Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([C@@H:8]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH2:9][N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+]>O.CO.CCOCC.CCCCC>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([C@@H:8]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[OH:19])[CH2:9][N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C1CCCCC1[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCCCC
Product: O=[N+]([O-])C[C@@H](c1ccc(Cl)cc1)C1CCCCC1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 6.8 g (121 mmol) of potassium hydroxide in 40 ml of water is added dropwise while cooling within about 30 minutes to a solution of 28.2 g (100 mmol) of rac-(2S*)-2-[(R*)-4-chloro-α-(nitromethyl)benzyl]cyclohexanone in 200 ml of methanol so that the temperature does not exceed 5°. An ice-cold solution of 2.85 g (75 mmol) of sodium borohydride in 20 ml of water is subsequently added dropwise, whereupon the mixture is stirred at 0° for 3 hours. After treatment with 12 ml of acetic acid the solvent is distilled off. The residue obtained is treated with water, whereupon the mixture is extracted twice with 200 ml of ether each time. The organic phase is washed with water, dried over magnesium sulphate and evaporated. The oil obtained is taken up in ether/pentane, left to stand in a refrigerator and the crystalline product obtained is recrystallized from ether/hexan. There is obtained rac-(1S*)-2-[(R*)-4-chloro-α-(nitromethyl)benzyl]cyclohexanol of m.p. 82°-84°.
Reaction SMILES: O(P(O[C:18]1[C@H:24]([CH3:25])[C@H:23]2[N:20]([C:21](=[O:29])[C@@H:22]2[C@H:26]([OH:28])[CH3:27])[C:19]=1[C:30]([O:32]CC1C=CC([N+]([O-])=O)=CC=1)=[O:31])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:43][N:44]([CH3:66])[C:45]([C@@H:47]1[CH2:51][C@H:50]([SH:52])[CH2:49][N:48]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:46].C(N(C(C)C)CC)(C)C.CN1CCOCC1.Cl>CN1CCCC1=O.O.[C].[Pd]>[CH3:25][C@H:24]1[C:18]([S:52][C@@H:50]2[CH2:49][NH:48][C@H:47]([C:45]([N:44]([CH3:66])[CH3:43])=[O:46])[CH2:51]2)=[C:19]([C:30]([OH:32])=[O:31])[N:20]2[C@H:23]1[C@@H:22]([C@H:26]([OH:28])[CH3:27])[C:21]2=[O:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@H]12
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N(C)C)C3)[C@H](C)[C@H]12

Procedure:
4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (Formula VIIIA; 20 g) was dissolved in N-methyl-2-pyrrolidone (100 mL) and cooled to −20° to −15° C. 4-Nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-mercaptopyrrolidine-1-carboxylate (12 g) was added to the reaction mixture followed by the drop-wise addition of diisopropylethylamine (5.6 g) at −15° to −5° C. and the reaction mixture was stirred. The reaction mixture was subsequently added to a buffer containing 5% palladium-carbon (30 g) and hydrogenated for 3 to 4 hours at about 25° C. (The buffer was prepared using N-methylmorpholine (3.4 g) and appropriate quantity of hydrochloric acid so as to obtain a pH of 6.5 to 7.0 in distilled water (120 mL)). The catalyst was filtered after the completion of hydrogenation and washed with water (100 mL). The filtrate was treated with activated charcoal and acetone (1.6 L) was added to the filtrate at 0° to 5° C. The reaction mixture was stirred for 6 hours at 0° to 5° C. and filtered to obtain the title compound.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.Cl.[NH2:20][OH:21].[OH-].[Na+].Cl>C(O)C.O>[OH:21][N:20]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C(=O)O)c1ccc(CC2CCCC2=O)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(CC2CCCC2=NO)cc1
Temperature: 0 °C
Yield: 88 %

Procedure:
To a solution of 1.5 g of 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid in 10 ml of ethanol was added a solution of 0.43 g of hydroxylamine hydrochloride in 2 ml of water, subsequently a solution of 0.76 g of sodium hydroxide in 2 ml of water, and the mixture was heated under reflux for 3 hours. The reaction mixture was poured into an ice-water, acidified by addition of hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent removed by distillation to give 1.4 g of crystals of the desired compound. Recrystallization of the product from a mixture of ether-n-hexane afforded colorless crystals, m.p. 146°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: CC(C)c1ccnc(C(=O)CBr)c1
Product: COC(=O)Cc1c(C(=O)c2cc(C(C)C)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-4-isopropylpyridine*.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([CH:18]3[CH2:20][CH2:19]3)[C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:29]=[C:30]([Cl:36])[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1>CO.C(Cl)Cl>[Cl:36][C:30]1[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=[C:28]([NH:27][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([CH:18]3[CH2:20][CH2:19]3)[C:13]=2[C:14]([F:17])([F:16])[F:15])[CH:29]=1
Reactant: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)cc(Cl)c1=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (Step 40.2) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2) at RT for 3 days. tR: 1.24 min (LC-MS 2); ESI-MS: 529 [M+H]+ (LC-MS 2); Rf=0.52 (5% MeOH/CH2Cl2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[C:10]([C:19]([OH:21])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClC(OC(C)C)=O.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[C:10]([C:19]([NH:39][CH:36]3[CH2:38][CH2:37]3)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: O=C(O)c1nn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1nn(-c2cccc(Br)c2)c2ncccc2c1=O
Yield: 96.7 %

Procedure:
To 1-(3-bromophenyl)-4-oxo-1,4-dihydropyridino[2,3-c]pyridazine-3-carboxylic acid (3.25 g, 9.4 mmol) in dichloromethane (50 mL) was added triethylamine (2.37 g, 23.5 mmol), isopropyl chloroformate (1.49 g, 12.2 mmol), reacted at room temperature for 2 h, cyclopropylamine (0.54 g, 9.4 mmol) was added, reacted at room temperature overnight, extracted with H2O/DCM, organic phase was rotated for dryness to obtain product 3.5 g.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][C:12]2=[O:17])=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[S:24][C:23]=2[CH:31]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25]([S:27]([N:14]3[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:5]4[CH:6]=[CH:7][N:2]=[N:3][CH:4]=4)[C:12](=[O:17])[CH2:13]3)(=[O:29])=[O:28])[S:24][C:23]=2[CH:31]=1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: O=C1CNCCN1CCNc1ccnnc1
Agent: Cl
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CCNc1ccnnc1
Yield: 50 %

Procedure:
1-[2-(Pyridazin-4-ylamino)-ethyl]-piperazin-2-one hydrochloride (0.5 g, 1.7 mmol), EXAMPLE 95, is reacted with 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (0.40 g, 1.5 mmol), EXAMPLE 1, using essentially the same procedure as described in EXAMPLE 719. Reverse phase HPLC purification gives the title compound (0.34 g, 0.75 mmol) as a white solid. MS m/z (M+H=452); 1H NMR (CD3OD, 300 MHz) δ8.6 (d, 1H), 8.4 (d, 1H), 8.05 (s, 1H), 8.05 (s, 1H), 7.9 (d, 1H), 7.5 (d, 1H), 7.2 (d, 1H), 3.8 (s, 2H), 3.4-3.7 (m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14]I)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Na+].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1
Reactant: Fc1ccc(C2(CI)CCOCC2)cn1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2ccc(F)nc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a solution of (2-fluoro-5-(4-(iodomethyl)tetrahydro-2H-pyran-4-yl)pyridine (330 mg, 1.03 mmol) in THF (5 mL) at −15° C., was added N-selectride (2.26 mL, 2.26 mmol) dropwise. The solution was stirred at ambient temperature for 16 h. The solution was recooled in an ice bath, and 0.3 mL of water was added. The resulting solution was stirred for 10 min. The solvent was removed under vacuum, and the residue was dissolved in DCM. Insoluble solid was filtered, and the filtrate was purified by flash column chromatography on silica gel (ISCO) eluting with 0-80% ethyl acetate in heptane to give to 2-fluoro-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridine (110 mg, 0.56 mmol, 54.8% yield) as colorless oil with >90% purity. LCMS (m/z): 196 (MH+), 0.64 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=[O:11])[CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH3:10].C1(C)C=CC(S([N:22]=[N+:23]=[N-])(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:12])[C:4](=[N+:22]=[N-:23])[C:5](=[O:11])[CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH3:10]
Reactant: C/C=C/CCC(=O)CC(=O)OC
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Product: C/C=C/CCC(=O)C(=[N+]=[N-])C(=O)OC
Yield: 85.5 %

Procedure:
In accordance with the process of Example 2, (E)-3-oxo-6-octenoic acid methyl ester (3.42 g; 20.1 m mol), triethylamine (2.03 g; 20.1 m mol), p-toluenesulfonyl azide(3.99 g; 20 m mol) were used as starting materials to obtain 3.37 g of (E)-2-diazo-3-oxo-6-octenoic acid methyl ester as yellow oily product.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7](O)[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.FC(F)(F)CO.B(F)(F)F>C(OCC)C>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C:6]([CH3:20])=[CH:7][O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: FB(F)F
Solvent: CCOCC
Solvent: OCC(F)(F)F
Product: CC1=CO[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 6 h
Yield: 33.3 %

Procedure:
To a solution of dihydroartemisinin (426 mg, 1.50 mmol) and 2,2,2-trifluoroethanol (220 μl, 3.00 mmol) in diethyl ether (30 ml) at room temperature under nitrogen was added boron trifluoride dietherate (3 drops). The mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated NaHCO3 solution, dried (MgSO4) and concentrated in vacuo. Flash chromatography (SiO2: 8% ethyl acetate/hexanes) gave 10β-[(2′,2′,2′-trifluoroethyl)oxy]dihydroartemisinin (157 mg, 29%) and 9,10-anhydrodehydroartemisinin (133 mg, 46%) both as white solids. Ether: M.p. 113.4-114.2° C.; [α]D20: +133° (c 0.30/CHCl3); νmax (film): 2984, 2960, 2928, 2870, 1454, 1414, 1378, 1308, 1278, 1174, 1150, 1110, 1052, 1036, 990, 972, 918, 874, 824; δH: 5.43 (1H, s, H-12), 4.90 (1H, d, J=3.46 Hz, H-10), 4.15 (1H, dq, J=12.2, 8.87 Hz, H-1′), 3.89 (1H, d, J=12.2, 8.67 Hz, H-1′), 2.65-2.75 (1H, m, H-9), 2.40 (1H, ddd, J=17.5, 13.4, 4.02 Hz), 2.07 (1H, ddd, J=14.6, 4.83, 3.01 Hz), 1.64-1.96 (5H, m), 1.22-1.58 (4H, m), 1.46 (3H, s, H-14), 0.98 (3H, d, J=5.94 Hz, H-16), 0.97 (3H, d, J=7.69 Hz, H-15); δC: 104.13, 102.41, 87.93, 80.73, 64.91 (d, J=34.3 Hz), 52.32, 43.99, 37.29, 36.17, 34.39, 30.44, 25.90, 24.47, 24.11, 20.13, 12.47; m/z (CI, NH3): 384 (M+NH4+, 16%), 367 (M++1, 2), 284 (100), 267 (72).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(O)CCC>[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH:24][C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1ccc(-c2[nH]c3ncnc(Cl)c3c2C)cc1
Solvent: CCCCO
Product: COc1ccc(-c2[nH]c3ncnc(Nc4cccc(Cl)c4)c3c2C)cc1
Reaction time: 8 h

Procedure:
4 g of 4-chloro-5-methyl-6-(4-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 8.45 ml of 3-chloro-aniline are heated under reflux in 400 ml of n-butanol for 20 hours. The brown solution is concentrated, the desired product already precipitating. The solution is stored overnight in a refrigerator and the product is filtered off with suction and washed with hexane/ethyl acetate, yielding the title compound in the form of colourless crystals; m.p. 265-268° C.; FAB-MS: (M+H)+ =365.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[N:15]([CH3:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[C:30](OC(=O)C)(=[O:32])[CH3:31]>C1COCC1>[C:30]([NH:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[N:15]([CH3:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1)(=[O:32])[CH3:31]
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(/C=C/C(=O)N(C)Cc2cc3ccccc3n2C)cn1
Yield: 95.5 %

Procedure:
To a stirred suspension of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-[(1-methyl-1H-indol-2-yl)methyl]acrylamide (0.50 g, 1.56 mmole) and NaHCO3 (0.51 g, 6.09 mmole) in THF (75 mL) was added acetic anhydride (0.38 g, 3.74 mmole). The reaction was heated at reflux for 24 hrs and then concentrated. The remaining residue was extracted with EtOAc and purified on silica gel (95:5 CHCl3/CH3OH) to give the title compound (0.54 g, 96%) as an off-white solid: MS (ES) m/e 363 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH2:16][C@@H:17]([OH:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C@@H]1CO1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH2:16][C@H:17]([OH:19])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C[C@H](C)O)c1
Agent: C[C@@H]1CO1
Product: Cc1ccc(OCc2ccccc2)c(C[C@@H](C)O)c1

Procedure:
The title compound 5a was prepared according to the method for preparation of compound 3b of Example 3 by replacing (S)-2-methyloxirane with (R)-2-methyloxirane.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[Cl:6][C:7]1[C:8]([C:16]#[N:17])=[N:9][CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:13][C:11]1[CH:12]=[C:7]([Cl:6])[C:8]([C:16]#[N:17])=[N:9][CH:10]=1
Reactant: N#Cc1ncc([N+](=O)[O-])cc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1ncc(N)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.4 %

Procedure:
A solution of tin chloride (52 g) and 3-chloro-2-cyano-5-nitro-pyridine (10.3 g) was stirred in ethyl acetate (200 mL) at room temperature for 10 minutes and at 70° C. for 4 hours. The solution was cooled to room temperature and diluted with ethyl acetate (500 mL). Sodium bicarbonate (100 g) added in four portions to the mixture within 4 hours. The mixture was stirred vigorously for 20 hours. The suspension was filtered and the filtrate was washed with saturated aqueous sodium bicarbonate solution. The solvent was evaporated to give 5-amino-3-chloro-2-cyanopyridine (4.34 g) as an off-white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:22])[N:11]2[C:16]=1[C:15]([N:17]1[CH:21]=NC=N1)=[N:14][CH:13]=[N:12]2.[CH:23]1([C:26]2[N:27]=[CH:28][C:29]3[CH2:35]NC[CH2:32][C:30]=3[N:31]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:23]1([C:26]2[N:27]=[CH:28][C:29]3[CH2:35][N:17]([C:15]4[C:16]5=[C:8]([C:3]6[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=6[F:1])[N:9]=[C:10]([CH3:22])[N:11]5[N:12]=[CH:13][N:14]=4)[CH2:21][CH2:32][C:30]=3[N:31]=2)[CH2:25][CH2:24]1
Reactant: Cc1nc(-c2ccccc2F)c2c(-n3cncn3)ncnn12
Reactant: c1nc(C2CC2)nc2c1CNCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2F)c2c(N3CCc4nc(C5CC5)ncc4C3)ncnn12
Reaction time: 18 h

Procedure:
A mixture of C6 (6.40 g, 21.7 mmol), 2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.84 g, 21.9 mmol) and cesium carbonate (7.06 g, 21.7 mmol) was stirred in N,N-dimethylformamide (45 mL) for 2 hours at room temperature. The reaction mixture was concentrated in vacuo, then stirred with water (45 mL) for 18 hours. Filtration provided the product as an off-white powder. Yield: 6.68 g, 16.6 mmol, 76%. This material was combined with product from two similar runs (total weight: 20.37 g) and triturated with a mixture of heptane (100 mL) and ethyl acetate (100 mL) for 3 days at room temperature. Filtration provided the product as an off-white powder (19.6 g). LCMS m/z 402.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.97 (s, 1H), 7.92 (br s, 1H), 7.63 (ddd, J=7.6, 7.4, 1.8 Hz, 1H), 7.36-7.41 (m, 1H), 7.27 (ddd, J=7.6, 7.6, 1.1 Hz, 1H), 7.07 (br ddd, J=9, 9, 1 Hz, 1H), 4.51 (s, 2H), 3.86-3.90 (m, 2H), 2.73 (s, 3H), 2.71-2.76 (m, 2H), 2.12-2.18 (m, 1H), 1.00-1.08 (m, 4H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1.N1[CH:27]=[C:26]([C:28]2[S:32][C:31]([O:33][C@@H:34]3[CH:41]4[CH2:42][N:37]5[CH2:38][CH:39]([CH2:43][CH:35]3[CH2:36]5)[CH2:40]4)=[N:30][N:29]=2)[CH:25]=N1.N>>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:26]([C:28]1[S:32][C:31]([O:33][C@@H:34]2[CH:41]3[CH2:42][N:37]4[CH2:38][CH:39]([CH2:43][CH:35]2[CH2:36]4)[CH2:40]3)=[N:30][N:29]=1)([CH3:27])([CH3:12])[CH3:25]
Reactant: c1n[nH]cc1-c1nnc(OC2C3CC4CC2CN(C4)C3)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Product: CC(C)(C)c1nnc(OC2C3CC4CC2CN(C4)C3)s1

Procedure:
The free base of the title compound was prepared from the product of Example 56A (929 mg, 3.02 mmol) according to Method C, and then converted to the p-toluenesulfonate salt using the procedure of Method H: 1H NMR (300 MHz, methanol-D4) δ ppm 1.42 (s, 9H) 1.99 (d, J=13.6 Hz, 2H), 2.21 (s, 1H), 2.32 (s, 2H), 2.36 (s, 3H), 2.73 (s, 2H), 3.52-3.81 (m, 6H), 5.52 (s, 1H), 7.23 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H). MS (DCI/NH3) m/z=294 (M+H)+. Anal. Calcd. for C15H23N3OS.C7H8O3S: C, 56.75; H, 6.71; N, 9.02. Found: C, 56.62; H, 6.81; N, 8.98.
Reaction SMILES: [C:1]([CH:3]([CH2:7][C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:9]=1[O:17][CH3:18])C(O)=O)#[N:2]>CN(C)C(=O)C>[Br:14][C:13]1[C:8]([CH2:7][CH2:3][C:1]#[N:2])=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[CH:11][CH:12]=1
Reactant: COc1ccc(Br)c(CC(C#N)C(=O)O)c1OC
Solvent: CC(=O)N(C)C
Product: COc1ccc(Br)c(CCC#N)c1OC
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A solution of 2-cyano-3-(6-bromo-2,3-dimethoxyphenyl)-propionic acid (39.25 g, 0.125 mole), and 80 mL N,N-dimethylacetamide was stirred at 160° for 1.25 hr. After cooling to room temperature, the solution was poured onto ice with stirring. The solid was filtered, washed with water, dried (in-vacuo) to yield 32.7 g white solid, (97%); M+ 269.
Reaction SMILES: [C:1]([NH:20][C@H:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:42][CH:41]=1>O1CCCC1>[CH2:47]([O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][CH:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][C@@H:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:45][CH:44]=1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(Cc1ccc(OCc2ccccc2)cc1)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35.8 %

Procedure:
Di-tert-butyl N-trityl-L-glutamate (1.63 g, 3.25 mmol) was dissolved in tetrahydrofuran (12 ml) and the solution was cooled to −78° C. To the solution was added lithium 1,1,1,3,3,3-hexamethyldisilazide (1M in tetrahydrofuran, 7.14 ml) and, after stirring at −78° C. for 20 min, benzyl 4-(bromomethyl)phenyl ether (1.08 g, 3.90 mmol) in tetrahydrofuran (8 ml) was slowly added. The cooling bath was removed and the reaction mixture was stirred for 2 h. Then, 50 ml of 2 M aqueous hydrogen chloride solution were added and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure; the residue was purified by silica gel column chromatography to yield 813 mg (30%) of the product.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[CH:60][C:59]=2[C:65]([F:68])([F:67])[F:66])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[F:64][C:62]1[CH:61]=[CH:60][C:59]([C:65]([F:67])([F:66])[F:68])=[C:58]([CH:63]=1)[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:22]([C:19]2[CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[F:10])[NH:21][N:20]=2)=[O:24])[CH2:52][CH2:53]1)=[O:69]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccccc2F)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2F)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 46.2 %

Procedure:
DIPEA (123 mg, 0.16 mL, 0.95 mmol) was added to a stirred solution of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (56 mg, 0.27 mmol) in DMF (2 mL). HOBT (39 mg, 0.28 mmol) and EDCI (55 mg, 0.28 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (100 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitate. The solid was purified by recrystallisation from a mixture of ethyl acetate and hexane to afford 65 mg (33.16% yield) of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 97.49%. 1H NMR (DMSO-d6): δ 13.6 (s, 1H), 7.7 (m, 4H), 7.6 (m, 1H), 7.38 (m, 3H), 7.1 (m, 2H), 6.98 (m, 4H), 4.5 (m, 1H), 4.0 (m, 1H), 3.2 (m, 2H), 2.9 (m, 2H), 1.91 (m, 1H), 1.65 (m, 2H), 1.4 (m, 2H).