Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1.[C:27]([O-])(=[O:31])[C@H:28]([CH3:30])[OH:29].[Na+]>CN(C=O)C>[OH:29][C@@H:28]([CH3:30])[C:27]([N:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1)=[O:31]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Reactant: C[C@H](O)C(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(C(=O)[C@H](C)O)C3)cc1-2

Procedure:
Following the procedure for 318, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and sodium L-lactate were reacted in DMF to give 359. LCMS: RT=10.69 min, [M+H]+=440. 1H NMR δ (ppm) (CDCl3): 8.36 (1 H, s), 7.90 (1 H, s), 7.20-7.11 (1 H, m), 7.09-7.01 (1 H, m), 5.84-5.75 (1 H, m), 4.62-4.30 (4 H, m), 4.26-4.07 (3 H, m), 3.98-3.87 (1 H, m), 3.43-3.35 (2 H, m), 1.61 (6 H, d, J=6.65 Hz), 1.32 (3 H, dd, J=10.70, 6.64 Hz). 1 Exchangeable not observed
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.[OH:15][CH:16]=[C:17]([O:24][CH3:25])[C:18](OCCC)=O.C(Cl)(Cl)Cl>O>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][CH:18]=[C:17]([O:24][CH3:25])[C:16](=[O:15])[N:6]2[N:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1nnc(SCc2ccccc2)s1
Reactant: CCCOC(=O)C(=CO)OC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cnc2sc(SCc3ccccc3)nn2c1=O
Reaction time: 0.33 h
Yield: 93 %

Procedure:
Four (4) grams of the thus obtained 2-amino-5-benzylthio-1,3,4-thiadiazole, 3.2 g of propyl 3-hydroxy-2-methoxy-propenoate and 11 g of polyphosphoric acid were heated to 135° C. and stirred for 20 minutes. After cooling, chloroform and water were added thereto, extraction was carried out. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was washed with an ethanol/hexane mixture and 5.1 g of 2-benzylthio-6-methoxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 93%. The compound was recrystallized from ethanol. m.p. 145°-147° C.
Reaction SMILES: [OH:1][NH2:2].[O:3]([C@H:10]1[CH2:15][C@H:14]([C:16](OC)=[O:17])[C@@H:13]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[O:21])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>CO>[OH:1][NH:2][C:16]([C@H:14]1[CH2:15][C@H:10]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:11][CH2:12][C@@H:13]1[C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21])=[O:17]
Reactant: COC(=O)[C@H]1C[C@H](Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(NO)[C@H]1C[C@H](Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydroxyamine in MeOH (1.5 M, 0.75 ml) was added to methyl (1S,2S,5R)-5-phenoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexane-carboxylate (0.29 mmol, 0.00029 mol) in MeOH (0.5 mL) at RT. The resulting mixture was stirred at RT for 2 hrs, and was adjusted to PH=2.0 with TFA, and then was purified by Prep-HPLC to give the desired product. LCMS: (M+H)+=424.2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: Ic1ccccc1
Product: c1ccc(-n2ccnc2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-imidazole (102 mg, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: hexane/ethylacetate=20/80) to provide 130 mg (90% isolated yield) of the desired product as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[Li]CCCC.C(OC([N:23]1[CH2:28][CH2:27][C:26]2([CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH2:25][CH2:24]1)=O)(C)(C)C>C1COCC1>[Cl:10][C:5]1[CH:4]=[CH:3][C:2]([C:31]2[CH2:32][CH2:33][C:26]3([CH2:27][CH2:28][NH:23][CH2:24][CH2:25]3)[CH2:29][CH:30]=2)=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: COc1cc(Br)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C2=CCC3(CCNCC3)CC2)ccc1Cl
Reaction time: 0.5 h

Procedure:
Was prepared according to method A with the following variation: A solution of 5-bromo-2-chloroanisol (1.26 g, 5.7 mmol) in THF (7 mL) was added drop-wise to a solution of n-BuLi (1.6 M in hexanes (3.8 mL, 6.1 mmol)) at −78° C. and stirred for 30 min. A solution of 9-oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (475 mg, 1.78 mmol) in THF (7 mL) was added. The mixture was stirred for 1 h. White solid. Mp. 182-185° C.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:22]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=O)=O)=CC=1.[C:34]([O-])(=[O:36])[CH3:35].[Na+]>CS(C)=O.CCOC(C)=O>[C:34]([O:11][CH2:12][C:13]12[CH2:18][CH2:17][C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:22]=3)([CH2:19][CH2:20]1)[O:15][CH2:14]2)(=[O:36])[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4cccc(Oc5ccccc5)c4)(CC2)OC3)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)OCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 70 °C
Reaction time: 72 h

Procedure:
A mixture of (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate (0.1 g, 0.215 mmol) and sodium acetate (0.212 g, 2.58 mmol) in DMSO (5 mL) was stirred at 70° C. in a seal tube for 3 days. The reaction was diluted with EtOAc (5 mL) and washed with water (3×5 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl acetate. The mixture of the above acetate (0.076 g, 0.216 mmol) and 1 M NaOH (0.65 mL, 0.647 mmol) in THF/MeOH (1:1 of a 2 mL solution) was stirred at rt for 18 h. The reaction was diluted with EtOAc (5 mL) and washed with water (3×5 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 50% EtOAc:hexanes) to afford the title compound (0.05 g, 75% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.39-7.26 (m, 3H), 7.21-7.14 (m, 2H), 7.14-7.08 (m, 1H), 7.05-7.00 (m, 2H), 6.88 (ddd, J=8.1, 2.5, 1.0 Hz, 1H), 3.99-3.89 (m, 2H), 3.38 (s, 2H), 2.16-2.00 (m, 4H), 1.84-1.71 (m, 3H), 1.71-1.57 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[CH:12]2C(OCC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl>[OH-].[K+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C2CC(=O)CC(=O)C2)cc1OC
Temperature: 50 °C
Yield: 90.7 %

Procedure:
10% Aqueous solution of potassium hydroxide (760 ml) was added to ethyl 2-(3,4-dimethoxyphenyl)-4,6-dioxocyclohexane carboxylate (122 g), and the mixture was refluxed for 3.5 hours. After cooling the reaction solution on ice, it was adjusted to pH1 with concentrated hydrochloric acid, and stirred at 50° C. for an hour. After allowing the reaction solution to cool, the deposited crystals were filtered by suction and washed with purified water and isopropyl ether to give 85.8 g of 5-(3,4-dimethoxyphenyl)cyclohexane-1,3-dione (90.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][S:5][CH:6]=1.[CH3:7][O:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12](B(O)O)=[CH:11][N:10]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[S:5]1[CH:6]=[C:2]([C:12]2[C:13]([O:15][CH3:16])=[N:14][C:9]([O:8][CH3:7])=[N:10][CH:11]=2)[CH:3]=[N:4]1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Brc1cnsc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ncc(-c2cnsc2)c(OC)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
4-bromoisothiazole (commercially available from Aurora, 500 mg, 3.05 mmol) was dissolved in degassed 1,2-Dimethoxyethane (DME) (5 ml). Pd(Ph3)4 (176 mg, 0.152 mmol) was added thereto. The reaction mixture was stirred at room temperature for 15 min. [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (commercially available from Aldrich, 1178 mg, 6.40 mmol) and 5 mL of degassed 1M/H2O solution of NaHCO3 were added to the reaction mixture under N2 atm. After 2 h 30 min stirring at 90° C. the mixture was diluted with water and extracted with DCM. The collected organic phases were evaporated. The residue was purified by flash chromatography eluting with cyclohexane/EtOAc 5:1. 686 mg of the title compound were isolated as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=Cc1ccc(C(C)(C)C)cc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(Cc1ccc(C(C)(C)C)cc1)C(=O)O
Reaction time: 5 h
Yield: 93.4 %

Procedure:
3-(4-tert-butylphenyl)-2-methylacrylic acid (40.9 mg, 0.19 mmol) and 10 wt. % palladium on activated carbon were added in methanol. The reaction mixture was stirred for 5 hrs under H2 gas. The reaction mixture was filtered with Celite. The filterate was concentrated in vacuo to obtain title compound (39.1 mg, 93.47%).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](C2N=CNN=2)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[CH:27]([NH2:30])([CH3:29])[CH3:28]>O1CCOCC1>[C:1]([NH:4][C:5]1[N:6]=[C:7]([NH:30][CH:27]([CH3:29])[CH3:28])[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2nc(-c3ccc(F)cc3)ccc2n1
Reactant: CC(C)N
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(NC(C)C)c2nc(-c3ccc(F)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
To a suspension of the 2-acetamido-4-(1,2,4-triazolyl)-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine of example 2 (70 mg) in dioxane (5 ml) was added isopropylamine (0.4 mmol). The reaction was stirred at room temperature for 24 hours. The solvents were evaporated in vacuo, yielding the crude title compound which was purified by preparative TLC on silica, using a mixture of methanol and dichloromethane, in a ratio of 10:90 as mobile phase, thus providing the title compound in 73% yield. The pure title compound was characterized by its mass spectrum as follows: MS (m/z): 340 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N:12]2[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]2)=[C:10]([Cl:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5]>O1CCOCC1.[OH-].[Na+].O>[Cl:1][C:2]1[C:11]([N:12]2[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]2)=[C:10]([Cl:19])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(Cl)c(-n2nnn(C)c2=O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nnn(-c2c(Cl)ccc(C(=O)O)c2Cl)c1=O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
To a solution of methyl 2,4-dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoate (4.10 g) in dioxane (70 ml), 10N sodium hydroxide (2.0 ml) and water (4 ml) were added and the mixture was stirred at 60° C. for 1.5 hours. After concentrating under reduced pressure and the addition of water (50 ml), an aqueous solution of sodium hydroxide was added and washed with ethyl acetate (150 ml). The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt water and dried with anhydrous magnesium sulfate. By distilling off of ethyl acetate, the objective 2,4-dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoic acid (3.42 g, yield 87%) was obtained. mp: 221-225° C.
Reaction SMILES: [O-]CC.[K+:4].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[C:15](#[N:18])[CH2:16][CH3:17]>CCO>[C:15]([C:16]([CH3:17])=[C:6]([C:5]([O:12][CH2:13][CH3:14])=[O:11])[O-:8])#[N:18].[K+:4]
Reactant: CCC#N
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C([O-])=C(C)C#N

Procedure:
Placed potassium ethoxide (1.0 eq.) in a sealed tube with EtOH and shook until dissolved. A mixture of diethyl oxalate (1.0 eq.) and propionitrile (1.0 eq.) was added to the sealed tube and the mixture was capped and stirred at reflux. After a time sufficient for reaction completion, the reaction was cooled and the precipitate collected and washed with diethyl ether to afford 47.
Reaction SMILES: [CH3:1]I.[Na].[NH2:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([O:25][CH3:26])[C:17]=2[CH3:27])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].O>CN(C=O)C>[NH2:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([O:25][CH3:26])[C:17]=2[CH3:27])=[O:15])=[CH:10][C:6]=1[C:7]([O:9][CH3:1])=[O:8]
Reactant: CI
Reactant: COc1c(C)c(C(=O)c2ccc(N)c(C(=O)O)c2)n2ccccc12
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1N
Reaction time: 1 h

Procedure:
1.51 ml (24.26 mmol) of methyl iodide are added, under an inert atmosphere at ambient temperature, to 8 g (23.1 mmol) of the sodium salt of 2-amino-5-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]benzoic acid (described in WO 03/084956) in 130 ml of DMF. After stirring for 1 hour, water is added. The precipitate formed is filtered off, rinsed with water, and then dried under reduced pressure at 50° C. overnight. 7.17 g of a yellow solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[CH:14]2)=[O:7].CO.[ClH:26]>[Pt]=O>[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][NH:13][CH2:14]2)=[O:7]
Reactant: COc1ccc(C(=O)Nc2cccc3cnccc23)cc1OC
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=O)Nc2cccc3c2CCNC3)cc1OC

Procedure:
5-(3,4-dimethoxybenzamido) isoquinoline (2.7 g) was dissolved in 10% hydrochloric acid (100 ml) and methanol (100 ml) with warming. This was hydrogenated over platinum oxide (200 mg) at 45 psi. The catalyst was removed by filtration and the filtrate cooled in the refrigerator. A white precipitate formed and was collected by filtration and recrystallized from methanol to yield 2.1 g of 5-(3,4-dimethoxybenzamido)-1,2,3,4-tetrahydroisoquinoline hydrochloride as a white crystalline powder, m.p., 287°-288° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6](Cl)=[N:7]2.[NH4+:14].[OH-]>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([NH2:14])=[N:7]2
Reactant: Clc1nc2cccc(Br)c2nc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2cccc(Br)c2nc1Cl
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a solution of 5-bromo-2,3-dichloroquinoxaline (Leadgen Labs, Orange, Conn.; 2.00 g, 7.20 mmol) in 50 mL DMF at 0° C. was added NH4OH (30% NH3 in water; 18.68 ml, 144 mmol) dropwise via syringe. A thick solid formed. 2 mL DMF was added to promote stirring. The thick reaction was sealed and stirred for 2 h at RT. The reaction was diluted with 250 mL water and let stand overnight. In the morning, it was filtered and the solid was air dried, treated with silica gel and DCM, and concentrated in vacuo. The material was purified by silica gel chromatography using 0-50% EtOAc/hexane to separately provide 5-bromo-3-chloroquinoxalin-2-amine (0.510 g, 1.973 mmol, 27% yield) as a peach-colored solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69-7.76 (1H, m), 7.43-7.61 (4H, m). m/z (ESI, +ve) 259.9 (M+H)+ and 8-bromo-3-chloroquinoxalin-2-amine (0.78 g, 3.02 mmol, 42% yield) as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (1H, dd, J=7.6, 1.4 Hz), 7.73-7.79 (1H, m), 7.61 (2H, br. s.), 7.30 (1H, t, J=7.9 Hz). m/z (ESI, +ve) 259.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[I:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[CH3:19])[NH2:15]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:12]([I:11])[CH:13]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Cc1ccc(N)cc1I
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1I
Yield: 89.7 %

Procedure:
2-Chloroisonicotinic acid (3.3 g) HATU (8.75 g) DIPEA (10.9 ml) and 3-iodo-4-methylaniline (5.00 g) in DMF (50 ml) were heated under nitrogen for 16 h. The reaction was cooled, the solvent was removed under vacuum and the residue was dissolved in dichloromethane (150 ml). The solution was washed with water (3×100 ml) and brine (100 ml) dried (magnesium sulphate) and the solvent was removed under vacuum. The residue was purified by column chromatography on silica eluting with ethyl acetate/cyclohexane (40:60) to give the title compound as a white solid (7.00 g).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH:9]([OH:12])[CH2:10][NH2:11].OC(COC1C2C(=CC=CC=2)C=CC=1)CN[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2>>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH:9]([OH:12])[CH2:10][NH:11][C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2
Reactant: OC(CNc1ncnc2[nH]cnc12)COc1cccc2ccccc12
Reactant: NCC(O)COc1ccccc1-c1ccccc1
Product: OC(CNc1ncnc2[nH]cnc12)COc1ccccc1-c1ccccc1

Procedure:
By substituting 3-[(1,1'-biphenyl)-2-yloxy]-2-hydroxypropylamine (4.88 g, 0.0174 moles) for the starting material of Example 2 and following the method of Example 2, the desired compound is obtained.
Reaction SMILES: [C:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:5]#[N:6])(=O)[CH3:2].Cl.[NH2:21][NH:22]C(N)=O.CO>O>[NH2:6][C:5]1[C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[C:1]([CH3:2])[NH:22][N:21]=1
Reactant: CC(=O)C(C#N)c1ccc(Sc2ccccc2)cc1
Reactant: NNC(N)=O
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1[nH]nc(N)c1-c1ccc(Sc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
A mixture of 520 mg of α-acetyl-4-phenylthiophenylacetonitrile, 217 mg of semicarbazide hydrochloride, 15 ml of methanol and 3 ml of water was stirred at 0° C. for 10 minutes. Removing the ice bath, 40 hours later, the mixture was stirred at room temperature for 1 hour while keeping the pH at 9 to 10 by using aqueous solution of 2N sodium hydroxide. Adding 50 ml of water, the mixture was stirred for 30 minutes in ice-cooling, and the precipitate was filtered. It was directly added to the mixed solution of 5 ml of aqueous solution of 2N sodium hydroxide and 50 ml of methanol, and the mixture was stirred for 4 hours at room temperature, and then 80 ml of water was added, and the mixture was stirred for 30 minutes in ice-cooling, then the precipitate was filtered, Washed in water and dried, thereby obtaining 500 mg of the title compound.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C@@H:7]1[CH2:11][C@H:10]([C:12]#[N:13])[C@@H:9]([O:14][CH3:15])[CH2:8]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)C>C1COCC1>[OH:6][C@@H:7]1[CH2:11][C@H:10]([C:12]#[N:13])[C@@H:9]([O:14][CH3:15])[CH2:8]1
Reactant: CO[C@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CO[C@H]1C[C@H](O)C[C@@H]1C#N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88.5 %

Procedure:
A solution of (1S,2R,4S) and (1R,2S,4R)-4-(tert-butyl-diphenyl-silanyloxy)-2-methoxy-cyclopentanecarbonitrile (3.86 g, 10.17 mmol) in THF (20 ml) was added to a solution of TBAF (20.3 ml, 20.3 mmol, 1M solution in THF) and acetic acid (1.2 ml, 20.9 mmol) in THF (50 ml) at 0° C. After the addition was completed, the icebath was removed and the light brown solution was allowed to stir at room temperature for 3.5 h. The solution was then diluted with water and extracted 3 times with EtOAc. The combined organic layers were washed with a mixture of brine and saturated NaHCO3 solution, dried over Na2SO4 and evaporated. The remaining yellow oil was purified by silica gel chromatography (heptane/EtOAc 70:30-45:55) to obtain the title compound as yellow oil (1.29 g, 9 mmol, 90%). MS (EI): 200.3 (M+OAc)−.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6](NCC3C=CC(F)=CC=3)[C:5]=2[C:4]([CH3:20])=[C:3]1[CH3:21].[ClH:22].CN1[C:32]2[CH:31]=[CH:30]N=[C:28]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:27]=2[C:26]([CH3:42])=C1C.C(=O)(O)[O-].[Na+].[F:49]C1C=CC(CBr)=CC=1>>[ClH:22].[F:49][C:30]1[CH:42]=[CH:26][C:27]([CH2:28][N:33]([C:9]2[C:10]3[N:2]([CH3:1])[C:3]([CH3:21])=[C:4]([CH3:20])[C:5]=3[CH:6]=[N:7][CH:8]=2)[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[CH:32][CH:31]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1c(C)n(C)c2ccnc(NCc3ccc(F)cc3)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(C)n(C)c2c(N(Cc3ccc(F)cc3)Cc3ccc(F)cc3)cncc12
Yield: 49.9 %

Procedure:
In accordance with the same procedures as in Example 47, except for using 1,2,3-trimethyl-4-(4-fluorobenzylamino)-1H-pyrrolo[3,2-c]pyridine obtained by treating the compound of Example 34 with a saturated sodium bicarbonate solution and 4-fluorobenzyl bromide, the titled compound was obtained as a white solid. (Yield: 49.9%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]=2)([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:36]([O:38][C:39]([CH3:41])=[CH2:40])=[O:37]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]([NH:20][C:36](=[O:37])[O:38][C:39]([CH3:41])=[CH2:40])([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: COc1ccc(C(N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(OC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a solution of 1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(5-methoxy pyridin-2-yl)-2-phenylethanamine (200 mg, 0.512 mmol) in THF (2 mL) was added 2N K2CO3 (0.5 mL, 1.0 mmol) and isopropenyl chloroformate (100 μl, 1.02 mmol). The resulting mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was dried in vacuo to yield prop-1-en-2-yl 1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(5-methoxypyridin-2-yl)-2-phenylethylcarbamate as white powder (120 mg, 50%). LCMS: RT=3.56 min [M+H] 475.2 (LCMS Method 1).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([I:10])=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CC#N.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([I:10])[CH:5]=1
Reactant: C1COCCN1
Reactant: Fc1cc(I)c(CBr)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: Fc1cc(I)c(CN2CCOCC2)cn1
Temperature: 81 °C
Yield: 99.7 %

Procedure:
In a flask, combine 5-bromomethyl-2-fluoro-4-iodo-pyridine (6.13 g, 19.4 mmol), morpholine (3.38 g, 38.8 mmol) and dry CH3CN (100 mL) under nitrogen. Add N,N-diisopropylethylamine (6.76 mL, 38.80 mmol, 2 M THF solution). Heat at 81° C. for 2 h and cool to RT. Dilute with DCM and wash with water and aqueous saturated sodium chloride. Separate the organic layer from the aqueous layer and dry over magnesium sulfate. After filtration, concentrate in vacuo to give the title compound 6.23 g (100%). MS (ES) m/z 323 [M+1]+.