COC(C)=O
Reactant: C=COC(=O)CCCCCCCCCCC
Agent: [Cs]
Solvent: O
Product: O=C1OC(=O)c2ccccc21
Reaction time: 18 h

Procedure:
For the preparation of the catalysts, 11.3 g of V2O5, 70.8 g of TiO2 (BET 8 m2/g), 17.7 g of TiO2 (BET 200 m2/g) and 0.2 g of cesium (as CsCO3) were suspended in 400 ml of demineralized water and stirred for 18 hours to obtain a homogeneous distribution. 1.5 g of organic binder, consisting of a copolymer of vinyl acetate and vinyl laurate in the form of a 50% strength by weight aqueous dispersion, were added to this suspension. The suspension obtained was then sprayed onto 1203 g of steatite rings, having in each case two notches in the upper side and two notches in the lower side, and was dried. The notches were offset by 90 degrees relative to one another. The rings had dimensions of 7×7×4 mm and the notch width was 1.4 mm and the notch depth 2 mm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:25])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH:10]2O)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:25])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[C:11]([CH3:22])([CH3:23])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (6.4 g, 15 mmol) and triethylsilane (10 mL) at 25° C. was added trifluoroacetic acid (10 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium bicarbonate solution (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(5% ethyl acetate/hexanes) to afford 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (2.51 g, 41%) as a white solid: LC/MS m/e calcd for C19H19BrClNO2 M+: 408.7, observed: 408.8.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41])[N:33]=[N:32]1>C(Cl)Cl>[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[CH:14]=3)=[O:10])[CH2:5][CH2:4]2)=[O:41])[N:33]=[N:32]1
Reactant: N#Cc1cc(Cl)cc(COC(=O)N2CCC(N)CC2)c1
Reactant: O=C(Cl)CCCCc1c[nH]nn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(COC(=O)N2CCC(NC(=O)CCCCc3c[nH]nn3)CC2)c1
Reaction time: 20 h

Procedure:
To a suspension of 3-chloro-5-cyanobenzyl 4-aminopiperidine-1-carboxylate hydrochloride salt (195 mg, 0.591 mmol) in DCM (5 mL) at RT under nitrogen was added Huenig's Base (0.206 mL, 1.182 mmol). 5-(1H-1,2,3-Triazol-4-yl)pentanoyl chloride (111 mg, 0.591 mmol) in DCM (2 mL) was then added and the reaction mixture stirred for 20 hours. The reaction mixture was diluted with DCM and washed with a 10% solution of citric acid, a saturated solution of brine and the organic portion was then dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH in DCM to afford the title product.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:1][C@@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.7 %

Procedure:
To a solution of 1,1-dimethylethyl(3R)-3-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (may be prepared as described in Description 3) (3.39 g, 8.30 mmol) in 1,4-dioxane (20 ml) was added HCl (4M in 1,4-dioxane) (10.4 ml, 41.5 mmol) and the resultant mixture stirred under an atmosphere of Ar for 16 hours. A further 5 ml of 4M HCl in dioxane was added and the mixture stirred at rt for 72 hours. The mixture was concentrated to dryness and the residue triturated with diethyl ether and the solid collected by filtration giving the title compound (2.51 g) as a white powder.
Reaction SMILES: CON(C)[C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].Br[C:21]1[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:24]=[C:25]([F:27])[CH:26]=1.C([Mg]Cl)(C)C>C1COCC1.[Cl-].[Na+].O>[F:27][C:25]1[CH:26]=[C:21]([C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:6])[CH:22]=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:24]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(F)cc(C(F)(F)F)c1
Temperature: -20 °C

Procedure:
To a solution of the commercially available benzyl {(2S)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate (5.48 g, 20.58 mmol) and 3-bromo-5-fluorobenzotrifluoride (5 g, 20.58 mmol) in THF (52 ml) at −30° C. was added isopropylmagnesium chloride (20.58 ml, 41.2 mmol) dropwise under nitrogen. Removed the cold bath and allowed the reaction to age overnight to ambient temperature. The crude was cooled to −20° C. followed by addition of HC (1N, ice bath cold). The resulting mixture was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated. The pot residue was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 40% ethyl acetate). Related fractions were pooled and evaporated under reduced pressure to afford a yellow oil of 5.4655 g as the titled compound. 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.57 (d, J=8 Hz, 1H), 7.38-7.30 (m, 5H), 5.7 (d, J=7.5 Hz, 1H), 5.3 (ps quintet, J=7.5 Hz, 1H), 1.45 (d, J=7 Hz, 3H).
Reaction SMILES: C(CO[C:6]1[CH:7]=[C:8](/[C:13](=[CH:46]\[CH:47]=[C:48]2\[N:49]([CH2:71][CH2:72][CH2:73][S:74]([O-:77])(=[O:76])=[O:75])[C:50]3[CH:51]=[CH:52][C:53]4[C:62](S([O-])(=O)=O)=[CH:61][C:60](S([O-])(=O)=O)=[CH:59][C:54]=4[C:55]=3[C:56]\2([CH3:58])[CH3:57])/[CH:14]=[CH:15]/[C:16]2[C:24]([CH3:26])([CH3:25])[C:23]3[C:22]4[CH:27]=[C:28](S([O-])(=O)=O)[CH:29]=[C:30](S([O-])(=O)=O)[C:21]=4[CH:20]=[CH:19][C:18]=3[N+:17]=2[CH2:39][CH2:40][CH2:41][S:42]([O-:45])(=[O:44])=[O:43])[CH:9]=[C:10](F)[CH:11]=1)(O)=O.[Na+:78].[Na+].[Na+].[Na+].[Na+].Br/C(=C\C=C1\N(CCCS([O-])(=O)=O)C2C=CC3C=CC=CC=3C=2C\1(C)C)/C=C/C1C(C)(C)C2C3C=CC=CC=3C=CC=2[N+]=1CCCS([O-])(=O)=O.[Na+].[OH:134][CH2:135][CH2:136][CH2:137][CH2:138][O:139]C1C=C(B(O)O)C=CC=1>>[CH3:58][C:56]1([CH3:57])[C:55]2[C:54]3[CH:59]=[CH:60][CH:61]=[CH:62][C:53]=3[CH:52]=[CH:51][C:50]=2[N:49]([CH2:71][CH2:72][CH2:73][S:74]([O-:77])(=[O:75])=[O:76])/[C:48]/1=[CH:47]/[CH:46]=[C:13](\[C:8]1[CH:7]=[CH:6][CH:11]=[C:10]([O:134][CH2:135][CH2:136][CH2:137][CH2:138][OH:139])[CH:9]=1)/[CH:14]=[CH:15]/[C:16]1[C:24]([CH3:25])([CH3:26])[C:23]2[C:22]3[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=3[CH:20]=[CH:19][C:18]=2[N+:17]=1[CH2:39][CH2:40][CH2:41][S:42]([O-:45])(=[O:43])=[O:44].[Na+:78]
Reactant: OCCCCOc1cccc(B(O)O)c1
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cc(F)cc(OCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Agent: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4ccccc4c3C2(C)C)=[N+](CCCS(=O)(=O)[O-])c2ccc3ccccc3c21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4ccccc4c3C2(C)C)c2cccc(OCCCCO)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3ccccc3c21

Procedure:
Compound 40 is prepared analogously to compounds 16 and 29, except with sodium 3-(2-((1E,3Z,5E)-3-bromo-5-(1,1-dimethyl-3-(3-sulfonatopropyl)-1H-benzo[e]indol-2(3H)-ylidene)penta-1,3-dienyl)-1,1-dimethyl-1H-benzo[e]indolium-3-yl)propane-1-sulfonate and 3-(4-hydroxybutoxy)phenylboronic acid as starting materials.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:19][C:18]2[C:5](=[CH:6][C:7]3[C:8](=[O:21])[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[O:15][C:16]=3[C:17]=2[CH3:20])[CH2:4]1.CC(C)=[O:24].S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6].O>[CH3:20][C:17]1[C:16]2[O:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8](=[O:21])[C:7]=2[CH:6]=[C:5]2[CH2:4][CH:3]([C:2]([OH:24])=[O:1])[O:19][C:18]=12
Reactant: CC(C)=O
Reactant: Cc1c2c(cc3c(=O)c4ccccc4oc13)CC(CO)O2
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: Cc1c2c(cc3c(=O)c4ccccc4oc13)CC(C(=O)O)O2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled mixture of 16.1 of the 2,3-dihydro-2-hydroxymethyl-11-methyl-5-oxo-5H-furo[3,2-b]xanthene obtained in Example 25 and 3,000 ml of acetone, a mixture of chromium trioxide (57 g), water (280 ml) and concentrated sulfuric acid (84 g) was added dropwise under agitation. The resulting mixture was left to stand overnight and filtered. The filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from a mixed solvent of methanol and dichloromethane gave 11.1 g of 2,3-dihydro-11-methyl-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 297°-299° C. This compound produced a mass spectrum having a molecular ion peak at m/e 296.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:14]2[NH:18][C:17]([CH3:19])=[N:16][N:15]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[CH3:19][C:17]1[NH:18][C:14]([C:11]2([NH2:10])[CH2:13][CH2:12]2)=[N:15][N:16]=1
Reactant: Cc1nnc(C2(NC(=O)OCc3ccccc3)CC2)[nH]1
Agent: [Pd]
Solvent: CO
Product: Cc1nnc(C2(N)CC2)[nH]1
Reaction time: 1.5 h
Yield: 103.4 %

Procedure:
[1-(5-methyl-4H-[1,2,4]triazol-3-yl)-cyclopropyl]-carbamic acid benzyl ester (57 mg, 0.21 mmol) was dissolved in MeOH (5 ml), followed by the addition of 10% Pd/C (20 mg). The reaction mixture was stirred under H2 balloon for 1.5 h. The reaction mixture was filtered through celite. The solvent was concentrated under high vacuum pump to afford 30 mg of 1-(5-methyl-4H-[1,2,4]triazol-3-yl)-cyclopropylamine, m/z 139.6 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:15])([CH3:14])[CH:12]=[CH2:13])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:19]([F:36])=[C:20](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])\[C:26]#[N:27])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[C:19]=2[F:36])[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])([C:26]#[N:27])[CH:9]([CH2:10][C:11]([CH3:15])([CH3:14])[CH:12]=[CH2:13])[NH:8]1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 28.6 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3-dimethyl-pent-4-en-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 80a (2.1 g, 9.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2 g, 6.4 mmol) prepared in Example 52a, AgF (0.9 g, 7.1 mmol), and triethylamine (1.5 g, 15 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.98 g, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Nc1ccccc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4ccccc4)cc3)c2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.17 mmol), aniline (16 mg, 0.17 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (33 mg, 0.17 mmol) and DMF (20 drops) were suspended in dry DCM (5 ml) and stirred at room temperature under nitrogen for 4 h. The mixture was absorbed onto an SPE (silica, 10 g), eluted with DCM and then with a DCM/ethanol/ammonia gradient (250:8:1 to 100:8:1). The solvent was evaporated from the product fractions under vacuum to yield 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-phenyl-1,1′-biphenyl-4-carboxamide as a white solid (32 mg, 51%). NMR; δH [2H6]—DMSO 10.34,(1H, b), 8.06,(2H, d), 7.91,(1H, dd), 7.80,(3H, m), 7.57,(3H, m), 7.36,(2H, t), 7.11,(1H, t), 2.57,(3H, s), 2.34,(3H, s). LCMS; retention time 3.39 min, MH+ 370.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Br:6][C:7]1[N:8]=[CH:9][C:10]2[N:16]=[C:15](O)[CH:14]=[CH:13][C:11]=2[N:12]=1>CN(C)C=O>[Br:6][C:7]1[N:8]=[CH:9][C:10]2[N:16]=[C:15]([Br:3])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1ccc2nc(Br)ncc2n1
Solvent: CN(C)C=O
Product: Brc1ccc2nc(Br)ncc2n1
Temperature: 90 °C
Reaction time: 0.02 h

Procedure:
A roundbottom flask was charged with N,N-dimethylformamide (4.2 L). Phosphorus oxybromide (646.9 g, 2.26 mol, 2.30 equiv) was added followed by dropwise addition of 2-bromopyrido-[3,2-d]-pyrimidin-6-ol (170 g, 752.1 mmol). The resulting solution was allowed to react, with stirring, for 1 minute while the temperature was maintained at 90° C. The reaction mixture was then quenched by the addition of 10 L of water/ice. The resulting solution was extracted once with ethyl acetate. The organic layer was washed with aqueous NaHSO4 and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with dichloromethane to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([NH2:11])[CH:3]=1.[N:12]([O-])=O.[Na+].O.O.Cl[Sn]Cl>>[Br:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([NH:11][NH2:12])=[C:5]([O:9][CH3:10])[CH:6]=1
Reactant: O=N[O-]
Reactant: COc1cc(Br)c(Cl)cc1N
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(Br)c(Cl)cc1NN
Yield: 67.3 %

Procedure:
The title compound was prepared by the general procedure described above for Preparations 2a-i using 4-chloro-5-bromo-2-aminoanisole (7.68 g), NaNO2 (2.25 g), and SnCl2.2H2O (15 g). Workup gave 5.5 g (73%) of (4-bromo-5-chloro-2-methoxyphenyl)hydrazine which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29](B(O)O)[C:24]=2[O:23][CH2:22][CH2:21]1>>[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=4)[N:3]=3)[C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1cccc2c1OCCO2
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3cccc4c3OCCO4)n2)c1

Procedure:
Example 18 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and 2,3-dihydro-1,4-benzodioxin-5-ylboronic acid (Combi-Blocks Inc.). The batch was purified by preparative HPLC.