Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[N:30]1([CH2:36][C:37]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:38])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]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>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:9]([C:27]([N:33]3[CH2:32][CH2:31][N:30]([CH2:36][C:37](=[O:38])[N:39]4[CH2:40][CH2:41][CH2:42][CH2:43]4)[CH2:35][CH2:34]3)=[O:29])[NH:10][CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:12]2([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)N2CCN(CC(=O)N3CCCC3)CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 70.8 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (65.0 mg, 0.33 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-Chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile (60.5 mg, 70.8%).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[F:19][C:20]([F:41])([F:40])[CH2:21][NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30]2[C:35]([NH2:36])=[CH:34][N:33]=[C:32]3[CH:37]=[CH:38][S:39][C:31]=23)[CH2:25][CH2:24]1>O1CCCC1.C(O)C>[F:41][C:20]([F:19])([F:40])[CH2:21][NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([N:29]2[C:30]3=[C:31]4[S:39][CH:38]=[CH:37][C:32]4=[N:33][CH:34]=[C:35]3[N:36]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:27][CH2:28]1
Reactant: C[C@@H](O)C(N)=O
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](NCC(F)(F)F)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](NCC(F)(F)F)CC1
Reaction time: 0.25 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (21 mg, 0.24 mmol) and triethyloxonium tetrafluoroborate (45 mg, 0.24 mmol) in tetrahydrofuran (0.3 mL) became a solution after stirring for 15 min. After another 45 min, this solution was added to a mixture of N7-{trans-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}thieno[3,2-b]pyridine-6,7-diamine (27 mg, 0.078 mmol) in ethanol (0.62 mL) and heated at reflux for 2 h. The resulting mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (3.2 mg, 10%). LCMS calculated for C18H22F3N4OS (M+H)+: m/z=399.1. Found: 399.2.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][CH:17]([SH:19])[CH3:18]>CN(C=O)C>[CH:17]([S:19][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:18])[CH3:16]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Sc1ccccc1C=O
Temperature: 50 °C
Yield: 88.9 %

Procedure:
2-fluoro-benzaldehyde (2.00 g, 16.1 mmol), potassium carbonate (2.45 g, 17.1 mmol) and 2-propanethiol (1.35 g, 17.1 mmol) were dissolved in 10.0 mL, DMF in a 50 mL round-bottomed flask under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 50° C. for 48 h. After cooling the mixture was added to 50 mL of saturated potassium carbonate solution, and the mixture was extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The yellow oil residue of the crude product was further purified by chromatography on silica gel using 95:5 petroleum ether (60-80) and dichloromethane as eluent to afford a yellow oil (2.58 g, 89%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][N:20]=1)[C:13]([O:15]CC)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][N:20]=1)[C:13]([OH:15])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A solution of ethyl 2-benzamidoisonicotinate (1.38 g, 5.09 mmol) and lithium hydroxide monohydrate (1.07 g, 24.45 mmol) in a mixture of tetrahydrofuran (30 mL) and water (15 mL) was stirred at ambient temperature for 4 hours and the organic solvent was removed in vacuo. The aqueous solution was acidified with 10% aqueous hydrochloric acid solution until pH 7. The colorless solid was collected and dried in vacuo to give 2-benzamidoisonicotinic acid as a colorless solid (1.10 g, 89%): 1H NMR (300 MHz, DMSO-d6) δ 13.69 (s, 1H), 11.95 (s, 1H), 8.71 (s, 1H), 8.57-8.56 (m, 1H), 8.05-8.03 (m, 2H), 7.61-7.50 (m, 4H); MS (ES+) m/z 243.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:50][O:51][C:52](=[O:65])[CH2:53][CH2:54][NH:55][C:56](=[O:64])[C:57]1[CH:62]=[CH:61][C:60](O)=[CH:59][CH:58]=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:50][O:51][C:52](=[O:65])[CH2:53][CH2:54][NH:55][C:56](=[O:64])[C:57]1[CH:62]=[CH:61][C:60]([O:16][CH2:15][C:12]2[CH:13]=[N:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:59][CH:58]=1
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (120 mg, 0.47 mmol) in THF (2 mL) and toluene (4 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 179.5 mg, 0.71 mmol) at 0° C., followed by the addition of tributylphosphine (0.18 mL, 0.71 mmol) and 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (127 mg, 0.57 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 3-{4-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-benzoylamino}-propionic acid methyl ester. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 3-{4-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-benzoylamino}-propionic acid (33 mg). MS (ES): 443.2 [M+H]−.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:22])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:22])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cnc3ccc(Br)cc3c2n1-c1ccccc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(-c2ccccc2Cl)c2c3cc(Br)ccc3ncc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
300 mg (0.8 mmol) of 8-bromo-1-(2-chloro-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one [see under B)] are dissolved in 5 ml of anhydrous N,N-dimethylformamide and 35 mg (0.8 mmol) of NaH are added portionwise. The suspension is stirred for 90 min at room temperature and 113 mg (0.8 mmol) of methyl iodide dissolved in 3 ml of N,N-dimethylformamide are added. After stirring for 18 h at room temperature, the solution is cooled at 0° C. and 20 ml of water are added slowly to the stirred suspension. The suspension is extracted with ethyl acetate and the water phase is discarded. The organic phase is washed with brine, dried with Na2SO4 and evaporated to dryness. The crude compound is purified by flash-chromatography (dichloromethane with 2% methanol) to provide the title compound: Analytical HPLC: tret=7.64 min (Grad. 2); ES-MS: m/e0=388.0, 390.0.
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1)[CH3:2].C1C=CC=CC=1.[Cl:20][CH:21]([Cl:25])[C:22](Cl)=[O:23]>C(N(CC)CC)C>[CH2:1]([CH:3]1[N:7]([C:22](=[O:23])[CH:21]([Cl:25])[Cl:20])[CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1)[CH3:2]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCC1NCC(c2ccccc2)O1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC1OC(c2ccccc2)CN1C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Twenty-one and three tenths (21.3) ml. of a solution containing 5.3 g. of 2-ethyl-5-phenyl oxazolidine was diluted with 25 ml. of benzene and 3.1 g. of triethylamine was added. The mixture was cooled in a room temperature water bath and 4.4 g. of dichloroacetyl chloride was added dropwise with stirring. The stirring was continued for about 30 minutes after addition was complete. The solution was washed with water, separated, dried over magnesium sulfate and removed under vacuum. There was obtained a yield of 8.7 g. of the title compound, an oil, ND30 =1.5600.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C)(=O)C.[N+:23]([O-])([OH:25])=[O:24]>O>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([N+:23]([O-:25])=[O:24])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)Nc1ccc(C2CCCC2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C2CCCC2)cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
To a suspension of N-(4-cyclopentylphenyl)acetamide (Preparation 97, 18.5 g, 91.0 mmol) in acetic anhydride (148 mL, 1570 mmol) cooled in an ice/brine bath was added dropwise a solution of nitric acid (5.7 mL, 140 mmol) in acetic anhydride (40 mL, 400 mmol). After stirring for 4 hours, the reaction mixture was added water and extracted with methylene chloride (3×). The organic layers were combined, dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. This provided product (19.48 g, 86%) as a brown oil that was used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9](Cl)[C:8]([CH3:12])=[C:7]([Cl:13])[N:6]=1)(=O)[CH3:2].[OH2:14]>O1CCCC1.C(N(CC)CC)C.CN1CCNCC1>[C:7]([NH:6][CH:1]1[CH2:2][N:4]([CH3:5])[CH2:1][CH2:2][N:4]1[C:5]1[N:10]=[CH:9][C:8]([CH3:12])=[C:7]([Cl:13])[N:6]=1)(=[O:14])[CH3:8]
Reactant: CC(=O)Nc1nc(Cl)c(C)c(Cl)n1
Reactant: O
Agent: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC1CN(C)CCN1c1ncc(C)c(Cl)n1
Reaction time: 6 h

Procedure:
8.8 parts of 2-acetylamino-4,6-dichloro-5-methylpyrimidine are dissolved in 100 parts by volume of tetrahydrofuran in the presence of 4 parts of triethylamine and 4 parts of N-methylpiperazine. The mixture is held for 6 hours at the reflux temperature. The reaction mixture is poured into water and the insoluble material is filtered off which is recrystallised from ethanol. M.p. 202° C.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:21][NH2:22]>C(O)CCC>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:21][NH2:22])=[O:2])[CH2:6][CH2:7]1)#[N:19]
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cccc(C#N)c2)CC1
Solvent: CCCCO
Solvent: O
Product: N#Cc1cccc(O[C@H]2CC[C@H](C(=O)NN)CC2)c1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(3-cyano-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.277 g, 1.07 mmol) and hydrazine hydrate (0.104 ml, 2.14 mmol) in n-butanol (0.5 ml) was heated at 120° C. for 18 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The layers were separated and the aqueous layer was extracted with a 50-ml portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated in methanol (7 ml). The solids were removed by filtration and the filtrate was concentrated in vacuo to give the crude title compound (0.15 g, 55%) as light red solid, which was used in the next step without further purification. MS m/e: 260 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][N:12]2[CH:16]=[C:15](C)[N:14]=[CH:13]2)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:18].[CH3:19]C1N=CNC=1.CN1CCNCC1.CN(C=O)C>CCO>[CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][N:12]2[C:16]([CH3:19])=[CH:15][N:14]=[CH:13]2)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:18]
Reactant: Cc1cn(Cc2cc(C)c3c(c2)C(=O)CC3)cn1
Reactant: Cc1c[nH]cn1
Agent: CN1CCNCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cncc2C)cc2c1CCC2=O

Procedure:
A mixture of Example 922A and Example 922B was obtained by substituting Example 917G for Example 54, 4-methylimidazole for N-methypiperazine, and DMF for EtOH in Example 56. The isomers were separated by flash chromatography.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:15][O-:16].[Na+].CO>O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([O:16][CH3:15])=[N:3][CH:4]=[CH:5][N:6]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2nccnc2Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nccnc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
Next, 3.87 g of 2-chloro-3-(4-fluorophenyl)pyrazine, 2.01 g of sodium methoxide, and 30 mL of methanol were put in a three-neck flask equipped with a reflux pipe, and reacted by being heated and refluxed under a nitrogen atmosphere for three hours. After the reaction, the reaction solution was cooled down to room temperature, water was added thereto, and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with a saturated saline and water, and dried with magnesium sulfate. Then, magnesium sulfate was removed by filtration and the solvent was distilled off, so that 2-(4-fluorophenyl)-3-methoxypyrazine was obtained (milky white powder, yield: 96%). A synthetic scheme of Step 2 is shown in the following (a1-2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].Cl>N1CCCCC1.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Br)c1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(Br)c1
Temperature: 100 °C
Yield: 94.4 %

Procedure:
3-Bromobenzaldehyde (10.0 g, 54 mmol), malonic acid (10.1 g, 97 mmol) and piperidine (0.267 mL, 2.7 mmol) are treated with pyridine (30 mL) and heated at 100° C. for 3.5 h. The reaction mixture is cooled to room temperature, poured into 200 ml of 20% hydrochloric acid at 0° C.; the resultant precipitate is collected, washed with copious amounts of water and dried in a vacuum dessicator overnight to afford the title compound (11.64 g, 51 mmol).
Reaction SMILES: [Cl-].[NH2:2][C:3]1([CH2:33][CH2:34][OH:35])[CH2:7][CH2:6][C@@H:5]([C:8]([NH:10][C@H:11]([CH:30]([CH3:32])[CH3:31])[C:12]([N:14]2[CH2:19][CH2:18][C@@:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([OH:20])[C:16]([CH3:29])([CH3:28])[CH2:15]2)=[O:13])=[O:9])[CH2:4]1.[C:36](C1NC=CN=1)(C1NC=CN=1)=[O:37].C(N(CC)CC)C>C1COCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@@:17]2([OH:20])[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C@H:11]([NH:10][C:8]([C@@H:5]3[CH2:6][CH2:7][C:3]4([CH2:33][CH2:34][O:35][C:36](=[O:37])[NH:2]4)[CH2:4]3)=[O:9])[CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2([CH3:29])[CH3:28])=[CH:22][CH:23]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)[C@@H](NC(=O)[C@@H]1CCC(N)(CCO)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)[C@@H]1CCC2(CCOC(=O)N2)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.33 %

Procedure:
To a solution of (1R)-3-amino-N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-(2-hydroxyethyl)cyclopentanecarboxamide (from step F, 30 mg, 0.061 mmol) in THF (1 mL) was added carbonyl diimidazole (14.77 mg, 0.091 mmol) and triethylamine (0.021 mL, 0.152 mmol). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and subjected preparative HPLC(Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA; wavelength: 220 nM) to yield the desired product as a diastereomer mixture. The diastereomer mixture was subjected to chiral preparative HPLC (Column: ChiralPak ASH, 250×3 cm, 5 μm; Flow rate: 120 mL/min; Mobile Phase: CO2/MeOH=80/20; Inj. Vol.=2.0 mL, Wavelength=220 nM; isomer 1, retention time=5.75 min; isomer 2, retention time=9.10 min) to yield the individual diasteromers (2 mg for each isomer, 3.85 μmol, 6.33% yield) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[I-:14].[Na+].C(N)CCN>C(O)CCCC>[I:14][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: [I-]
Agent: NCCCN
Agent: [Na+]
Solvent: CCCCCO
Product: Ic1ccc(-c2ccccc2)cc1

Procedure:
30 g of 4-bromobiphenyl is dissolved in 40 mL of n-pentanol. 2 equivalents of sodium iodide and 10 mole % of 1,3-propanediamine are added to the 4-bromobiphenyl solution. The reaction mixture is refluxed at 130° C. for sixteen (16) hours to produce 4-iodobiphenyl, as shown in reaction scheme (5).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[O:10])=[N:4][C:5]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2nc(Br)cnc2N)C1
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2nc(-c3cccc(CO)c3)cnc2N)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
1,1-dimethylethyl (3S)-3-{[(3-amino-6-bromopyrazin-2-yl)carbonyl]amino}piperidine-1-carboxylate (765.0 mg, 1.91 mmol) was dissolved in DMF followed by addition of 3-hydroxymethyl phenylboronic acid (349.0 mg, 2.23 mmol), K2CO3 (660.0 mg, 4.77 mmol) and Pd(PPh3)4 (10 mol %, 220 mg). This mixture was stirred at 90° C. under nitrogen for 12 hours. The reaction mixture was poured into water (150 mL), and extracted with ethyl acetate (3×50 mL). The organic layers were washed with brine (50 mL) then dried over anhydrous sodium sulfate. Filteration, concentration and column chromatography on silica (50% ethylacetate/hexanes) gave a solid which was dried to affored 765.0 mg (92% yield) of 1,1-dimethylethyl (3S)-3-[({3-amino-6-[3-(hydroxymethyl)phenyl]pyrazin-2yl}carbonyl)amino]piperidine-1-carboxylate: MS (EI) for C22H29N5O4: 428.23 (MH+).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[CH3:10][C:11]([S:14]([NH:16][C@@H:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1)[C:18]#[CH:19])=[O:15])([CH3:13])[CH3:12].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].C(O)CCC.O>O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][N:1]1[CH:19]=[C:18]([C@H:17]([NH:16][S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[CH:22][N:21]=2)[N:3]=[N:2]1)[CH3:9]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C#C[C@@H](NS(=O)C(C)(C)C)c1ccc(OCC(F)(F)F)cn1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CCOC(=O)Cn1cc([C@H](NS(=O)C(C)(C)C)c2ccc(OCC(F)(F)F)cn2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
To a 50 ml round bottom flask equipped with a magnetic stir bar were added ethyl azidoacetate (0.193 g, 1.495 mmol), 2-methyl-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]prop-2-yn-1-yl}propane-2-sulfinamide (0.500 g, 1.495 mmol), freshly made 1.0 N sodium ascorbate (0.150 ml, 0.150 mmol), and 1.0 N Cu2SO4 (0.150 ml, 0.150 mmol) into 6.0 ml of a mixed solvent BuOH/H2O (1:1). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by flash chromatography (SiO2, 50-80% ethyl acetate in hexanes, gradient) gave the title compound as a light yellow solid (0.365 g, 53%). 1H NMR (CDCl3, 400 MHz) δ 8.291 (d, J=2.93 Hz, 1H), 7.634 (s, 1H), 7.452 (d, J=8.79 Hz, 1H), 7.247 (ABq, J=3.03 Hz, 1H), 5.879 (d, J=5.50 Hz, 1H), 5.349 (d, J=5.31 Hz, 1H), 5.125 (ABq, J=7.49 Hz, 2H), 4.381 (q, J=7.87 Hz, 2H), 4.255 (q, J=7.14 Hz, 2H), 1.290 (t, J=7.14 Hz, 3H), 1.271 (s, 9H). ES-MS [M+1]+: 464.1.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Brc1cnc2ccc(N3CCOCC3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and morpholine according to general procedure 1 providing the amino compound (235 mg, 85%) as a yellow solid: Rf=0.79 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J=9.9 Hz, 1H), 7.53 (s, 1H), 6.81 (d, J=9.9 Hz, 1H), 3.86 (t, J=5.0 Hz, 4H), 3.55 (t, J=4.8 Hz, 4H); ES-MS: (M+H)=283, 285 m/z.