Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:24]([O-])=O)=[C:12]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=2)[CH2:4][CH2:3]1.O.NN.CO[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=1[S:39]([Cl:42])(=[O:41])=[O:40].C1C[O:46][CH2:45]C1>[Ni]>[ClH:42].[CH3:45][O:46][C:35]1[CH:34]=[C:33]([S:39]([NH:24][C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:13][C:12]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])(=[O:40])=[O:41])[CH:32]=[CH:37][C:36]=1[CH3:38]
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: C1CCOC1
Agent: [Ni]
Agent: NN
Solvent: O
Product: COc1cc(S(=O)(=O)Nc2ccc(N3CCN(C)CC3)cc2NS(=O)(=O)c2ccccc2)ccc1C
Product: Cl
Reaction time: 1 h
Yield: 28 %

Procedure:
N-[5-(4-Methyl-1-piperazinyl)-2-nitrophenyl]benzenesulfonamide (0.600 g, 1.59 mmol) was dissolved in THF (20 mL) followed by the addition of Raney-Ni (0.322 g, in ethanol) and hydrazine hydrate (0.100 g, 2.0 mmol). The reaction mixture was stirred for 1 h, filtered through Celite and concentrated. The residue was dissolved in pyridine (12 mL) and divided in 12 equal parts. To one part was added 2-methoxy-4-methyl-benzenesulfonylchloride (44 mg, 0.20 mmol). The reaction mixture was stirred overnight, poured into petroleum ether to form a precipitate that was collected by centrifugation. The precipitate was purified by purified by column chromatography (SiO2, CH2Cl2/MeOH 95:5 to 9:1). The pure product was dissolved in MeOH and treated with HCl/diethyl ether to give 21 mg, (28% yield). MS (posES-FIA) m/z=found: 530.1635; Calcd: 530.1658.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([OH:7])=[O:6].[CH:13]1[CH:18]=CC=C[CH:14]=1>C(O)(C)C>[ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([O:7][CH:13]([CH3:18])[CH3:14])=[O:6]
Reactant: c1ccccc1
Reactant: CC(C)C[C@H](N)C(O)C(=O)O
Agent: Cl
Solvent: CC(C)O
Product: CC(C)C[C@H](N)C(O)C(=O)OC(C)C

Procedure:
Hydrogen chloride was passed into a solution of 4.0 g of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoic acid in 50 ml of isopropyl alcohol with stirring under ice-cooling, and then 100 ml of dry benzene was added to the reaction mixture, and the mixture was heated under reflux for 10 minutes while removing water formed during the reaction using a molecular sieve. The reaction mixture was evaporated to dryness under reduced pressure to obtain 5.7 g of isopropyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride as a white powder.
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:6]=[C:7]([CH3:16])[O:8][C:9]=1[C:10](=O)[C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])[CH3:3].[OH-].[NH4+:18]>>[CH3:1][C:2]([C:5]1[C:9]([OH:8])=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:18]=[C:7]([CH3:16])[N:6]=1)([CH3:4])[CH3:3]
Reactant: [NH4+]
Reactant: Cc1nc(C(C)(C)C)c(C(=O)C(C)(C)C)o1
Agent: [OH-]
Product: Cc1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Yield: 75 %

Procedure:
A mixture of 1-[4-(1,1-dimethylethyl)-2-methyl-5-oxazolyl]-2,2-dimethyl-l-propanone (8.5 g, and concentrated ammonium hydroxide (100 mi) is heated at 180° C. for 36 hours in a steel bomb. The reaction mixture is cooled and the excess ammonia is evaporated on the rotovap. The pH of the resulting mixture is adjusted to pH 6 with concentrated HCl with ice bath cooling. The product is extracted into ether (3×250 mL) and the organic layer is dried (MgSO4) and evaporated. The residue is purified by flash chromatography (silica, 7% EtOAc/hexane) to give pure 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-methylpyrimidine (6.35g, 75%) as a partial hydrate; mp 62°-65° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=2)[N:11]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[CH:10]=1)=[O:8].N[C:25]1SC=C(C)N=1>>[CH3:25][C:4]1[N:3]=[C:2]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=3)[N:11]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:10]=2)=[O:8])[S:1][CH:5]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(Nc1nccs1)c1cn(CC2CC2)c2cc(CO)ccc12
Product: Cc1csc(NC(=O)c2cn(CC3CC3)c3cc(CO)ccc23)n1

Procedure:
The compound was prepared according to the procedure given for 1-Cyclopropylmethyl-6-hydroxymethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide using 2-amino4-methyl-thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=O)[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[S:32])[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=O)N3C)C(=O)O1
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=S)N3C)C(=O)O1
Temperature: 75 °C
Yield: 89.2 %

Procedure:
To a stirred suspension of the (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 62, Step 5, 1.26 g, 3.907 mmol) in dry dioxane (25 mL) is added Lawesson's reagent (2.37 g, 5.861 mmol). This reaction mixture is heated at 70-80° C. for 1.5-2 h at which time the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is washed with EtOAc (15 mL×3), sonicated and filtered to give the title compound as a yellow solid (1.18 g, 89%), MS (m/z): 339.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([CH2:23]SC)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[CH:4][N:3]=1.O[O:32][S:33]([O-:35])=O.[K+].O1CCC[CH2:38]1>O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([CH2:23][S:33]([CH3:38])(=[O:35])=[O:32])[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[CH:4][N:3]=1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CCOC(=O)CCCCc1c(CSC)nn2c(CC)ccc2c1-c1ccnc(Cl)c1
Agent: [K+]
Solvent: O
Product: CCOC(=O)CCCCc1c(CS(C)(=O)=O)nn2c(CC)ccc2c1-c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylthio)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate (139 mg) in tetrahydrofuran (4 mL) and water (1 mL) was added oxone (287 mg) and the mixture was stirred at ambient temperature for 4 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with saturated sodium bicarbonate solution, sodium thiosulfate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1–1:1) to give ethyl 5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylsulfonyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate as an yellow oil (124 mg).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)[O:12]2)=[C:4]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:3]=1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.CS(C)=[O:42]>>[CH:18]([OH:22])=[O:42].[CH2:23]([C:20]1[N:19]=[C:18]([C@@H:13]2[C@@H:14]([OH:17])[C@@H:15]([OH:16])[C@H:11]([N:8]3[CH:7]=[N:6][C:5]4[C:9]3=[N:10][C:2]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[N:3][C:4]=4[NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[O:12]2)[O:22][N:21]=1)[CH3:24]
Reactant: CCc1noc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CS(C)=O
Reactant: NCCc1ccccn1
Product: CCc1noc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(NCCc5ccccn5)nc43)[C@H](O)[C@@H]2O)n1
Product: O=CO
Temperature: 80 °C

Procedure:
Intermediate 9 (0.070 g, 0.161 mmol) and 2-(2-aminoethyl) pyridine (0.096 ml, 0.807 mmol) were dissolved in DMSO (0.03 ml) and heated at 80° C. in a sealed vial (eg Reacti vial™), for 46 h, a further portion of 2-(2-aminoethyl) pyridine (0.096 ml, 0.807 mmol) was added after the first 20 h. The product was purified by Autoprep. HPLC to give the title compound after freeze drying as a beige solid (0.035 g). LC/MS system B Rt=2.38 min, m/z=524 MH+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:9](=[O:20])[N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[C:7]2=[O:32])(=[O:3])[CH3:2].[CH3:33][Mg]I>CCOCC>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[CH2:21][N:8]1[C:7](=[O:32])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:1]([OH:3])([CH3:33])[CH3:2])[CH:5]=2)[N:10]([CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:9]1=[O:20]
Reactant: C[Mg]I
Reactant: COc1ccc(Cn2c(=O)c3cc(C(C)=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Solvent: CCOCC
Product: COc1ccc(Cn2c(=O)c3cc(C(C)(C)O)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
0.1 g of 6-acetyl-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione is added to a solution of 0.143 g of methylmagnesium iodide in 1 ml of Et2O. This mixture is stirred for 30 minutes at 0° C. and then overnight at room temperature. The reaction mixture is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with EtOAc to give 0.01 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[OH:18][C:19]1([C:25]#[C:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)=[CH:26][C:25]([C:19]3([OH:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)cc1
Reactant: Cc1ccc(C(=O)C#CC2(O)CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2nc(C3(O)CCCCC3)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44054.4 %

Procedure:
To a suspension of 4-methoxyphenylhydrazine (165 mg, 0.944 mmol) in ethanol (5.0 mL), triethylamine (258 μL, 1.88 mmol) was added, and the obtained solution was stirred at room temperature for 30 minutes. The resulting solution was added to a solution of 3-(1-hydroxycyclohexyl)-1-(4-tolyl)-2-propyn-1-one (Reference Example 14) (214 mg, 0.883 mmol) in ethanol (3.0 mL), and the resulting mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and distilled water was added to the residue. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound (141 mg, 0,389 mmol, 44%) as a yellow amorphous product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=[O:22])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH3:20])([CH3:21])[C:17](=[O:22])[C:16]=2[Br:30])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.2 %

Procedure:
To a room temperature solution of 5-(4(benzyloxy)phenyl)-2,2-dimethylfuran-3(2H)-one (1.5 g, 0.005 mol) in CHCl3 (50 mL), NBS (1.37 g, 0.007 mol) was added portionwise. The reaction mixture was stirred for 2 h at RT and then concentrated in vacuo to obtain the crude product. The residue was partitioned between water and DCM. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated in vacuo to afford 5-(4-(benzyloxy)phenyl)-4-bromo-2,2-dimethylfuran-3(2H)-one (2.0 g) as a solid. This material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([OH:20])=O)[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[O:20])[NH:15][C:14]=12)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccncc1
Reactant: O=C(O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccncc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
A mixture of 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Reference Example 4) (398 mg, 1.11 mmol), 4-(aminomethyl)pyridine (169 mg, 1.56 mmol), 1-ethyl-3-dimethylaminopropylcarbodiimide (EDCI) (299 mg, 1.56 mmol), 1-hydroxybenzotriazole (HOBt) (211 mg, 1.56 mol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 h. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0:10 to 1:10 methanol/ethyl acetate). Recrystallization from hexanes/ethyl acetate gave 7-(dibenzylamino)-N-(4-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (419 mg, 84%) as colorless crystals: Rf 0.20 (silica gel, ethyl acetate); mp 119-120° C.; 1H NMR (300 MHz, CDCl3) δ4.62 (2H, d, J=6.0 Hz), 4.90 (4H, s), 6.40-6.52 (1H, m), 6.75 (1H, s), 7.01 (1H, d, J=5.6 Hz), 7.21 (2H, d, J=5.9 Hz), 7.25-7.38 (10H, m), 7.91 (1H, d, J=5.6 Hz), 8.57 (2H, d, J=5.9 Hz), 8.98 (1H, br s); ESI MS m/z 448 [C28H25N5O+H]+; HPLC (Method A) >99% (AUC), tR=15.7 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9][NH2:10])=[N:5][CH:6]=[CH:7][N:8]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[CH2:42]([O:49][C:50]([NH:52][CH2:53][C@H:54]1[CH2:59][CH2:58][C@H:57]([C:60](O)=[O:61])[CH2:56][CH2:55]1)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl>[CH2:42]([O:49][C:50](=[O:51])[NH:52][CH2:53][C@H:54]1[CH2:59][CH2:58][C@H:57]([C:60](=[O:61])[NH:10][CH2:9][C:4]2[C:3]([Cl:2])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:56][CH2:55]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reactant: NCc1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of C-(3-chloropyrazin-2-yl)methylamine hydrochloride salt (0.100 g, 0.533 mmol) in DCM (1.35 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.16 g, 0.83 mmol), N,N-diisopropylethylamine (0.14 mL, 0.83 mmol), 1-hydroxybenzotriazole (0.075 g, 0.56 mmol) and trans-4-({[(benzyloxy)carbonyl]amino}methyl)cyclohexanecarboxylic acid (0.21 g, 0.70 mmol). The reaction was stirred at rt overnight then diluted with DCM, washed with sat. NaHCO3 (aq) and brine, then dried over Na2SO4 and the solvent removed in vacuo. The residue thus isolated was chromatographed over silica gel eluting with EtOAc/hexane (1:1) to afford 0.173 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.00-1.03 (m, 2H), 1.45-1.51 (m, 2H), 1.83-1.89 (m, 2H), 1.99-2.03 (m, 2H), 2.20 (m, 1H), 3.05-3.12 (m, 3H), 4.68 (d, J=4.4 Hz, 2H), 4.79 (br, 1H), 5.10 (s, 2H), 6.79 (br, 1H), 7.31-7.37 (m, 5H), 8.33 (d, J=2.8 Hz, 1H), 8.46 (d, J=2.8 Hz, 1H). MS (ES+): m/z 417.14 [MH+].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])(C)(C)C.CC1(C)O[C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])=[CH:29][C:28](=[O:40])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:30]([C:32]4[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=4)[C:35]#[N:36])[CH2:29][C:28](=[O:40])[NH:23][C:9]=3[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(Cl)cc2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccc(Cl)cc4)cc3NC(=O)C2)c1
Yield: 47 %

Procedure:
Prepared from [2-amino-4-(4-chloro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G13) (187 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (184 mg, 0.6 mmol) according to the general procedure K. The obtained material (234 mg) was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (93 mg).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1O)[CH:24]=[O:25].O>CN(C=O)C>[CH2:8]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:4][CH2:1][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])[CH:24]=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCBr
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1OCCCCCCCCCCCC
Temperature: 100 °C
Yield: 75.4 %

Procedure:
K2CO3 (50.03 g, 0.362 mol) and 1-bromododecane (90.3 g, 0.362 mol) were added to a solution of 3,4-dihydroxybenzaldehyde (25.0 g, 0.181 mol) in 500 mL of DMF. The reaction mixture was heated at 100° C. for 2 days. The mixture was poured into H2O and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The crude product was recrystallized from MeOH to give an off-white solid (64.8 g, 72.8%). mp 69-70° C. 1H NMR (200 MHz, CDCl3, δ): 9.80 (s, 1H), 7.36-7.41 (m, 2H), 6.92 (d, J=8.6 Hz, 1H), 4.03 (q, J=6.2 Hz, 4H), 1.81 (m, 4H), 1.44 (m, 4H), 1.24 (s, 32H), 0.85 (t, J=6.4 Hz, 6H). 13C{1H} NMR (200 MHz, CDCl3, δ): 190.92, 154.65, 149.42, 129.85, 126.54, 111.72, 110.93, 69.08, 31.89, 29.58, 29.34, 29.04, 28.96, 25.92, 22.66, 14.07. IR (cm−1): 2916, 2847, 1686, 1672, 1584, 1506, 1277, 1236, 1133, 807, 800. HRMS-FAB (m/z): [M+H]+ calcd for C31H55O3, 475.4151; found, 475.4156. Anal. Calcd for C31H54O3: C, 78.43; H, 11.46. Found: C, 78.46; H, 11.72.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.CO.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1
Temperature: 50 °C

Procedure:
Methyl 4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-carboxylate (94 mg, 0.25 mmol) was suspended in THF (3 mL), MeOH (3 mL), and water (1.5 mL), and NaOH (0.10 g, 2.5 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated in vacuo, acidified with 2N HCl, and the resulting solid was collected by filtration. This yielded 90 mg (99%) of the title compound. LC/MS m/z 365.2 (MH+), retention time 3.46 min. 1H NMR (400 MHz, DMSO-d6) δ 7.08 (t, 1H), 7.49-7.80 (m, 6H), 7.82-8.01 (m, 4H), 10.75 (br, 1H).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:50][NH:51][O:52][CH3:53]>C(Cl)Cl>[CH3:53][O:52][N:51]([CH3:50])[C:3](=[O:5])[CH2:2][NH:1][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 114.1 mmol) and BOP (50.5 g, 114.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (11.2 g, 114.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred for 16 h then washed with 1N HCl (3×120 mL), H2O (3×120 mL), saturated NaHCO3 aqueous solution (3×120 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 27 as a white solid (20 g, 80%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:34](Cl)(=[O:40])[O:35][CH2:36][C:37]#[C:38][CH3:39]>C(#N)C.CO>[CH3:1][N:2]([CH3:26])[C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:15][CH2:16][N:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:34]([O:35][CH2:36][C:37]#[C:38][CH3:39])=[O:40])[CH2:22][CH2:21]3)[CH2:18][CH2:19]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CCC2(CCN(C3CCNCC3)CC2)c2ccccc21
Reactant: CC#CCOC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: CC#CCOC(=O)N1CCC(N2CCC3(CCN(C(=O)N(C)C)c4ccccc43)CC2)CC1
Reaction time: 1 h

Procedure:
N,N-dimethyl-1-(piperidin-4-yl)-2′,3′-dihydrospiro[piperidine-4,4′-quinoline]-1′-carboxamide 2ae (35.7 mg, 0.1 mmol) was dissolved in acetonitrile (1 mL) and triethylamine (100 uL) and treated with but-2-ynyl carbonochloridate (26.5 mg, 0.2 mmol). The reaction was stirred for 1 hour, then diluted with methanol (0.5 mL) and purified by HPLC (2-99% CH3CN gradient, 0.05% TFA) to yield compound no. 5. LC/MS (10-99% CH3CN/0.05% TFA gradient over 5 min): m/z 453.2, retention time 2.31 minutes. 1H-NMR (CDCl3, 400 MHz): δ 12.65 (br s, 1H), 7.69 (d, J=6.9 Hz, 1H), 7.13 (t, J=8.3 Hz, 1H), 7.02 (t, J=8.1 Hz, 1H), 6.83 (d, J=9.2 Hz, 1H), 4.66 (s, 2H), 4.38 (br s, 2H), 3.58 (m, 2H), 3.45 (m, 2H), 3.31 (m, 1H), 3.08 (m, 5H), 2.85 (s, 6H), 2.37 (m, 2H), 1.97 (m, 2H), 1.86 (t, J=2.3 Hz, 3H), 1.81 (m, 3H), 1.42 (t, J=7.3 Hz, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:13][C:11]=2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:28](OC)(OC)[CH3:29]>CO>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[C:14]1[CH:15]=[CH:16][C:10]2[N:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:28]([CH3:29])=[N:12][C:11]=2[CH:13]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCCc1ccccc1
Reactant: COC(C)(OC)OC
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.5 %

Procedure:
To a methanol (5 mL) solution of 2-(2-(2-phenylethyl)aminoanilin-5-yl)benzoxazole (see Working Example 52-1) (140 mg, 0.425 mmol) was added 1,1,1-trimethoxyethane (61.3 mg, 0.510 mmol), and this was stirred at room temperature for 6 hours. After the reaction was complete, this was concentrated, and the residue obtained was purified by silica gel column chromatography to yield the title compound (98.4 mg, 66% yield) as white crystals.