Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:4]([C:1](=[O:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:13]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Brc1cccnc1
Product: CC(=O)N(c1ccccc1)c1cccnc1
Yield: 101 %

Procedure:
Acetanilide (6.0 g) and 3-bromopyridine (14.1 g) were used to make a reaction in the same manner as in 1) of Production Example 2. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane:=1:1 to 2:1) produced N-(3-pyridyl)-acetanilide (9.52 g, quantitative) as a pale red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:20]([O:22]C)=[O:21].CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1cc2c(OCCCO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(OCCCO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 16 h

Procedure:
Methyl N-(3,4-Dichlorobenzyl)-4-(3-hydroxypropyloxy)indole-2-carboxylate (6.9 g) was dissolved in THF (140 ml) and methanol (140 ml) and sodium hydroxide (3M, 110 ml) was added and the reaction stirred for 16 hours. The reaction was then concentrated in vacuo and the residue dissolved in water. The solution was acidified by dropwise addition of acetic acid, resulting in the precipitation of a white solid which was filtered, washed with water and dried in vacuo to give the desired end product (5.58 g. 84%); NMR d (CD3SOCD3) 1.92 (m, 2H), 3.60 (dd, 2H), 4.13 (dd, 2H), 5.89 (s, 2H), 6.52 (s, 1H), 6.94-7.11 (m, 4H), 7.32 (d, 1H), 7.47 (d, 1H); M/z (−) 392 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N+:9]([O-])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.P(Cl)(Cl)Cl.[OH-].[NH4+]>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: [O-][N+]1=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2ncncc2C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cncnc1-2

Procedure:
A mixture of 0.5 g (1.3 mmol) of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide and 1.0 ml (10 mmol) of phosphorous trichloride in 20 ml of methylene chloride was refluxed for 3 hr. The mixture was cooled, poured over ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue crystallized upon the addition of ether to give colorless prisms, mp 121°-123° C.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:33][OH:34])[CH:18]=[C:19]([F:32])[C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1.[H-].[Na+].Cl>CN(C)C=O>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([F:32])[C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[CH2:33][O:34][C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3ccc(C(F)(F)F)nc3)c(F)c1)nc2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol. An exemplary process is shown below: To a solution of 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-c]pyrimidin-6(2H)-one, trifluoroacetic acid salt (43 mg, 0.137 mmol) and (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol (46.0 mg, 0.151 mmol) in N,N-dimethylformamide (DMF) (1.5 mL) were added NaH (16.45 mg, 0.411 mmol). The mixture was stirred at room temperature for 30 mins. Sufficient aqueous HCl solution (1 M) was added to adjust the solution to pH to ˜7. The resulted mixture was purified by Mass Directed AutoPrep (basic mobile phase) to afford the title compound (18 mg, 0.038 mmol, 28.0% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[NH2:4][C:3]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:2]=1/[CH:15]=[CH:14]/[C:13]([O:17][CH3:18])=[O:16]
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C(F)(F)F)cc1N
Temperature: 90 °C
Yield: 35.5 %

Procedure:
A 100 ml 3-neck flask with magnetic stirrer was charged with 2-bromo-5-(trifluoromethyl)aniline (500 mg, 2.08 mmol), methyl acrylate (538 mg, 6.25 mmol), Pd(OAc)2 (23.3 mg, 0.104 mmol), P(o-tolyl)3 (64 mg, 0.21 mmol), triethylamine (422 mg, 4.7 mmol) and acetonitrile (20 mL). The flask was purge with N2 and heated to 90° C. overnight. Saturated aqueous NH4Cl (40 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduce pressure. The crude product was purified by silica gel chromatography to give (E)-methyl 3-(2-amino-4-(trifluoromethyl)phenyl)acrylate (180.9 mg, 37%) as a light green solid. 1H NMR (400 MHz, CDCl3): δ 7.71 (d, J=16 Hz, 1H), δ 7.38 (d, J=8 Hz, 1H), δ 6.92 (d, J=8 Hz, 1H), δ 6.86 (s, 1H), δ 6.34 (d, J=8 Hz, 1H), δ 4.05 (s, 2H), δ 3.73 (s, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](=[O:12])[N:6]([CH3:11])[C:7](=[O:10])[NH:8][N:9]=1.[F:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17]I>CN(C=O)C>[Br:3][C:4]1[C:5](=[O:12])[N:6]([CH3:11])[C:7](=[O:10])[N:8]([CH2:17][CH2:16][CH2:15][C:14]([F:20])([F:19])[F:13])[N:9]=1
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Reactant: FC(F)(F)CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c(Br)nn(CCCC(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
0.85 g (21.3 mmol) of NaH (at 60% in paraffin) are placed in 10 mL of DMF under nitrogen. A solution of 4 g (19.4 mmol) of intermediate 2a in 40 mL of DMF is poured dropwise. The reaction medium is stirred for 1 h at room temperature and then 5 g (21.3 mmol) of 1,1,1-trifluoro-4-iodo-butane are added dropwise, and stirring is then continued for 3 h at room temperature. After dry concentration, the obtained residue is taken up with H2O and extracted with ethyl acetate. After drying on MgSO4, the organic phases are evaporated and the obtained oil is purified by flash chromatography on silica (petroleum ether-AcOEt: 80-20). 5.3 g of crystals corresponding to the compound 4a (yield=87%) are isolated.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:17][CH2:16]1)=[O:13])[CH3:10].[Br:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([N:32]2[CH2:33][CH2:34][N:29]([CH2:28][C:15]3([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=4)[CH2:19][CH2:20]3)[C:30](=[O:35])[CH2:31]2)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc(Br)cc3)CC2=O)CCN(c2ccnc(C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
Triethylamine (400 mg) was added to a solution of 1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone hydrochloride (440 mg) obtained in Reference Example 11 in dichloromethane (15 ml), 4-bromobenzenesulfonyl chloride (255 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. An aqueous sodium carbonate solution was added to the reaction solution, the material was extracted with dichloromethane, dried, concentrated, and purified by silica gel column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (403 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31]C1C=CC(F)=CC=1C[Mg]Br>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:17]=[C:18]([F:31])[CH:19]=[CH:20][C:21]=2[F:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: Fc1ccc(F)c(C[Mg]Br)c1
Product: OC(Cc1cc(F)ccc1F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 18a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2,5-difluorobenzyl magnesium bromide as starting material (available from Rieke Metals) was followed making non-critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+=410 @ Rt 3.11 min. major peak.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](/[CH:8]=[N:9]/[OH:10])[CH:5]=[CH:4][CH:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[OH:10][N:9]=[C:8]([Cl:11])[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cccc(/C=N/O)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C(Cl)=NO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a mixture of commercially available (E)-6-methylpicolinaldehyde oxime (2 g, 14.69 mmol) in DMF (25 mL) was added 1-chloropyrrolidine-2,5-dione (2.158 g, 16.16 mmol). The reaction mixture was stirred overnight at room temperature. LCMS shows reaction was complete. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl (×3). The organic layer was dried with MgSO4, filtered, and concentrated to yield 2.5 g of N-hydroxy-6-methylpicolinimidoyl chloride. MS (m+1)=171. HPLC Peak RT=0.79 minutes (Analytical Method B).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([Si](C(C)C)(C(C)C)C(C)C)[CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C1COCC1.O>[N:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(N2CCOCC2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(N3CCOCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
Add 1N solution of tetrabutylammonium fluoride (0.70 mL, 0.70 mmol) to a solution of 3-Morpholin-4-yl-1-triisopropylsilanyl-1H-indole (0.20 g, 0.56 mmol) in THF (2.0 mL). Stir at room temperature for 2 h, dilute with water, and extract with EtOAc. Wash EtOAc with saturated NaHCO3, water, dry (Na2SO4), and concentrate under vacuum. Purify the residue by flash chromatography using 20 to 80% of EtOAc in hexanes to give the title compound (0.10 g 89%). MS (ES) 203.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl.[CH3:19][CH:20]([CH3:27])[CH2:21][O:22][CH2:23][CH2:24][NH:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:1][C:2]1([CH3:18])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:25]([CH2:24][CH2:23][O:22][CH2:21][CH:20]([CH3:27])[CH3:19])[CH3:26]
Reactant: CC1(C)[C@H]2CC[C@@H](CCOCCCCCCl)[C@@H]1C2
Reactant: CNCCOCC(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COCCN(C)CCCCCOCC[C@@H]1CC[C@H]2C[C@@H]1C2(C)C
Temperature: 80 °C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
15 g of 5-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethoxy]pentyl chloride were dissolved in 100 ml of dimethylformamide. 5.13 g of N-[2-(2,2-dimethylethoxy)ethyl]-N-methylamine (Example 12 B)), 12 g of potassium carbonate and 1 g of potassium iodide were added to the solution. The reaction mixture was stirred at a temperature of 80° C. for 12 hours. The reaction mixture was worked up by concentrating it under reduced pressure, adding 100 ml of water to the residue, and extracting the mixture three times with 80 ml portions of dichloromethane. The combined dichloromethane extracts were dried over sodium sulfate, filtered and concentrated. The crude product remaining as a residue was purified by chromatography on silica gel using dichloromethane/methanol as the eluent. 4.1 g of oily N-(5-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethoxy]pent yl)-N-[2-(2,2-dimethylethoxy)ethyl]-N-methylamine were obtained.
Reaction SMILES: [NH3:1].Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[N:6]=[CH:5][N:4]=1>O1CCOCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH2:1])[CH:8]=1
Reactant: COc1ccccc1-c1cc(Cl)ncn1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccccc1-c1cc(N)ncn1
Temperature: 110 °C

Procedure:
25% ammonia solution (10 ml) was added to a solution of 4-chloro-6-(2-methoxy-phenyl)-pyrimidine (2 g, 9.06 mmol) in 1,4-dioxane (10 ml) and the mixture was heated in a sealed tube at 110° C. for 8 hours with continuous stirring. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine as a white solid. Yield: 1.6 g, 87.9%.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:10]Br.N#N>C(Cl)(Cl)(Cl)Cl>[Br:10][CH:8]([CH3:9])[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: BrBr
Reactant: CCC(=O)CC(=O)OC
Agent: N#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of methyl 3-oxopentanoate (9.62 mL, 76.8 mmoles, Acros) in carbon tetrachloride (60 mL) is added dropwise over a period of 45 minutes a solution of bromine (3.96 mL, 76.8 mmoles) in carbon tetrachloride (10 mL). After 30 minutes, let stir at room temperature for one hour. Bubbled N2 through reaction mixture for twenty minutes. Concentrated to yield the title compound as a brown oil. MS (EI) 208, 210 (M)+, Br pattern.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(Cl)(Cl)=O.[CH2:14](O)[CH3:15]>>[CH2:14]([O:8][C:7]([C@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][NH:5]1)=[O:9])[CH3:15]
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1C[C@@H](O)CN1
Temperature: 25 °C

Procedure:
To a stirred solution of cis-4-hydroxy-pyrrolidine-2-carboxylic acid (1 g, 7.6 mmol) in absolute ethanol (20 mL) is added dropwise thionyl chloride (0.67 mL, 9.15 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture is then refluxed under nitrogen for about 2 h. The mixture is cooled to room temperature, and all solvent is removed under reduced pressure. The white precipitate is filtered and washed with diethyl ether (1×25 mL), to obtain compound (1) as a white solid.
Reaction SMILES: [I:1][C:2]1[C:7]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])=[C:6]([I:13])[C:5]([N:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[C:4]([I:19])[C:3]=1[C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([C:29](O)=[O:30])=[C:22]([N+:32]([O-:34])=[O:33])[CH:21]=1.[C:35]([O:38][CH:39]1[O:53][C@H:52]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[C@@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:40]1[NH2:41])(=[O:37])[CH3:36].Cl.CN(C)CCCN=C=NCC>>[N+:32]([C:22]1[CH:21]=[C:20]([C:3]2[C:4]([I:19])=[C:5]([N:14]([CH3:18])[C:15](=[O:17])[CH3:16])[C:6]([I:13])=[C:7]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[C:2]=2[I:1])[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]=1[C:29]([C:39]1([O:53][C@H:52]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[C@@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:40]1[NH2:41])[O:38][C:35](=[O:37])[CH3:36])=[O:30])([O-:34])=[O:33]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)N(C)c1c(I)c(-c2cc([N+](=O)[O-])c(C(=O)O)c([N+](=O)[O-])c2)c(I)c(N(C)C(C)=O)c1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(=O)OC[C@H]1OC(OC(C)=O)(C(=O)c2c([N+](=O)[O-])cc(-c3c(I)c(N(C)C(C)=O)c(I)c(N(C)C(C)=O)c3I)cc2[N+](=O)[O-])[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
2′,4′,6′-triiodo-3′,5′-bis(N-methylacetamido)-3,5-dinitrobiphenyl-4-carboxylic acid (14) is coupled with 1,3,4,6-tetra-O-acetyl-D-glucosamine in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and N-hydrosuccinamide to yield 2,6-dinitro-4-[3′,5′-bis(N-methylacetamido)-2′,4′,6′-triiodophenyl]-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine. The protecting acetyl groups on the glucosamine moiety are removed by treatment with sodium carbonate in methanol to yield 2,6-dinitro-4-[3′,5′-bis(N-methylacetamido)-2′,4′,6′-triiodophenyl]-benzoyl-D-glucosamine (15).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@:8]1([CH2:17][N+:18]([O-])=O)[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[C:11]([CH2:15][CH3:16])[CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@:8]1([CH2:17][NH2:18])[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[C:11]([CH2:15][CH3:16])[CH2:12]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCC1=C[C@@H]2[C@H](C1)C[C@@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCC1=C[C@@H]2[C@H](C1)C[C@]2(CN)CC(=O)OC(C)(C)C
Reaction time: 5.5 h

Procedure:
Tert-butyl[(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (7.0 g, 23.7 mmol) was dissolved in ethanol (60 mL) and water (21 mL). To the solution, iron powder (13.27 g, 237 mmol) and ammonium chloride (628.1 mg, 11.9 mmol) were added, and the mixture was stirred for 5.5 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (7.02 g, <100%).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10]/[C:11](=[CH:21]\[F:22])/[CH2:12][NH:13]C(=O)OC(C)(C)C)=[CH:7][CH:6]=1)=[O:4].FC(F)(F)C(O)=O.[ClH:33]>C(Cl)Cl>[ClH:33].[NH2:13][CH2:12]/[C:11](=[CH:21]/[F:22])/[CH2:10][O:9][C:8]1[CH:23]=[CH:24][C:5]([C:3]([N:2]([CH3:25])[CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)c1ccc(OC/C(=C\F)CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccc(OC/C(=C\F)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a stirring solution of (Z)-tert-butyl 2-((4-(dimethylcarbarnoyl)-phenoxy)methyl)-3-fluoroallylcarbamate (520.0 mg, 1.48 mmol) in CH2Cl2 (8.0 mL) at room temperature was added trifluoroacetic acid (2.0 mL). The resulting mixture was stirred at room temperature for 30 min. All volatiles were removed in vacuo and the residue was co-evaporated with CH2Cl2 (2×20 mL) to remove trifluoroacetic acid. The resulting oil was taken up in ethyl acetate (3.0 mL) and then ethereal HCl (2.0 M in diethyl ether; 1.0 mL, 2.0 mmol) was added. The precipitate formed was isolated and dried under reduced pressure to afford (Z)-4-(2-(aminomethyl)-3-fluoroallyloxy)-N,N-dimethylbenzamide hydrochloride (301 mg, 71%) as a pale yellow solid; m.p.=135-137° C.; 1H-NMR (300 MHz; MeOD) δ ppm: 3.06 (3H, br s), 3.10 (3H, br s), 3.71 (2H, d, J 3.0 Hz), 4.88 (2H, dd, J 2.8, 0.8 Hz), 7.11 (2H, d, J 8.9 Hz), 7.13 (1H, d, J 80.8 Hz), 7.45 (2H, d, J 8.9 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:10])=[C:7]([NH2:9])[CH:8]=1.[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[NH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[Cl:10])[CH2:2][NH:1][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: NCc1ccc(Cl)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-83 by using 5-(aminomethyl)-2-chlorobenzenamine (2.0 g), pivaloyl chloride (0.2 mL), TEA (2 mL) and THF (10 mL) to afford 2.0 g of the desired product.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:13]=2)=[CH:5][C:4]=1[C:27]1[O:28][C:29]2[C:35]([C:36](=[O:39])[NH:37][CH3:38])=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>C(O)(C)C>[NH2:2][C:3]1[C:4]([C:27]2[O:28][C:29]3[C:35]([C:36]([NH:37][CH3:38])=[O:39])=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:13]=2)=[CH:7][N:8]=1
Reactant: CNC(=O)c1cccc2nc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)oc12
Agent: Cl
Solvent: CC(C)O
Product: CNC(=O)c1cccc2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)oc12
Temperature: 75 °C
Yield: 57 %

Procedure:
A 5M solution of hydrogen chloride in isopropanol (0.773 ml) was added to tert-butyl 4-[4-[6-amino-5-[7-(methylcarbamoyl)-1,3-benzoxazol-2-yl]-3-pyridyl]pyrazol-1-yl]piperidine-1-carboxylate (200 mg) dissolved in isopropanol (5 ml). The resulting solution was heated at 75° C. for 2 hours. The mixture was evaporated to dryness, diisopropylethyamine (1 ml) was added and the mixture was adsorbed on silica gel with 7N methanolic ammonia and dichloromethane. The crude product was purified by flash chromatography on silica gel eluting with 2 to 8% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 2-[2-amino-5-[1-(4-piperidyl)pyrazol-4-yl]-3-pyridyl]-N-methyl-1,3-benzoxazole-7-carboxamide (92 mg) as a solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)=[CH:20][N:21]=3)[N:18]=2)[CH2:8][CH2:7]1)=[O:4].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:28][C:24]1[CH:23]=[C:22]([C:19]2[N:17]3[N:18]=[C:13]([NH:12][C@H:9]4[CH2:10][CH2:11][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:7][CH2:8]4)[CH:14]=[CH:15][C:16]3=[N:21][CH:20]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CCl)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCOCC1)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-N-(trans-4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)acetamide (50 mg, 0.12 mmol), morpholine (0.3 mL) and DIPEA (0.2 mL) in CH2Cl2 (0.6 mL) was stirred at 50° C. for 3 h. LCMS showed the reaction was complete. The mixture was concentrated in vacuo. The residue was partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-84 (9.6 mg, 17%) as a white solid.