Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[ClH:12]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.ClC(C(F)(F)F)=C>[Cl:12][CH:3]([C:2]([F:11])([F:10])[F:1])[CH2:4][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7]
Reactant: Cl
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: C=C(Cl)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#CC(C#N)(CCC(F)(F)F)CC(Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.6 g of 2-(3,3,3-trifluoropropyl)malononitrile was dissolved in 20 ml of a solution (1 mol/L) of tetrabutylammonium fluoride in tetrahydrofuran, 5 ml of 2-chloro-3,3,3-trifluoropropene was added thereto at 0° C., and the mixture was stirred at room temperature for 3 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.22 g of 2-(2-chloro-3,3,3-trifluoropropyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (58)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Cl.[CH3:12][NH:13][CH3:14].[CH2:15]=O.Cl>CC(C)=O.CCO>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: C=O
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: CN(C)CCC(=O)c1ccc(Cl)cc1
Temperature: 40 °C
Yield: 112 %

Procedure:
To EtOH (80 mL), p-chloroacetophenone (77.3 g, 0.50 mol), dimethylamine hydrochloride (52.7 g, 0.65 mol), paraformaldehyde (19.8 g, 0.66 mol) and concentrated aqueous HCl (1 mL) were added and the mixture was refluxed for 5 h. The mixture was cooled to 40° C., acetone (400 mL) was added, and under stirring the mixture was cooled further to 20° C. The precipitate was filtered, washed with acetone and PA, and air dried to obtain 69.5 g of product which was used without further purification in the subsequent step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:29]=[CH:28][S:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[C:33]([CH3:39])=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:29]=[CH:28][S:27][CH:26]=3)[C:17]=2[O:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([F:31])[C:33]=2[CH3:39])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccsc3)c3ccccc23)CC1
Reactant: Cc1c(O)cccc1F
Product: Cc1c(F)cccc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1-c1ccsc1

Procedure:
From the compound of step 3 (50 mg, 112 μmol), the title compound was prepared analogously as described in example 1, step 2, using 3-fluoro-2-methylphenol. Yield: 11 mg.
Reaction SMILES: [CH3:1][NH2:2].C1COCC1.[C:8]([C:11]1[C:12]([C:32]([F:35])([F:34])[F:33])=[N:13][N:14]([CH2:16][C:17]([NH:19][C:20]2[S:24][C:23]3[CH2:25][CH2:26][CH2:27][CH2:28][C:22]=3[C:21]=2[C:29]([NH2:31])=[O:30])=[O:18])[CH:15]=1)(=O)[CH3:9].[Na]>C(O)(=O)C.CO>[CH3:1][NH:2][CH:8]([C:11]1[C:12]([C:32]([F:34])([F:35])[F:33])=[N:13][N:14]([CH2:16][C:17]([NH:19][C:20]2[S:24][C:23]3[CH2:25][CH2:26][CH2:27][CH2:28][C:22]=3[C:21]=2[C:29]([NH2:31])=[O:30])=[O:18])[CH:15]=1)[CH3:9]
Reactant: CN
Reactant: CC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CNC(C)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Yield: 14 %

Procedure:
To MeOH (1.5 mL) was added 2M methylamine in THF (0.724 mL, 1.448 mmol). Acetic acid was added to the mixture to adjust the pH to 4-5. 2-(2-(4-acetyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (50 mg, 0.121 mmol) and sodium cyanoborohyde (7.58 mg, 0.121 mmol) were added before heating the reaction to 100° C. for 30 min by microwave irradiation. The reaction mixture was quenched with water before purification by preparative reverse phase HPLC. The product fractions were acidified to pH 3 with acetic acid before applying to a strong cation exchange cartridge (500 mg). The cartridge was washed with DCM/MeOH (1:1) before eluting the product with 2M NH3 in MeOH. The solvent was removed in vacuo to give the title compound (7.1 mg, 0.017 mmol, 14%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH2:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH2:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc2c(c1)CCC2
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)CCC3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and indan-5-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[N:18][C:10]3[O:11][CH2:12][C:13]4[N:14]([CH:15]=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:38]N1C(=O)CCC1=O>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][C:9]4[N:14]5[C:15]([Br:38])=[N:16][N:17]=[C:13]5[CH2:12][O:11][C:10]=4[N:18]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:34])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3cnnc3CO4)cc2)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(Br)nnc3CO4)cc2)CCC1
Yield: 68.5 %

Procedure:
A mixture of tert-butyl 1-(4-(8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutylcarbamate (200 mg, 0.404 mmol) and 1-bromopyrrolidine-2,5-dione (114.9275 mg, 0.646 mmol) in DCM (12 ml) and CCl4 (18 ml) was heating at 50 degree for 24 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (40 ml) and water (40 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (30 ml). The combined organic phase was washed with water (50 ml) brine (30 ml) and concentrated to give product 159 mg. 1H NMR (500 MHz, CDCl3): 8.55 (s, 1H), 7.22-7.35 (m, 9H), 5.58 (s, 2H), 5.1 (br, 1H), 2.4-2.5 (m, 4H), 2.01-2.11 (m, 1H), 1.79-1.89 (m, 1H), 1.24-1.43 (br, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:25]1([CH2:31][C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:36]([C:35]3[CH:34]=[CH:33][C:32]([CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:39][CH:38]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.050 g, 0.13 mmol) and EtOH (4.5 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.032 g, 0.16 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.50 ml, 0.50 mmol). The reaction mixture was stirred at 70° C. for 9 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 15%) in ethyl acetate/dichloromethane (v:v; 4:1). afforded a yellow solid. This material was triturated with diethyl ether, and the pale yellow precipitate was collected by filtration, successively washed with diethyl ether, water, and diethyl, then dried in vacuo (0.002 g, 3%). 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=5.0 Hz, 4H) (morpholine protons), 2.63 (br s, 4H, piperazine N(CH2)2), 3.69 (br s, 4H, piperazine N(CH2)2), 3.54 (s, 2H) and 3.62 (s, 2H) (NCH2-pyridyl and C6H4CH2), 7.40 (d, J=4.9 Hz, 2H pyridine 3-H and 5-H), 7.48 (d, J=8.2 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.5 Hz, 2H, pyridine 2-H and 6-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH3:29]
Reactant: CCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
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: CCO
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-ethoxyphenyl borate (0.44 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 16 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The resulting solid was recrystallized from ethyl acetate/hexane to give pale yellow crystals of methyl 7-(4-ethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (739.5 mg).
Reaction SMILES: C([C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]3[CH3:27])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.C1(P(=[CH:47][CH:48]=[O:49])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1(C)C=CC=CC=1>>[CH:48]([CH:47]=[CH:50][C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:25])([CH3:26])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]3[CH3:27])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[O:49]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Reactant: Cc1ccccc1
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=CC=O)cc3ccccc13)O2

Procedure:
A solution of 0.36 g (1 mmol) of the compound of Example 1 and of 0.30 g (1 mmol) of (triphenylphosphoranylidene)acetaldehyde in 10 ml of toluene is heated to reflux for 24 hours. The solvent is then evaporated off and the mixture purified on a silica column (70/30 pentane/ether eluent).
Reaction SMILES: Br[C:2]1[C:3]([CH:16]=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[C:19]1[S:20][CH:21]=[CH:22][N:23]=1.[F-].[K+].[C:26](OCC)(=O)[CH3:27]>C1(C)C=CC=CC=1.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>[CH3:12][C:9]1([CH3:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]2[CH:4]=[C:3]([CH:16]=[O:17])[C:2](/[CH:26]=[CH:27]/[C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:11][C:10]1=2
Reactant: Brc1nccs1
Reactant: CCOC(C)=O
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C)(C)c2cc(/C=C/c3nccs3)c(C=O)cc21
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 0.147 g (0.498 mmol) of 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde, 0.302 g (0.498 mmol) of trans-1,2-bis(tri-n-butylstannyl)ethylene,and 0.012 g (0.00996 mmol) of tetrakis(triphenylphosphine)palladium(0) in 5 ml toluene was heated to reflux under an atmosphere of argon for 1 hour. This was cooled. 0.082 g (0.498 mmol) of 2-bromothiazole and 0.012 g (0.00996 mmol) of tetrakis(triphenylphosphine)palladium(0) were added. This was stirred at reflux for 2 hours and at room temperature for 16 hours. 20 ml of 5% aqueous potassium fluoride and 15 ml of ethyl acetate were added. The resulting mixture was stirred vigorously for 2 hours and was filtered through celite. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and was concentrated in vacuo. The product was purified by flash chromatography with elution with 15% ethyl acetate/hexane to afford 0.065 g (40%) of 5,5,8,8,-tetramethyl-3-((E)-2-thiazol-2-yl-vinyl)-5,6,7,8-tetrahydro-2-naphthaldehyde (M+H=326).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:46])[CH2:32][N:31](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:30]2)=[C:25]([F:47])[CH:24]=1)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C1C=CC=CC=1>[C:2]([N:31]1[CH2:32][C:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:24][C:25]=2[F:47])([OH:46])[CH2:30]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(Nc1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1)OCc1ccccc1
Solvent: c1ccccc1
Product: O=C(Nc1ccc(C2(O)CN(C(=O)OCc3ccccc3)C2)c(F)c1)OCc1ccccc1

Procedure:
Benzyl chloroformate (3.8 mL, 26.6 mmol) was added to a solution of 3-(N-carbobenzyloxy-3-fluoroanilin-4-yl)-3-hydroxy-1-(1,1-diphenylmethyl)azetidine (Example 81, Step 2, 1.60 g, 3.32 mmol) in benzene (30 mL) and then heated under reflux under nitrogen for 2 hr. The benzene was evaporated and the residue chromatographed over silica gel (150 g, 40-60 μm) eluting with 20-60% ethyl acetate-hexane. The title compound was obtained as a white foam. 1H NMR δ (CDCl3): 3.32, 4.19, 4.42, 5.08, 5.17, 6.98, 7.11, 7.19, 7.24-7.43.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[CH2:7]([C:14]1[CH:23]=[C:22]2[C:17]([C:18](Cl)=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:28]([C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][C:39]([N+:45]([O-:47])=[O:46])=[C:38]2Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl>[CH2:7]([C:14]1[CH:23]=[C:22]2[C:17]([C:18]([NH:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4])=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1.[CH2:28]([C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][C:39]([N+:45]([O-:47])=[O:46])=[C:38]2[NH:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2cc(Cc3ccccc3)ccc2c1Cl
Reactant: O=[N+]([O-])c1cnc2ccc(Cc3ccccc3)cc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Cc3ccccc3)ccc12
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccc(Cc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 1-amino-2-methylpropan-2-ol (1.2 equivalents) was added to a 0.2 M solution of 7-benzyl-4-chloro-3-nitroquinoline or 6-benzyl-4-chloro-3-nitroquinoline (1 equivalent) and triethylamine (3 equivalents) in dichloromethane, and the reaction was stirred overnight at ambient temperature. The volatiles were removed under reduced pressure, and the residue was stirred with water (50 mL) for one hour. The resulting yellow solid was isolated by filtration and washed with water to provide 1-(7-benzyl-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol or 1-(6-benzyl-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol, respectively.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]#[N:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.C(N(CC)CC)C.Cl.[NH2:38][OH:39]>O>[OH:39]/[N:38]=[C:25](/[C:23]1[N:22]=[CH:21][N:20]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:24]=1)\[NH2:26]
Reactant: NO
Reactant: N#Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: N/C(=N\O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture containing 1-trityl-1H-imidazole-4-carbonitrile (1.6 g, 4.77 mmol), ethanol (20 ml), triethylamine (1.995 ml, 14.31 mmol) and hydroxylamine hydrochloride (0.663 g, 9.54 mmol) was heated to 70° C. and stirred 4 h. The mixture was cooled with an ice bath, some water (10 ml) was added and the precipitated product filtered and washed well with water. The product was dried with vacuum at 40° C. 1H-NMR (400 MHz; DMSO-d6): δ 5.43-5.50 (m, 2H), 7.01 (d, 1H), 7.04-7.13 (m, 6H), 7.36-7.46 (m, 10H), 9.10 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:9][CH:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccnc(Cl)n2)C1
Temperature: 80 °C
Yield: 95 %

Procedure:
A flask was charged with a solution of 2,4-dichloropyrimidine (300 mg, 2.0 mmol) in N,N-dimethylformamide (10 mL). tert-Butyl 3-hydroxyazetidine-1-carboxylate (349 mg, 2.0 mmol) and cesium carbonate (1.11 g, 3.42 mmol) were added and the resulting mixture was heated to 80° C. for 2 h. Upon completion, the mixture was diluted with ethyl acetate (20 mL) and washed with 1:1 water:brine (3×40 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by Chromatography on silica gel (0-80% ethyl acetate in hexanes) afforded tert-butyl 3-[(2-chloropyrimidin-4-yl)oxy]azetidine-1-carboxylate (550 mg, 1.9 mmol, 96%). MS ESI: [M+H]+ m/z 286.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[CH:3]=1.[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Sn](CCCC)(CCCC)CCCC)[N:42]=2)[CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[N:42]=[C:43]([C:6]3[CH:5]=[C:4]([C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:44]=[CH:45][CH:46]=2)[CH:36]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)n1
Reactant: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cc(OS(=O)(=O)C(F)(F)F)n1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Temperature: 25 °C

Procedure:
A stirred mixture of trifluoro-methanesulfonic acid 6-methyl-4-(4-trifluoromethoxy-phenyl)-pyridin-2-yl ester (Example A.63) (0.221 g, 0.55 mmol), N-tert-butyl-3-(6-tributylstannanyl-pyridin-2-yl)-benzenesulfonamide (Example F.6) (0.290 g, 0.50 mmol), tetrakis(triphenyl-phosphine)palladium (0.032 g, 5 mol %) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, extracted with ethyl acetate and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the title compound after trituration with diethyl ether as a white solid (100 mg, 34%). MS (ISP) 542.8 [(M+H)+]; mp 148° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:4]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])#[CH:2].Cl[C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:22]=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)[N:20]=1.F[B-](F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][O:16][C:14](=[O:15])[CH2:13][C:4]1[C:5]([C:9]([F:11])([F:10])[F:12])=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:23]1[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:19][N:20]=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)=[CH:32][CH:31]=2)[N:22]=1
Reactant: C#Cc1cccc(C(F)(F)F)c1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cccc1C(F)(F)F
Temperature: 110 °C

Procedure:
A mixture of methyl 2-(2-ethynyl-6-(trifluoromethyl)phenyl)acetate (A93) (0.113 g, 0.468 mmol), tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.222 g, 0.487 mmol), copper(I) iodide (0.005 g, 0.03 mmol), PdCl2(PPh3)2 (0.021 g, 0.030 mmol) and t-Bu3PH.BF4 (0.011 g, 0.038 mmol) in DMF (2.0 mL) was degassed with nitrogen for several minutes before the addition of DIPEA (2.0 mL, 12 mmol) then further degassed with nitrogen for several minutes. The resulting mixture was heated under microwave irradiation 110° C. for 20 minutes and then a further 30 minutes. The volatiles were evaporated under reduced pressure and the residue purified using silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound A94 (0.127 g, 41%); 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.88 (d, J=7.3 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.47 (t, J=7.7 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J=8.5 Hz, 2H), 4.25 (m, 2H), 4.17 (s, 2H), 3.69 (s, 3H), 2.81 (t, J=12.5 Hz, 2H), 2.65 (m, 1H), 1.83 (d, J=12.6 Hz, 2H), 1.63 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 7.12 min; m/z 661.1 [M−H]+.