Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of (R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.14 mmol, 1.0 eq) in THF (2.5 mL) was added to a suspension of sodium hydride (1.15 eq) in THF (2.5 mL) cooled at 0° C. and the resulting mixture was stirred for 45 min. A solution of 4-chlorobenzyl bromide (1.31 mmol, 1.15 eq) in THF (2.0 mL) was then added drop wise and reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with water (1.0 ml) and diluted with ethyl acetate. The combined organics were dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (10%) to hexane/ethyl acetate (30%). 1H-NMR (CDCL3) δ: 1.45 (9H, s), 1.80–2.05 (2H, m), 3.30–3.55 (4H, m), 4.05 (1H, m), 4.45 (2H, s), 7.15–7.30 (4H, m). ESI-MS m/z:311 (M+1), UV retention time: 2.94 min.
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[S:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(OC)(O[CH3:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([O:17][CH3:24])=[O:16])=[S:12])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C=CC(=S)c1ccc(-c2ccccc2)cc1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C=CC(=S)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of 8.53 g of 3-(4-phenylthiobenzoyl)acrylic acid in 50 ml of dimethylformamide were added 4.54 g of dimethyl sulfate and 2.50 g of potassium carbonate, and the resulting mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the mixture was extracted from diethyl ether. The organic layer was washed, in turn, with water, a saturated aqueous solution of sodium hydrogen-carbonate and water, and dried over magnesim sulfate. The diethyl ether was removed from the solution by evaporation, and the residue was recrystallized from a mixture of hexane and dichloromethane to give 6.80 g of methyl 3-(4-phenylthiobenzoyl)acrylate.
Reaction SMILES: [CH:1]1([OH:7])[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CN(C=O)C>[Si:13]([O:6][CH:3]1[CH2:4][CH2:5][CH:1]([OH:7])[CH2:2]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: OC1CCC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
To a solution of 1,3-cyclopentanediol (5 g, 49 mmol) and imidazole (5 g, 74 mmol) in DMF (20 mL) added tert-butyldimethylsilyl chloride (5.9 g, 39 mmol). The reaction stirred for 3 h at room temperature and was then poured into water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (10% diethyl ether:hexanes) to afford 3.5 g (33%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 4.3-4.5 (m, 2H), 1.9-2.15 (m, 2H), 1.65-1.8 (m, 2H), 1.4-1.6 (m, 2H), 1.32-1.41 (m, 1H), 0.86 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O1CCCC1.[OH-].[Na+].Cl[CH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1>CN(C)C=O>[S:31]1[CH:32]=[CH:33][N:34]=[C:30]1[CH2:29][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[O:12][N:11]=2)=[CH:15][CH:16]=1
Reactant: ClCc1nccs1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3nccs3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (50.0 mg, 0.19 mmol) described in Manufacturing Example 5-1-1 were added tetrahydrofuran (3 mL) and a 5N aqueous sodium hydroxide solution (37.3 μL, 0.19 mmol), which was dissolved by irraidiating ultrasonic wave for 1 minute. The reaction mixture was then concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-thiazole (29.8 mg, 0.22 mmol) described in Manufacturing Example 88-1-2 was added to a suspension of this solid and N,N-dimethylformamide (2 mL), which was stirred for 1 hour at 60° C. This mixture was cooled to room temperature, and partitioned into water and ethyl acetate. 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 (heptane:ethyl acetate=1:1) to obtain the title compound (53.0 mg, 78%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:13]=[C:12]([Cl:14])[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A solution of 125 g of nitric acid in 153 g of sulfuric acid which had been prepared with ice-cooling at (−5)° C. was added dropwise to a solution of 262.5 g (1.5 mol) of 2,4-dichlorobenzaldehyde in 560 ml of sulfuric acid. After the reaction mixture had been stirred for 2 hours at 10° C., it was poured onto 4 kg of ice. The resulting solids were subsequently separated off, washed with water and dissolved in 2 l of dichloromethane. The resulting solution was washed with saturated aqueous sodium hydrogen carbonate solution, then dried over magnesium sulfate and finally concentrated. Yield: 329.5 g; m.p.: 61-63° C.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:9]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:9][C:6]1[O:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccco1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(Br)o1

Procedure:
To a one-neck-flask charged with 2-acetylfuran (5.51 g, 50 mmol) in DMF (40 ml) at 0° C., was added N-Bromosuccinimide (9.79 g, 55.0 mmol) portionwise with stirring. The reaction mixture was stirred at rt overnight. The reaction mixture was poured into water (400 mL), extracted with ether (150 mL×3). The combined organic layers was dried, concentrated and purified on a silica gel column (Hexanes:EtOAc=4:1) to afford a white solid GC-4-89 (3 g, 31.7%). 1H-NMR (400 MHz, CDCl3) δ: 7.12 (d, J=3.6 Hz, 1H), 6.49 (d, J=3.2 Hz, 1H), 2.46 (s, 3H)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.[CH:17]1([C:20]2[N:42]=[C:23]3[N:24]=[C:25]([C:34]4[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=4)[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:27][N:22]3[N:21]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[N:42]=[C:23]3[N:24]=[C:25]([C:34]4[CH:41]=[CH:40][C:37]([CH2:38][N:1]5[CH2:4][CH:3]([C:5]6[N:6]=[C:7]([C:10]7[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=7)[NH:8][N:9]=6)[CH2:2]5)=[CH:36][CH:35]=4)[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:27][N:22]3[N:21]=2)[CH2:19][CH2:18]1
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Reactant: O=Cc1ccc(-c2nc3nc(C4CC4)nn3cc2-c2ccccc2)cc1
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(C7CC7)nn6cc5-c5ccccc5)cc4)C3)n[nH]2)n1

Procedure:
The compound is prepared in analogy to example 40.0. 211.6 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure) are reacted with 250 mg (0.73 mmol) 4-(2-cyclopropyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (intermediate example 4.0) After the usual work-up and purification 97 mg (23.3%) of the desired compound are obtained.
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][N:12]3[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:25]N1C(C)(C)C(=O)N(Cl)C1=O>C(Cl)(Cl)Cl>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][N:12]3[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][C:6]=2[Cl:25])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)ccc2c1=O
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(Cl)cc2c1=O

Procedure:
A solution of EXAMPLE 81C (0.50 g) and 1,3-dichloro-5,5-dimethylhydantoin (0.30 g) in chloroform (100 mL) was refluxed for 2 hours then cooled, diluted with chloroform, washed with 10% sodium bisulfate and brine, and dried (MgSO4), filtered, and concentrated; and the concentrate was crystallized from dichloromethane/ethyl acetate/hexanes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([Cl:20])[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.Cl>[Fe].C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([Cl:20])[CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccc(Br)cc2)cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2ccc(Br)cc2)cc1Cl

Procedure:
Iron powder (2.5 g) was added to a stirred mixture of 4-(4-bromophenylsulphonyl)-2-chloro-nitrobenzene (Method 13) (0.6 g), water (2 ml), concentrated hydrochloric acid (0.5 ml) and ethanol (10 ml). The mixture was heated under reflux for 1 hour then evaporated to near dryness and partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (3×15 ml) and the organic extracts were combined and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-25% ethyl acetate/hexane followed by trituration with ether to give the title compounde (0.11 g) as a solid. NMR: 6.42 (s, 2H), 6.82 (d, 1H), 7.5 (d, 1H), 7.8 (m, 5H); MS: 346 (M−H)−.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+](=[CH2:17])=[N-]>>[CH3:17][O:13][C:12](=[O:14])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: C=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Product: COC(=O)Cc1ccc(S(C)(=O)=O)cc1

Procedure:
(4-Methanesulfonyl-phenyl)-acetic acid was treated with an etheral solution of diazomethane until completion of esterification by TLC. The solvent was evaporated, the residue triturated in hexane/ether and filtered to afford the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][NH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][NH:15][CH2:29][CH2:28][CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CCNCCCOc2ccc3ccccc3c2)cc1
Temperature: 145 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 2-phenylethylamine (0.51 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 145° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(2-phenylethyl)-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 270° C., (yield 0.65 gm, 93.7%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12)(=[O:22])[CH3:21]
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Temperature: 10 °C

Procedure:
To a stirred solution of 5-hydroxy-12H-benzo[a]phenothiazine (50 g) in pyridine (115 ml) was added acetic anhydride (48 ml). The reaction was exothermic stirring was continued without cooling for 30 minutes, then the mixture was cooled to 10° C. using an ice bath. The yellow crystalline solid was filtered and washed with ether to afford the title compound (23.4 g). The product was crystallized from ethyl acetate, m.p. 185°-186° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:24][CH3:25])[C:9]3[C:14]([CH2:15][NH:16]C4CCNCC4)=[CH:13][N:12]=[CH:11][C:10]=3[N:23]=2)=[N:4][O:5][N:6]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37]N[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:24]([N:8]1[C:9]2[C:14]([CH2:15][N:16]3[CH2:35][CH2:34][N:33]([C:30]4[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=4)[CH2:38][CH2:37]3)=[CH:13][N:12]=[CH:11][C:10]=2[N:23]=[C:7]1[C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[CH3:25]
Reactant: CCn1c(-c2nonc2N)nc2cncc(CNC3CCNCC3)c21
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCn1c(-c2nonc2N)nc2cncc(CN3CCN(c4ccc(F)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product of Example 191 Step 1 (0.10 g, 0.38 mmole) in 1,2-dichloroethane (5 ml) was treated with 1-(4-fluorophenyl)piperazine (0.10 g, 0.58 mmole) and stirred at ambient temperature for 15 minutes. Sodium triacetoxyborohydride (0.16 g, 0.76 mmole) was added and the reaction mixture stirred at ambient temperature for 18 hours. The mixture was diluted with dichloromethane, washed (×2) with saturated sodium hydrogen carbonate solution followed by saturated brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to afford the title compound; MS (ES+) m/e 357 [M+H]+. The following examples were prepared from the product of Example 191 Step 1 using the method described in Example 200.
Reaction SMILES: [C:1]([O:10]C1C=CC=CC=1)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:4])=[CH:20][CH:19]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Product: O=C(Nc1ccc(F)cc1)c1ccccc1O

Procedure:
The 4′-fluoro-salicylanilide was prepared by condensing phenyl salicylate with 4-fluoroaniline then purified as described in Example 2a. The ligand mixture was then prepared from 4′-fluoro-salicylanilide and 1,1′-bi-2-naphthol using the procedure described in Example 5a. 31P NMR (121.77 MHz): several peaks between 117.1-117.7 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7](=[S:13])[S:8][CH2:9][C:10](Cl)=[CH2:11])=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:2]1([CH3:1])[CH:15]=[CH:14][C:5]([N:6]=[C:7]2[S:13][C:10]([CH3:11])=[CH:9][S:8]2)=[CH:4][CH:3]=1
Reactant: C=C(Cl)CSC(=S)Nc1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(N=c2scc(C)s2)cc1
Yield: 79 %

Procedure:
2-Chloroallyl 4-methyldithiocarbanilate (7.3 g, 0.0286 mol) and concentrated hydrochloric acid (9.1 ml 0.112 mol) are mixed and heated at reflux temperature for 2 hours. The resulting solution is cooled, diluted with water, and neutralized with sodium carbonate. The reaction mixture is extracted with ether. The ether extract is washed with 6N hydrochloric acid and the aqueous layer is separated, neutralized with sodium carbonate, and extracted with ether. The ether phase is separated, washed with water and dried over anhydrous magnesium sulfate. The ether is evaporated to dryness in vacuo to leave 5.0 g of crude 2-(p-tolyl)imino-4-methyl-1,3-dithiole, a brown oil which crystallizes on standing. The crystalline mass is triturated with petroleum ether, filtered off and dried to yield 2.7 g of purified product melting at from 46.5° C. to 49.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][O:43][C:44]([C@H:46]1[CH2:51][C@@H:50](O)[CH2:49][CH2:48][N:47]1[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:45]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][C@@H:50]4[CH2:49][CH2:48][N:47]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])[C@@H:46]([C:44]([O:43][CH3:42])=[O:45])[CH2:51]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
DTAD (7.26 g, 31.5 mmol) dissolved in 50 ml of DCM was added over a period of 10 minutes to a stirred suspension of 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-ol (5.00 g, 15.7 mmol), triphenylphosphine (8.57 g, 62.6 mmol) and (2R,4S)—N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic acid methyl ester (ex ACROS, 5.42 g, 20.9 mmol) in DCM (150 ml) at −15° C. (acetone/ice). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, concentrated to approximately 50 ml and purified directly by flash chromatography (silica gel, eluting with a gradient from 100% DCM to DCM/EtOAc (80/20) to DCM/EtOAc (50/50) to give 1-tert-butyl 2-methyl (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1,2-dicarboxylate (6) (5.5 g, 81%) as a white foam; 1H NMR Spectrum: (DMSO d6) 1.47-1.53 (m, 11H), 1.86-1.91 (m, 1H), 2.25-2.36 (m, 1H), 2.95-3.13 (m, 1H), 3.70 (s, 3H), 3.95 (s, 3H), 3.98-4.04 (m, 1H), 4.45 (m, 1H), 4.86-4.94 (m, 1H), 7.31 (t, 1H), 7.51-7.64 (m, 3H), 7.80 (s, 1H), 8.39 (s, 1H), 9.54 (s, 1H); Mass Spectrum: (M+H)+ 561.1.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[N:14]1[CH2:30][CH2:29][C:17]2([CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:16][CH2:15]1>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[N:14]1[CH2:30][CH2:29][C:17]2([CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ncccn3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc(N2CCC3(CCNC3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1 ml) is added to a solution of tert-butyl 8-(pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.53 mmol, 1.0 eq.) in methylene chloride (5 ml) at 0° C. and the reaction mixture is stirred at 25° C. for 1 h. When the reaction was complete, the solvent was removed in vacuo in order to obtain the desired amine (AMN-25).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15]C(OC(C)(C)C)=O)[CH2:12][N:11]([C:23]2[C:32]([N:33]3[CH2:38][C@@H:37]([NH:39]C(OC(C)(C)C)=O)[CH2:36][C@@H:35]([NH:47]C(OC(C)(C)C)=O)[CH2:34]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH:55][C:56]([C:58]4[CH:63]=[CH:62][C:61]([NH:64][C:65]([C:67]5[CH:76]=[CH:75][C:74]6[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=6)[C:68]=5[OH:77])=[O:66])=[CH:60][CH:59]=4)=[O:57])[CH:29]=3)[N:24]=2)[CH2:10]1)=O)(C)(C)C.Cl>C(O)(C(F)(F)F)=O.CO>[NH2:15][C@@H:13]1[CH2:14][C@H:9]([NH2:8])[CH2:10][N:11]([C:23]2[C:32]([N:33]3[CH2:34][C@@H:35]([NH2:47])[CH2:36][C@@H:37]([NH2:39])[CH2:38]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH:55][C:56]([C:58]4[CH:63]=[CH:62][C:61]([NH:64][C:65]([C:67]5[CH:76]=[CH:75][C:74]6[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=6)[C:68]=5[OH:77])=[O:66])=[CH:60][CH:59]=4)=[O:57])[CH:29]=3)[N:24]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc(NC(=O)c4ccc(NC(=O)c5ccc6ccccc6c5O)cc4)cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N[C@@H]1C[C@H](N)CN(c2nc3ccc(NC(=O)c4ccc(NC(=O)c5ccc6ccccc6c5O)cc4)cc3nc2N2C[C@H](N)C[C@H](N)C2)C1
Reaction time: 0.01 h
Yield: 78.7 %

Procedure:
1-Hydroxy-naphthalene-2-carboxylic acid [4-(2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-quinoxalin-6-ylcarbamoyl)-phenyl]-amide (253) (9 mg, 8.5 μmmol) was dissolved in TFA (1 mL) and the mixture was shaken in a Teflon septum capped vial at room temperature for 3 hours. LC-MS indicated complete de-protection at this point. The solution was concentrated to give an orange oil. The oil was dissolved in MeOH (1 mL) and HCl (1 mL, 4.0 M in dioxane) was added and the mixture was vortexed for 20 seconds. A fine suspension was observed. The mixture was concentrated to an orange powder. Ethyl ether (5 mL) was added to the powder and vortexed for 2 minutes. The solid was collected by filtration and dried under high vacuum for 16 hours to give the desired product (254) as a yellow/green powder (5.4 mg, 6.69 μmmol, 78.7% yield, assuming a 4 HCl salt). LC-MS (ESI): (exact mass: 660.33) m/e=661.6 [M+1]+. 1H NMR (400 MHz, D2O): δ 1.70–1.82 (m, 2H), 2.61–2.65 (m, 2H), 2.78–2.94 (m, 2H), 3.57–3.60 (m, 2H), 3.67–3.68 (m, 4H), 3.97 (d, 2H, J=9.6 Hz), 4.23 (d, 2H, J=9.6 Hz), 6.89 (d, 1H, J=8.8 Hz), 7.14 (d, 1H, J=8.4 Hz), 7.18–7.29 (m, 3H), 7.32–7.53 (m, 6H), 7.74 (d, 2H, J=7.6 Hz).