Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:4][C:3]=1[NH:19][C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].O>CN(C)C=O>[C:20]([NH:19][C:3]1[C:2]([F:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([CH:4]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:30][C:31]([O:33][CH3:34])=[O:32])(=[O:22])[CH3:21]
Reactant: COC(=O)CBr
Reactant: CC(=O)Nc1cc(Oc2ccccc2O)c([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
First, 3.02 g of N-[2-fluoro-5-(2-hydroxyphenoxy)-4-nitrophenyl]acetamide was dissolved in 20 ml of N,N-dimethylformamide, to which 1.5 g of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. Then, 1.6 g of methyl bromoacetate was added at room temperature. After stirring at the same temperature for 2 hours, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid and water, dried over magnesium sulfate, and then concentrated. The resulting crystals were washed with t-butyl methyl ether to give 3.01 g of methyl [2-(5-acetylamino-4-fluoro-2-nitrophenoxy)phenoxy]acetate.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:13][CH:12]=1)=O.[OH-].[K+].NN>C(O)COCCO>[CH3:22][N:2]([CH3:1])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:15][CH:16]=1
Reactant: CN(C)C1CCCCC1C(=O)c1ccc(-n2ccnc2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: CN(C)C1CCCCC1Cc1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Example 28, react [2-(dimethylamino)cyclohexyl][4-(1H-imidazol-1-yl)phenyl]methanone with potassium hydroxide and hydrazine in diethylene glycol to obtain the title compound.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.CCCCCC.[F:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][C:37]([C:39]3[CH:40]=[C:41]4[C:46]5=[C:47]([CH2:49][CH2:50][N:45]5[C:44](=[O:51])[CH2:43][CH2:42]4)[CH:48]=3)=[O:38])[CH2:31][CH2:30]2)[CH:25]=[CH:26][CH:27]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:62])(=O)=O)=CC=1>O1CCCC1.O>[F:62][CH:36]([CH2:35][CH:32]1[CH2:31][CH2:30][N:29]([CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=2)[CH2:34][CH2:33]1)[C:37]([C:39]1[CH:40]=[C:41]2[C:46]3=[C:47]([CH2:49][CH2:50][N:45]3[C:44](=[O:51])[CH2:43][CH2:42]2)[CH:48]=1)=[O:38]
Reactant: O=C(CCC1CCN(Cc2cccc(F)c2)CC1)c1cc2c3c(c1)CCN3C(=O)CC2
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cc2c3c(c1)CCN3C(=O)CC2)C(F)CC1CCN(Cc2cccc(F)c2)CC1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
Into a nitrogen-flushed, three-necked flask, a solution of 1,1,1,3,3,3-hexamethyldisilazane (1.38 g, 8.60 mmol) in tetrahydrofuran (50 ml) was placed and the resulting mixture was cooled in a dry ice/acetone bath. Thereto was added dropwise a solution of n-butyl lithium in hexane (1.6 M)(5.4 ml, 8.6 mmol) and then the resulting solution was stirred at −20° C. for 10 minutes. To this solution, which was cooled again in a dry ice/acetone bath, was added dropwise a solution of 8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo-[3,2,1-ij]quinolin-4-one (3.0 g, 7.1 mol), which was obtained in Example 1, in tetrahydrofuran (20 ml). The resulting mixture was stirred at −20° C. for 20 minutes and then cooled again in a dry ice/acetone bath. To this solution was added dropwise a solution of N-fluorobenzenesulfonimide (1.38 g, 8.6 mmol) in tetrahydrofuran (20) and the temperature was gradually raised to room temperature. The reaction mixture was mixed with water and was extracted with ethyl acetate. Then, the organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate, and concentrated to remove the solvent. The resulting residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to obtain of the title substance as a colorless oily substance (42 mg).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3CCC[CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1SC([Br:37])=C(C)C=1C(OCC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]([Br:37])=[C:13]([CH3:19])[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: CCOC(=O)c1c(N)sc(Br)c1C
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc(Br)c1C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-5-bromo-4-methylthiophene-3-carboxylate (Intermediate 35) and benzenesulphonyl chloride
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:24]1([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:36][C:33]1[CH:34]=[CH:35][C:30]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:31][CH:32]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(C2CCCCC2)cc1
Product: COC(=O)C(Oc1ccc(C2CCCCC2)cc1)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Yield: 86.8 %

Procedure:
As described in Example 44, 8.0 g of methyl bromo{p-[2-(p-chlorophenoxy)ethoxy]phenyl}acetate is reacted with 4.05 g of p-cyclohexylphenol to give 8.6 g of product as tan crystals. Recrystallization from methanol gives off-white crystals, mp 108°-110° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39]Br>C(#N)C>[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([S:10](=[O:12])(=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)=[CH:14][CH:15]=2)[CH2:20]1
Reactant: COC(=O)c1ccccc1CBr
Reactant: O=S(=O)(Nc1cccc(Cl)c1)c1ccc2c(c1)CNCC2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1CN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
To a mixture of 7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.8 g, 5 mmol) and triethylamine (0.51 g, 5 mmol) in dry acetonitrile (25 ml), heated to 70° C., was added half of a solution of methyl-2-(bromomethyl)benzoate (1.15 g, 5 mmol) and triethylamine (0.51 g, 5 mmol) in acetonitrile (25 ml) over 0.5 hr. After 1.5 hr, the remainder of the solution was added slowly over 2 hr and stirred for a further 1 hr. After cooling and filtration the concentrated filtrate was chromatographed (silica gel, ether) to give a methyl-2-[[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]methyl]benzoate (0.66 g, 28%) as an oil. To this, in methanol (30 ml), was added 15% sodium hydroxide solution (8 ml) and the mixture was stirred for 3 hr. The solvent was removed in vacuo, water was added and the pH was adjusted to 6 with 2N HCl to give, after recrystallisation from IPA, 2-[[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]methyl]benzoic acid, H2O, 0.6HCl, 0.48(CH3)2CHOH.
Reaction SMILES: [N:1]1[N:2]=[C:3]([S:6]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[O:7])[NH:4][CH:5]=1.N1N=C(S(CC2C=CC(C(O)=O)=CC=2)(=O)=O)NC=1.[Cl:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][C:38]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>>[N:1]1[N:2]=[C:3]([S:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:41][C:40]3[CH:42]=[CH:43][C:37]([Cl:36])=[C:38]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=4)[CH:39]=3)=[O:15])=[CH:16][CH:17]=2)=[O:7])[NH:4][CH:5]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(CS(=O)c2nnc[nH]2)cc1
Agent: O=C(O)c1ccc(CS(=O)(=O)c2nnc[nH]2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CS(=O)c2nnc[nH]2)cc1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with 4H-1,2,4-triazole-3-thiol via Procedure Q. 542 mg of methyl 4-((4H-1,2,4-triazol-3-ylthio)methyl)benzoate was subsequently reacted via Procedure R to give an approximate 1:9 mixture of methyl 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoate and methyl 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoate. The mixture of 467 mg was hydrolyzed via Procedure M to give 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid. 107 mg of the mixture of 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid was coupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was separated on reverse phase HPLC to give 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 438.1 (M)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]=2[N:8]=1.Cl.[NH2:25][NH:26][C:27](=[O:30])[O:28][CH3:29]>C(O)(=O)C.CO.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11]/[C:10](=[N:25]\[NH:26][C:27](=[O:30])[O:28][CH3:29])/[C:9]=2[N:8]=1
Reactant: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(=O)CCC2
Reactant: COC(=O)NN
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)N/N=C1\CCCc2ccc(-c3sc(-c4cccnc4)nc3C)nc21
Temperature: 75 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A solution of 2-[4-methyl-2-(3-pyridyl)thiazol-5-yl]-6,7-dihydro-5H-quinolin-8-one (0.030 g, 0.093 mmol), methyl N-aminocarbamate hydrochloride (0.018 g, 014 mmol)) and acetic acid (1drop) were dissolved in methanol (0.9 mL) at ambient temperature and the resulting orange solution was stirred at 75° C. for 1 hour: LC-MS after this time showed reaction completion. The mixture was diluted with ethyl acetate, and then washed successively with saturated aqueous NaHCO3 and then water. The organic phase was, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with 0%-10% Methanol: Dichlormethane gradient gave the title product (29 mg, 79%) as yellow-orange solid. mp: 194-200° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[C:29](F)=[C:28]([F:31])[C:27](F)=[C:26](F)[C:25]=3F)=[CH:15][CH:14]=2)=[C:7]2[C:3]=1[C:4]([CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:5]([CH3:41])[N:6]2[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].[C:48](OC)(C)(C)C>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([F:31])[C:29]=3[CH3:48])=[CH:15][CH:14]=2)=[C:7]2[C:3]=1[C:4]([CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:5]([CH3:41])[N:6]2[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]
Reactant: COC(C)(C)C
Reactant: Cc1c(CCCC(=O)O)c2c(F)ccc(C#Cc3ccc(OCCCCc4c(F)c(F)c(F)c(F)c4F)cc3)c2n1CCCC(=O)O
Product: Cc1c(F)cccc1CCCCOc1ccc(C#Cc2ccc(F)c3c(CCCC(=O)O)c(C)n(CCCC(=O)O)c23)cc1
Temperature: 25 °C

Procedure:
The compound (30 mg) prepared in Example 14 (2) was dissolved in methyl tertiary butyl ether (2.4 mL) at 60° C. The solution was cooled to room temperature to induce crystallization. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (24 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25].[NH4+].[OH-]>C(#N)C.C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:21][CH2:22][CH2:23][C:24]#[N:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCCCBr
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCNCCCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
To a solution of the BOC protected diamine 9 (2.10 g, 0.01 mol) in anhydrous acetonitrile (50 mL) was added potassium carbonate (5.14 g) and the suspension was stirred at RT for 10 minutes. A solution of 4-bromobutyronitrile (1.65 g, 0.01 mol) in acetonitrile (25 mL) was added and the resulting mixture stirred at 50° C. for 24 hours. TLC (1:10:89 NH4OH:MeOH:CHCl3) showed that the reaction was 95% complete. The mixture was filtered to remove most of the inorganic salts and the acetonitrile was removed in vacuo to give a solid/oily residue that was purified by flash column chromatography (1:5:94 NH4OH:MeOH:CHCl3) to yield the product 10 as a clear oil (1.74 g, 61%), Rf=0.5 (1:10:89 NH4OH:MeOH:CHCl3); 1H NMR (CDCl3) d 4.79 (br s, 1H, NHCO), 3.12 (q, 2H, CH2), 2.74 (t, 2H, CH2), 2.60 (t, 2H, CH2), 2.46 (t, 2H, CH2), 1.81 (quin, 2H, CH2) 1.57-1.37 (m, 13H, 2×CH2, 3×CH3).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[C:14]1([C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:10][NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: NNC(=O)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NN=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 68.0 g (0.5 mol) of benzohydrazide, 700 ml of methanol and 3.5 ml of acetic acid. Added thereto was 109.2 g (0.6 mol) of benzophenone while stirring at room temperature, and heating under reflux was continued for 12 hours. The reaction liquid was cooled down to 5° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1>[C].[Pd]>[F:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(F)c(NCC3=Cc4ccccc4CC3)cc2o1
Agent: [Pd]
Product: O=c1[nH]c2cc(F)c(NCC3CCc4ccccc4C3)cc2o1

Procedure:
In a manner similar to Example 3A starting with 5-fluoro-6-[(3,4-dihydro-2-naphthyl)methylamino]benzoxazolin-2-one but employing palladium carbon (5%) instead of platinum oxide, the title compound was prepared: m.p. 177°-178° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([OH:15])[CH2:13][CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[F:25][C:26]1[CH:27]=[C:28]([N+:33]([O-:35])=[O:34])[CH:29]=[C:30](F)[CH:31]=1>CN(C=O)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([O:15][C:30]2[CH:29]=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=[C:26]([F:25])[CH:31]=2)[CH2:13][CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a 0° C. solution of (2R,3S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-hydroxypyrrolidine-1-carboxylate (1 equiv) in DMF (0.5 M) was added NaH (1.3 equiv) as a solid. After stirring for 15 min at 0° C., 3,5-difluoronitrobenzene (1.2 equiv) was added by syringe. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched by the addition of water, and the mixture was diluted with EtOAc. The organic layer was washed four times with water and once with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (0-20% EtOAc/Hexanes) provided the title compound in 82% yield.
Reaction SMILES: [CH:1]([C:4]1[N:13]=[C:7]2[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:27])[C:23]=1[C:24](O)=[O:25])=[O:18])[CH3:15].CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]([C:4]1[N:13]=[C:7]2[CH:8]=[C:9]([NH:12][C:24]([C:23]3[N:22]([CH3:27])[N:21]=[CH:20][C:19]=3[C:17]([O:16][CH2:14][CH3:15])=[O:18])=[O:25])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: CC(C)c1nc2cc(N)ccn2n1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(C(C)C)nc2c1
Reaction time: 1 h
Yield: 103.3 %

Procedure:
A mixture of 2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (159 mg, 902 μmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (215 mg, 1.08 mmol), propylphosphonic anhydride (50% in ethyl acetate, 1.33 ml, 2.26 mmol) and diisopropylethylamine (473 μl, 2.71 mmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The solvent is evaporated and the residue stirred for 1 hr with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed with water and dried affording ethyl 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (332 mg, 103%) as a white solid. Mp.: 175-7° C. MS: m/z=357.2 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]=2[NH2:19])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]([NH:4][C:1](=[O:3])[CH3:2])[CH:14]=1)[C:9]=2[NH2:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(N)c3ccccc3nc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc2c(N)c3ccc(NC(C)=O)cc3nc2c1
Temperature: 140 °C
Yield: 175.2 %

Procedure:
4′-Bromodiphenylamine-2-carboxylic acid 3 (430 mg, 1.47 mmol) and phosphorus oxychloride (5 mL) were charged to a 25 mL rbf equipped with a reflux condenser and nitrogen bubbler. The reaction mixture was refluxed at 140° C. for 1 hour until a red colour was obtained. The excess POCl3 was removed in vacuo. The reaction mixture was carefully quenched with ice, basified with concentrated aqueous ammonia solution (the flask was kept cold with an ice bath), and extracted with chloroform. The combined organic layers were dried over magnesium sulphate, filtered and concentrated to yield the crude product. Purification by dry chromatography using a gradient elution (Hexane e Hexane:EtOAc 96:4) afforded pure 3-bromo-9-chloroacridine 4 as a cream solid (397 mg, 92%). Analyses by 1H NMR and LCMS conformed to structure.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C@@H:9]([OH:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([O:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2O)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([O:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[O:11][C@@H:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)[CH3:10])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Reactant: C[C@H](O)c1cccc(C(F)(F)F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(Cl)cc1OC1CN(C(=O)OC(C)(C)C)C1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 90.5 %

Procedure:
To (S)-1-(3-trifluoromethyl-phenyl)-ethanol (2.30 g, 12.1 mmol), 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (3.80 g, 12.7 mmol) and PPh3 (3.80 g, 14.5 mmol) in THF (60 mL) at 0° C. was added DEAD (2.3 g, 2.1 mL, 13 mmol) in THF (10 mL) dropwise over 30 min. After 48 h, the reaction was concentrated and 15% EtOAc in hexanes was added. The flask was cooled to 0° C. and filtered. The filtrate was concentrated and this procedure repeated 2 more times. The resulting oil was then purified using silica gel chromatography (10-40% EtOAc in hexanes) to give 5.17 g (91%) of the title compound as a clear oil. 1H NMR (CDCl3): 7.66 (s, 1H), 7.56-7.53 (m, 2H), 7.46 (t, J=7.7 Hz, 1H), 6.79 (dd, J=8.6, 2.4 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 5.29 (q, J=6.5 Hz, 1H), 4.88-4.82 (m, 1H), 4.33-4.29 (m, 2H), 4.08-4.01 (m, 2H), 1.67 (d, J=6.5 Hz, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:18]=[C:17]([N:19]2[C@H:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][C@H:21]([C:29]([NH:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:30])[CH2:20]2)[CH:16]=[C:15]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[C:40](F)[CH:39]=2)[N:14]=1.O.[NH2:48][NH2:49]>C(O)C>[NH2:45][C:44]1[C:41]2[C:40](=[CH:39][C:38]([C:15]3[N:14]=[C:13]([NH:12][CH2:11][C:4]4[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=4[O:2][CH3:1])[N:18]=[C:17]([N:19]4[C@H:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][C@H:21]([C:29]([NH:31][CH:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)=[O:30])[CH2:20]4)[CH:16]=3)=[CH:43][CH:42]=2)[NH:49][N:48]=1
Reactant: COc1ccc(CNc2nc(-c3ccc(C#N)c(F)c3)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(CNc2nc(-c3ccc4c(N)n[nH]c4c3)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To cis-1-[2-({[2,4-bis(methyloxy)phenyl]methyl}amino)-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (304 mg, 0.48 mmol) in ethanol (6 mL) was added hydrazine monohydrate (0.47 mL, 9.5 mmol), and the reaction mixture was stirred overnight at 100° C. into a sealed tube. The reaction was allowed to cool to room temperature and poured onto water (˜200 mL). A white precipitate was formed. The mixture was filtered, and the solid was air dried for 2 hours to afford the title compound (270 mg) as a white solid. LC-MS (ES) m/z=653 [M+H]+.