Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:7]=[C:6]([NH:17][CH3:18])[N:5]=1.[C:19]([O:23][C:24](=[O:35])[NH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32][CH:33]=O)[CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[C:19]([O:23][C:24](=[O:35])[NH:25][C@H:26]1[CH2:27][CH2:28][C@H:29]([CH2:32][CH2:33][N:14]2[CH2:15][CH2:16][N:11]([C:8]3[C:9]([Cl:10])=[C:4]([Cl:3])[N:5]=[C:6]([NH:17][CH3:18])[N:7]=3)[CH2:12][CH2:13]2)[CH2:30][CH2:31]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: CNc1nc(Cl)c(Cl)c(N2CCNCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5.36 g (16 mmol) of (4,5-dichloro-6-piperazin-1-yl-pyrimidin-2-yl)-methyl-amine dihydrochloride and 3.86 g (16 mmol) of trans-4-(2-oxoethyl)cyclohexyl-carbamic acid tert-butyl ester were dissolved in dichloromethane (320 ml). 6.7 ml (48 mmol) triethylamine was added, then 5.1 g (24 mmol) sodium triacetoxyborohydride was added portion wise and the reaction mixture was stirred for 20 hours at ambient temperature. 20% potassium carbonate solution in water (100 ml) was then added. The organic layer was separated, dried and evaporated to dryness in vacuo. The residue was triturated with diethyl ether to give the title compound (6.9 g, 88.5%), melting point: 199-202° C.
Reaction SMILES: OS(O)(=O)=O.[C:6]1([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>>[N+:18]([C:9]1[CH:8]=[CH:7][C:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][CH:10]=1)([O-:20])=[O:19]
Reactant: c1ccc(-c2cccnc2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of H2SO4 (6 mL) cooled in an ice bath to 0° C. was added 3-phenylpyridine (1.0 g, 6.4 mmol). The orange-red solution was vigorously stirred while HNO3 (1 mL) was slowly added dropwise to give a cloudy light yellow solution. After stirring at room temperature for 20 min the solution was carefully poured into a beaker filled with ice (200 g). The solution was neutralized with 20% NaOH to give a cloudy white suspension which was extracted with EtOAc (3×150 mL). The organic layers were combined, washed with brine (2×50 mL), dried (NaSO4) and concentrated in vacuo to give the desired product (1.2 g, 99%) as a light yellow solid. Data for 3-(4-nitrophenyl)pyridine: Rf =0.47 (silica gel, methanol/CHCl3, 5/95); 1H NMR (400 MHz, acetone-d6) 8.99 (s, 1H), 8.67 (s, 1H), 8.37 (d, J=7.0, 2H), 8.18 (m, 1H), 8.02 (d, J=7.0, 2H), 7.53 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([C:22]1[N:27]=[CH:26][C:25](Br)=[CH:24][N:23]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[O:19][CH2:20][CH3:21].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[NH:65]1[CH2:70][CH2:69][CH:68]([C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH2:67][CH2:66]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[O:19][CH2:20][CH3:21])[C:22]1[N:27]=[CH:26][C:25]([N:65]2[CH2:70][CH2:69][CH:68]([C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH2:67][CH2:66]2)=[CH:24][N:23]=1
Reactant: CCOc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2cnc(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)Cc3cc(C(F)(F)F)ccc3OCC)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-ethoxy-5-trifluoromethyl-benzyl)-amine (210 mg) is dissolved in toluene (5 ml) and thereto are added tris(dibenzylideneacetone)dipalladium (32 mg), 2-(di-tert-butylphosphino)biphenyl (42 mg), sodium tert-butoxide (50 mg) and ethyl piperidine-4-carboxylate (80 μl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=1:0→17:3) to give ethyl 1-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethoxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yl}-piperidine-4-carboxylate (121 mg). MS (m/z): 679 [M+H]+
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Cl.[N:22]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[CH:25][N:24]=[N:23]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:1][C:2]1[C:3]([N:29]2[CH2:30][CH2:31][CH:27]([N:22]3[CH:26]=[CH:25][N:24]=[N:23]3)[CH2:28]2)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: c1cn(C2CCNC2)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1COc2c(N3CCC(n4ccnn4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 9.3 %

Procedure:
To a suspension of 76 mg (0.27 mmol) of (-) -9,10-difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H -pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and 118 mg (0.675 mmol) of 3-(1,2,3-triazol-1-yl) pyrrolidine hydrochloride in 10 ml of dry acetonitrile was added 121 mg (0.81 mmol) of DBU. The reddish brown solution was refluxed for 31 hr. The solvent was then removed under reduced pressure. To the residue water was added and extracted with chloroform. The organic layer was then evaporated to dryness, and to the residue, water was added and solid collected to yield 10 mg of the desired product, m.p. 225°-229° C. 1H NMR (TFA) δ: 9.17 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 7.99 (d, 13.3Hz, 1H), 5.9-5.18 (m, 1H), 5.22-4.07 (m, 7H), 3.13-2.63 (m, 2H), 1.82 (s, 3H), 1.79 (s, 3H). Anal. calcd. for C19H18N5O4F . 1/2 H2O: C, 55.86; H, 4.69; N, 17.16. Found: C, 55.93; H, 4.59; N, 16.37.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].Cl.[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36](/[C:38](=[N:42]/[O:43][CH3:44])/[C:39](Cl)=[O:40])[N:37]=1)=[O:31].Cl>O1CCCC1.O>[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36](/[C:38](=[N:42]/[O:43][CH3:44])/[C:39]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]23)=[O:40])[N:37]=1)=[O:31]
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1csc(NC(=O)CCl)n1
Yield: 97.7 %

Procedure:
In a mixture of 500 ml of tetrahydrofuran and 500 ml of water is suspended 157 g of 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid. To the suspension is added little by little 141 g of sodium hydrogen carbonate with stirring. To the mixture is added 150 g of 2-(2-chloroacetamidothiazol-4-yl)-2(Z)-methoxyiminoacetyl chloride hydrochloride at 5° C., during 20 minutes with stirring, and the mixture was stirred for further one hour. After completion of the reaction, the reaction mixture is adjusted to pH 3.0 with 10% hydrochloric acid, and extracted twice with 1 l portions of a mixture is ethyl acetate-tetrahydrofuran (1:1). The extract is dried over anhydrous magnesium sulfate, and then the solvent is evaporated off under reduced pressure to leave colorless powder, which is triturated with 200 ml of ethyl acetate and collected by filtration to afford 253 g of the above-identified compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:19]#[N:20].[O:21]=[C:22]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][CH:32]=O)=[CH:30][C:25]=2[CH2:24][O:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:32][CH2:31][C:29]4[CH:28]=[CH:27][C:26]5[C:22](=[O:21])[O:23][CH2:24][C:25]=5[CH:30]=4)[CH2:14][C:13]3=[O:18])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:19]#[N:20]
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: N#Cc1c(F)ccc2c1CCC2CN1CCNCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1c(F)ccc2c1CCC2CN1CCN(CCc2ccc3c(c2)COC3=O)CC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask containing 5-Fluoro-1-[(2-oxopiperazin-1-yl)methyl]-2,3-dihydro-1H-indene-4-carbonitrile (5 mg, 0.018 mmol) and a stir bar was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (16 mg, 0.091 mmol), Sodium Triacetoxyborohydride (19 mg, 0.091 mmol), and DCM (1 mL). The mixture was allowed to stir at RT for 16 hours. LC-MS indicated formation of the desired product. The solvent was removed, and the residue was redissolved in MeOH (1 mL). The sample was subjected to purification by reverse phase HPLC to afford the title compound. LC-MS (IE, m/z): 434 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[C:19]([C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:31]2[CH:32]=[CH:33][C:28]([C:19]([CH3:21])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:20])=[CH:29][CH:30]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(C)(C)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 4-cumylphenol and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19](=[O:28])[CH:20](C3C=CC=CC=3)[CH3:21])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.NC(C1N=N[C:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42](OC)=[CH:41][CH:40]=2)=NC=1)C.CN1C2C(=CC=CC=2)C=C1C(O)=O>>[CH3:35][N:38]1[C:39]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:21]=[C:20]1[C:19]([NH:18][CH:16]([C:13]1[N:12]=[N:11][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:15][CH:14]=1)[CH3:17])=[O:28]
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)C(C)c3ccccc3)nn2)cc1
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Agent: Cn1c(C(=O)O)cc2ccccc21
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3cc4ccccc4n3C)nn2)cc1

Procedure:
In a similar manner as described for Intermediate 55, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 1-methylindole-2-carboxylic acid (79 mg, 0.45 mmol), to give 1-methyl-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-1H-indole-2-carboxamide (158 mg) as a yellow solid. MS m/z 403 (M+1).
Reaction SMILES: Br[C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C@H:3]1[OH:23])[C@:16]1([CH3:17])[C:11]([CH2:12][C@@H:13]([OH:21])[CH2:14][CH2:15]1)=[CH:10][C@@H:9]3[OH:22].[OH-:24].[Na+]>CN(C)C=O>[OH:21][C@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C:11](=[CH:10][C@H:9]([OH:22])[C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][C@@H:2]([OH:24])[C@@H:3]2[OH:23])[CH2:12]1
Reactant: [OH-]
Reactant: C[C@]12CC[C@H]3[C@@H]([C@@H](O)C=C4C[C@@H](O)CC[C@@]43C)[C@@H]1C[C@@H](Br)[C@@H]2O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@H]3[C@@H]([C@@H](O)C=C4C[C@@H](O)CC[C@@]43C)[C@@H]1C[C@@H](O)[C@@H]2O

Procedure:
16α-bromo-3β,7β,17β-trihydroxyandrost-5-ene (CLIII, X=Br) is reacted with sodium hydroxide in dimethylformamide to form 3β,7β,16α,17β-tetrahydroxyandrost-5-ene (CLXI)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:14]=O)[CH:9]=[C:10]([CH:13]=1)[CH:11]=O)[CH2:2][CH2:3][CH3:4].[NH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[BH4-].[Na+]>CO>[CH2:1]([O:5][C:6]1[CH:13]=[C:10]([CH2:11][NH:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:9]=[C:8]([CH2:14][NH:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCNCCCN
Reactant: CCCCOc1cc(C=O)cc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCOc1cc(CNCCCNCCCNC(=O)OC(C)(C)C)cc(CNCCCNCCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Butoxyisophthalaldehyde (0.80 g, 0.85 mmol) and MeOH (15 mL) were added to a round-bottom flask. To the solution was added tert-butyl (3-((3-aminopropyl)amino)propyl)-carbamate (0.39 g, 1.70 mmol), and the reaction mixture was stirred at rt for 24 h. Sodium borohydride (0.13 g, 3.40 mmol) was added and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure and aq. NaOH (10%, 50 mL) and EtOAc (50 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The organic layers combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product as a clear oil which was used without further purification.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][NH:8][C:9]1[C:18]2[CH:17]=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[N:12]=[C:11]2[C:20](=[O:25])[NH:21][NH:22][C:23](=[O:24])[C:10]=12)=[O:5])C.Cl>>[C:4]([CH2:6][CH2:7][NH:8][C:9]1[C:18]2[CH:17]=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[N:12]=[C:11]2[C:20](=[O:25])[NH:21][NH:22][C:23](=[O:24])[C:10]=12)([OH:5])=[O:3]
Reactant: CCOC(=O)CCNc1c2ccc(Cl)cc2nc2c(=O)[nH][nH]c(=O)c12
Agent: Cl
Product: O=C(O)CCNc1c2ccc(Cl)cc2nc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A mixture of 10-(2-ethoxycarbonylethylamino)-7-chloro-2,3-dihydropyridazino[4,5-b]quinoline-1,4-dione (0.08 g, 0.22 mM) and 1N hydrochloric acid was refluxed for 1 hr and then cooled to room temperature and filtered. The collected orange solid was washed with water and air dried to provide (0.07 g, 97%) the title compound as an orange powder, mp 356°-359° C.; MS(CI): 335 (M+H). Analysis for C14H11ClN4O4 ·0.3 H2O: Calculated: C, 49.4; H, 3.44; N, 16.47 Found: C, 49.3; H, 3.23; N, 16.25
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)CC(O)=O>CN(C=O)C.[NH4+].[Cl-].[Cu]I>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)cc1
Reactant: Brc1ccc(Br)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A mixture of 4-methylphenol (30.0 g), 1,4-dibromobenzene (54.5 g), copper (I) iodide (4.40 g), potassium carbonate (5.11 g) and N,N-dimethylglycine (2.86 g) in DMF (300 mL) was stirred at 100° C. under N2 for 18 hr. The mixture was diluted with sat. NH4Cl aq. at 0° C. and extracted with EtOAc. The organic layer was separated, washed with sat. NH4Cl aq., 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with hexane) to give the title compound (39.5 g) as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:20]([S:24](Cl)=[O:25])([CH3:23])([CH3:22])[CH3:21]>ClCCl>[C:20]([S:24]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:25])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)S(=O)Cl
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(NS(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
Ethyl 4-amino-1-piperidinecarboxylate (300 mg) and triethylamine (258 mg) were dissolved in 5 ml of dichloromethane. To the mixture, 2 ml of solution of t-butylsulfinyl chloride (222 mg) in dichloromethane was added and the mixture was stirred at room temperature for 4 hours. The solution was partitioned into an aqueous solution of potassium hydrogen sulfate and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give 378 mg of 4-t-butylsulfinylamino-1-ethoxycarbonyl piperidine.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([F:19])[C:6]=1[F:20])=[O:4].[OH-].[Na+]>O1CCCC1>[F:12][C:9]1[C:10]([F:11])=[C:5]([C:3]([OH:4])=[O:2])[C:6]([F:20])=[C:7]([F:19])[C:8]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1c(F)c(F)c(-c2ccccc2)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(F)c(-c2ccccc2)c(F)c1F
Temperature: 10 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
To a solution of 2,3,5,6-tetrafluoro-biphenyl-4-carboxylic acid methyl ester (20 g, 70.4 mmol) in tetrahydrofuran (350 mL) was added an aq, solution of 5 N sodium hydroxide (150 mL). The reaction mixture refluxed with stirring for 4 hours. Progress of the reaction was monitored by TLC. The reaction mixture was then concentrated and the resulting residue was cooled to 10° C. and acidified with an aq. Solution of 50% HCl. The formed precipitate was filtered, washed thoroughly with water and dried to obtain title compound as colorless solid (17 g, 89.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:19][NH:20][C@H:21]1[CH2:40][N:25]2[C:26]3[C:31]([C:32]([CH2:33][C:34]([O:36]CCC)=[O:35])=[C:24]2[CH2:23][CH2:22]1)=[CH:30][CH:29]=[CH:28][CH:27]=3>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([N:20]([CH3:19])[C@H:21]2[CH2:40][N:25]3[C:26]4[C:31]([C:32]([CH2:33][C:34]([OH:36])=[O:35])=[C:24]3[CH2:23][CH2:22]2)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C(c1ccc(F)cc1)c1ccc(F)cc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from bis(4-fluorophenyl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 489.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10]([CH3:11])=[C:6]2[N:5]=[C:4]([CH3:19])[C:3]=1[CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10]([CH3:11])=[C:6]2[N:5]=[C:4]([CH3:19])[C:3]=1[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(O)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (5.4 g, 12.33 mmol) in CH2Cl2 (100 ml) was added Dess-Martin periodinane (5.75 g, 13.56 mmol). The reaction was stirred 1 hr, then diluted with EtOAc (600 mL) and washed with saturated aqueous NaHCO3 (200 mL). The organic layer was then dried (NaHSO4), filtered, and concentrated. The residue was triturate with Et2O, stirring vigorously for 30 min, collecting solids by vacuum. The semi-pure product was purified by flash silica gel column and eluted with 10-20% EtOAc in hexanes, affording the product, ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (3.5 g, 8.92 mmol, 72.4% yield) as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.89-7.86 (m, 1H), 7.78-7.73 (m, 1H), 7.45-7.41 (m, 2H), 4.45 (q, J=7.1 Hz, 2H), 2.63 (s, 3H), 2.53 (s, 3H), 1.42 (t, J=7.2 Hz, 3H). LCMS (M+H)=392.1.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:13][C:14](ON1C(=O)CCC1=O)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:6]([O:13][C:14](=[O:15])[NH:5][CH2:4][CH2:3][Br:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCBr
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Br
Solvent: ClCCl
Product: O=C(NCCBr)OCc1ccccc1

Procedure:
2-Bromoethylamine hydrobromide (15 g, 73 mmol) and N-(benzyloxycarbonyloxy)succinimide (15.5 g, 62 mmol) are suspended in CH2Cl2 (150 mL) at 0° C. TEA (9 mL, 65 mmol) is added slowly keeping the temperature at 0° C. After 1 h the mixture is washed with 0.5M aqueous KHSO4 (50 mL) and brine (50 mL), the organic phase is dried (Na2SO4), filtered and evaporated to provide the title compound.