Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3[CH:28]=[CH:27][C:16]([CH2:17][NH:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([NH:40][C:41]2[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=2)=[O:39])=[C:33]([C:50]([F:53])([F:52])[F:51])[CH:32]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3[CH:28]=[CH:27][C:16]([CH2:17][N:18]([CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C:45](=[O:46])[C:44]4[CH:48]=[CH:49][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:34]5[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][C:33]=5[C:50]([F:53])([F:51])[F:52])=[CH:42][CH:43]=4)=[CH:15][CH:14]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(-c2coc(-c3ccc(Br)cc3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4coc(-c5ccc(Br)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a stirring solution of tert-butyl 2-((4-(2-(4-bromophenyl)oxazol-4-yl)benzyl)amino)acetate INT-44 (220 mg, 0.496 mmol), 4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid (175 mg, 0.496 mmol) and DIEA (137 μl, 0.744 mmol) in DMF (4 mL) was added HATU (198 mg, 0.521 mmol). The reaction mixture was stirred at room temperature for 16 h then diluted with DCM (4 mL), stirred with NaHCO3 (15 mL) for 15 min, split through a hydrophobic frit and evaporated. The crude product was purified by column chromatography (acetonitrile/DCM) to gave 262 mg (68%) of tert-butyl 2-(N-(4-(2-(4-bromophenyl)oxazol-4-yl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-45 as an off-white solid. LCMS-ESI (m/z) calculated for C39H35BrF3N3O6: 777; found 778 [M+H]+, tR=3.20 min (Method 5).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([O:23]C)=[O:22].[OH-].[K+].Cl>O.C1COCC1>[N+:10]([C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:20]([C:21]([OH:23])=[O:22])[O:1][C:2]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: COC(=O)CCl
Reactant: O=Cc1ccc([N+](=O)[O-])cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc([N+](=O)[O-])cc2o1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
5.8 g (34.7 mmol) of 2-hydroxy-4-nitrobenzaldehyde, 1.28 g (3.5 mmol) of tetra-N-butylammonium iodide and 19.2 g (138.8 mmol) of potassium carbonate are mixed, 7.9 g (72.9 mmol) of methyl chloroacetate are added and the mixture is heated at 130° C. for 12 h. 100 ml of THF and, with ice cooling, 11.7 g (208.2 mmol) of potassium hydroxide are added. Following the addition of 100 ml of water, the mixture is stirred at RT for 20 h. Using concentrated hydrochloric acid, the pH is adjusted to 0. The mixture is extracted with ethyl acetate. The organic phase is washed with water and dried over sodium sulfate. Following the addition of silica gel, the mixture is concentrated and chromatographed on silica gel (mobile phase gradient: toluene to toluene/methanol/glacial acetic acid 35:5:1). Concentration of the product fractions and drying under reduced pressure gives 1.31 g (18.2% of theory) of the title compound.
Reaction SMILES: BrCCC1C([Cl:10])=CC(Cl)=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1CCBr.Cl.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CO>[ClH:10].[Cl:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([Cl:20])[CH:16]=1)[O:12][CH2:5][CH2:6][NH:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCC1
Reactant: Clc1cc(Cl)c(CCBr)c(Oc2cc(Cl)cc(Cl)c2CCBr)c1
Agent: Cl
Solvent: CO
Product: Clc1cc(Cl)cc(OCCNC2CCCCC2)c1
Yield: 94.2 %

Procedure:
A solution of 27.2 g (0.1 mole) of 2-bromoethyl-3,5-dichlorophenyl ether in 300 ml of cyclohexylamine (excess) was stirred overnight at room temperature. The reaction mixture was filtered and the filtrate stripped to dryness on a rotary evaporator. The residue was partitioned between chloroform and water and between chloroform and 10% sodium hydroxide. The chloroform layer was evaporated to dryness leaving an oil (free base). The oil was dissolved in methanol and reacted with ethereal hydrogen chloride to give 25.8 g (94.2%) solid, m.p. 216.5°-220° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[N:20][OH:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:21][N:20]=2)=[CH:16][CH:17]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Br)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridine-2,6-diamine (50 mg, 0.376 mmol) described in Manufacturing Example 13-1-3 and 4-bromophenyl acetohydroximoyl chloride (150 mg, 0.602 mmol) described in Manufacturing Example 207-1-3 was added triethylamine (131 μL, 0.94 mmol), which was stirred for 2 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1, then ethyl acetate) to obtain the title compound (85 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23]([OH:25])=O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]2[CH2:39][O:38][B:37]([OH:40])[C:36]=2[CH:41]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:29])[F:27])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23]([NH:30][CH2:31][C:32]4[CH:33]=[CH:34][C:35]5[CH2:39][O:38][B:37]([OH:40])[C:36]=5[CH:41]=4)=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NCc1ccc2c(c1)B(O)OC2
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccn12
Product: O=C(NCc1ccc2c(c1)B(O)OC2)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccn12

Procedure:
The title compound can be prepared from 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylic acid and 6-(aminomethyl)benzo[c][1,2]oxaborol-1(3H)-ol as shown by the following scheme:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[NH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[CH2:31][C:32]([O:34]C)=[O:33]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[N:25]([CH2:31][C:32]([OH:34])=[O:33])[CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc[nH]c3=O)cc1-2
Reactant: COC(=O)CBr
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccn(CC(=O)O)c3=O)cc1-2
Yield: 62 %

Procedure:
Following the procedure for 477, compound 330 and methyl 2-bromoacetate gave the methyl ester of 501 (0.734 mg, 62%). 1H NMR (500 MHz, DMSO) δ 9.17 (d, J=2.4, 1H), 8.09 (s, 1H), 7.78 (dd, J=7.1, 2.0, 1H), 7.73 (dd, J=6.7, 1.9, 1H), 7.59 (dd, J=8.4, 2.4, 1H), 7.08 (d, J=8.4, 1H), 6.42 (t, J=6.9, 1H), 5.97 (dt, J=13.4, 6.7, 1H), 4.79 (s, 2H), 4.40 (t, J=4.9, 2H), 3.71 (s, 3H), 3.46 (t, J=4.9, 2H), 1.53 (d, J=6.6, 6H). MS (ESI(+)): m/z 478.2 (M+H)
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][CH2:15][CH:16]([OH:25])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[O:18]([CH2:17][CH:16]([OH:25])[CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC(CCCl)COc1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: OC(CCN1CCN(c2ccccc2)CC1)COc1ccccc1

Procedure:
A mixture of 6.5 g (0.04 mole) of 1-phenylpiperazine, 8.4 g (0.042 mole) of 4-chloro-1-phenoxy-2-butanol and 15.9 g (0.15 mole) of anhydrous sodium carbonate in 200 ml of 1-butanol was heated at reflux 20 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between water and benzene. The benzene layer was washed with water and aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to give the title product in the residue which was recrystallized from isopropyl alcohol to give 8.9 g (68%) of white powder, m.p. 93°-94° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[Br:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[Br:17][C:18]1[CH:19]=[C:20]([CH:21]=[C:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:33][CH2:34][CH:35]([NH:1][CH2:2][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=2)[OH:4])[CH2:36][CH2:37]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C=C3SC(=O)NC3=O)cc2Br)CC1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(=O)NC4=O)cc3Br)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) and 5-[3-bromo-4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 58) according to the procedure of Example 63 as a dull yellow solid; mp>200° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.70–1.82 (m, 2H), 2.07–2.17 (m, 2H), 2.65–2.73 (m, 3H), 2.95 (s, 3H), 3.07–3.17 (m, 4H), 4.74–4.77 (m, 3H), 6.00 (brs, 1H), 6.89 (d, J=8.3 Hz, 1H), 7.09 (dd, J=8.4, 2.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.26–7.27 (m, 2H), 7.50 (dd, J=8.4, 2.0 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 8.7 (brs, 1H), 9.9 (brs, 1H); MS (ES) m/z: 612.8 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]1([C:24]2[N:25]=[CH:26][N:27]([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[N:25]=[CH:26][N:27]([CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:28]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCn1cnc(-c2ccccc2)c1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCn1cnc(-c2ccccc2)c1-c1ccccc1

Procedure:
Batch size: 2.5 g (17.0 mmol) 3-(3-pyridyl)-acrylic acid, 5.9 g (46.3 mmol) oxalyl chloride and 4.5 g (15.4 mmol) 4-(4,5-diphenyl-imidazol-1-yl)-butylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:10]=1[CH:27]=O)=[O:8].[CH3:33][NH:34][CH3:35].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:10]=1[CH2:27][N:34]([CH3:35])[CH3:33])=[O:8]
Reactant: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C=O)n(Cc3ccccn3)c2c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(CN(C)C)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
General Procedure P. To a solution of N-(3,4-difluorobenzyl)-2-formyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 94, 70 mg, 0.16 mmol) in ClCH2CH2Cl (10 ml) at room temperature was added dimethylamine (2 M in THF, 0.24 ml, 0.48 mmol), HOAc (14 μl, 0.24 mmol), and NaBH(OAc)3 (102 mg, 0.48 mmol). The reaction was stirred at room temperature for 16 h, diluted with EtOAc, washed with aqueous Na2CO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (EtOAc, then 9:1 EtOAc-Et3N, then 7:2:1 CH2Cl2-MeOH-Et3N) to yield the title compound as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[CH3:17][S-:18].[Na+]>CO>[CH3:17][S:18][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16]
Reactant: C[S-]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [Na+]
Solvent: CO
Product: CSCCCCN1C(=O)c2ccccc2C1=O
Yield: 91 %

Procedure:
A solution of 2-(4-bromo-butyl)-isoindole-1,3-dione (1.00 g, 3.54 mmol) in MeOH (60 mL) was treated with sodium thiomethoxide (0.298 g, 4.25 mmol) and heated to reflux 18 h. The solvent was evaporated in vacuo and the residue partitioned between EtOAc and water. The aqueous layer was further extracted with EtOAc (1×75 mL). The organic layers were dried over MgSO4 and concentrated in vacuo to afford the product 2-(4-methylsulfanyl-butyl)-isoindole-1,3-dione (0.803 g, 91%). 1H NMR (MeOD) 7.844 (m, 4H), 3.704 (t, 2H, J=7.2 Hz), 2.549 (t, 2H, J=7.2 Hz), 2.063 (s, 3H), 1.792 (quint, 2H, J=7.2 Hz), 1.731 (quint, 2H, J=7.2 Hz).
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](Cl)(=[O:15])[O:11][CH:12]([Cl:14])[CH3:13]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:10](=[O:15])([O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:11][CH:12]([Cl:14])[CH3:13]
Reactant: CC(Cl)OC(=O)Cl
Reactant: OC1CCCCCCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(Cl)OC(=O)OC1CCCCCCC1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
To a solution of cyclooctanol (1.79 g) in chloroform (40 mL), pyridine (1.13 mL) was added, and then the reaction solution was cooled to −60° C. To the reaction solution, 1-chloroethyl carbonochloridate (1.53 mL) was added at the same temperature over 10 minutes. The reaction solution was thereafter heated to room temperature and stirred at the same temperature for 3 hours. Chloroform was added to the reaction solution and the organic layer was washed three times with brine and then dried over magnesium sulfate. The insoluble was filtered and the filtrate was concentrated under reduced pressure to give 1-chloroethyl cyclooctyl carbonate (A-11-1, 3.70 g) as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:28])[C@:13]([C@@H:21]2[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22]2)([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][CH2:4][CH:5]=[C:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:28])[C@:13]([C@@H:21]2[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22]2)([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:11]1
Reactant: [N-]=[N+]=NCC=C1CCN(C(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCC=C1CCN(C(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Yield: 89.3 %

Procedure:
To a solution of 18 mg of 4-(2-azidoethylidene)-1-{(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylacetyl}piperidine in 2.2 ml of 10% aqueous tetrahydrofuran, 15 mg of triphenylphosphine was added at room temperature, followed by reflux for 15 hours under heating. The solvent was distilled off under reduced pressure, and 15 mg of the title compound was obtained as a colorless oily substance by purifying the resulting residue by preparative thin-layer chromatography [Kieselgel™60F654, Art 5744 (Merck); chloroform/methanol/aqueous ammonia=20/1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[NH:10][CH2:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[CH:5][C:4]=1B(O)O.Cl[C:23]1[N:28]=[N:27][C:26]([N:29]([CH3:40])[CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[O:18])=[CH:5][C:4]=1[C:23]1[N:28]=[N:27][C:26]([N:29]([CH3:40])[CH:30]2[CH2:35][C:34]([CH3:36])([CH3:37])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[CH:25][CH:24]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1ccc(C(=O)NCc2cnn(C)c2)cc1B(O)O
Product: COc1ccc(C(=O)NCc2cnn(C)c2)cc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Yield: 100.2 %

Procedure:
Following standard GENERAL METHOD 1-4 for Suzuki coupling using (2-methoxy-5-(((1-methyl-1H-pyrazol-4-yl)methyl)carbamoyl)phenyl)boronic acid (613 mg, 2.12 mmol) and 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 300 mg, 1.06 mmol) afforded 4-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide (522 mg) MS [M+H+]=492.6.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:22]([F:25])([F:24])[F:23])=[N:10][C:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:12][CH:13]=1)(C)(C)C.O1CCOCC1.Cl>O1CCOCC1>[Cl:21][C:17]1[CH:16]=[C:15]([NH:14][C:11]2[N:10]=[C:9]([C:22]([F:24])([F:25])[F:23])[C:8]([NH2:7])=[CH:13][N:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
To a mixture of tert-butyl{2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}carbamate (267 mg) and 1,4-dioxane (3 mL) was added a 4 M hydrogen chloride-1,4-dioxane solution (3 mL), followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and to the obtained residue was added a saturated aqueous sodium hydrogen carbonate solution (20 mL), followed by extraction with ethyl acetate (50 mL). The extract was washed with saturated brine (20 mL), and the organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain N2-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidine-2,5-diamine (180 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:17])=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: CNCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (5.0 g) in CH2Cl2 (100 mL) at 0° C. was treated sequentially with N-methyl-N-(phenylmethyl)amine (3.0 mL), triethylamine (3.36 mL) and N,N-dimethylaminopyridine (0.26)). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was washed with 1N HCl (100 mL) and water (2×100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (6.9 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:11]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:16]=[CH:15][C:14]([CH2:17][C@@H:18]([NH:27]C(OC(C)(C)C)=O)[CH2:19][C@:20]([CH2:25][OH:26])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:13][CH:12]=1.CCN(CC)CC>CC(C)=O>[N:5]1([C:3](=[O:4])[CH2:2][O:23][C:21](=[O:22])[C@@:20]([CH2:25][OH:26])([CH3:24])[CH2:19][C@H:18]([NH2:27])[CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:12][CH:13]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Reactant: O=C(CCl)N1CCOCC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCC(=O)N1CCOCC1

Procedure:
4-(2-chloroacetyl)morpholine (63 mg, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-morpholin-4-yl-2-oxo-ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[N:4]([CH2:9][C:10]([CH3:12])=[CH2:11])[N:5]=[CH:6][C:7]=1[Cl:8].[Cl-:14].FC([NH3+])(F)F.Cl>C(Cl)(Cl)(Cl)Cl>[Cl:14][C:10]([CH3:12])([CH3:11])[CH2:9][N:4]1[C:3](=[O:13])[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[N:5]1
Reactant: C=C(C)Cn1ncc(Cl)c(Cl)c1=O
Reactant: [Cl-]
Agent: Cl
Agent: [NH3+]C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Cl)Cn1ncc(Cl)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 2234.6 %

Procedure:
In 100 ml of carbon tetrachloride were dissolved 5 g of 4,5-dichloro-2(2-methyl-2-propenyl)-3(2H)-pyridazinone and 0.1 g of trifluoromethyl ammonium chloride, and thereto were added 30 ml of concentrated hydrochloric acid. The mixture solution was stirred for 3 days at room temperature. The organic layer was separated and washed with water, and dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure to give 4.7 g of the intended compound.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH:7]2[C:11]3[NH:12][C:13]([C:15]([O:17]CC)=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+].CO>C1COCC1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH:7]2[C:11]3[NH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C(c1ccc(-c3ccccc3)cc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)C(c1ccc(-c3ccccc3)cc1)CC2
Yield: 30.1 %

Procedure:
The title compound was synthesized from ethyl 6-(biphenyl-4-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.1776 g, 0.54 mmol, 1 equiv) and sodium hydroxide (1.36 mL, 13.6 mmol, 10 M, 25 equiv), according to General Procedure 7. A 4-5:1 mixture of methanol (MeOH) and THF (5-6 mL) was used. The resulting product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 60% methanol and increasing to 100% over 7 minutes) afforded the title compound (49.3 mg, 30%) with purity by HPLC of 96.6% (UV). LCMS m/e 302.2 (M−H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.24-2.37 (m, 1H) 2.66 (ddd, J=8.74, 5.64, 5.53 Hz, 1H) 2.72-2.82 (m, 1H) 2.97 (dd, J=12.96, 4.98 Hz, 1H) 4.31 (dd, J=8.44, 5.37 Hz, 1H) 6.68 (s, 1H) 7.20 (d, J=8.20 Hz, 2H) 7.27-7.34 (m, 1H) 7.40 (t, J=7.63 Hz, 2H) 7.56 (dd, J=15.79, 7.71 Hz, 4H).