Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[OH:13])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[C:7]3([CH2:12][CH2:11][CH2:10][CH2:9][C:8]3([CH2:14][N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)[OH:13])[O:30]2)=[CH:20][CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC1(Cn2cncn2)CCCCC1=Cc1ccc(Cl)cc1
Solvent: O
Solvent: ClCCl
Product: OC1(Cn2cncn2)CCCCC12OC2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
A mixture of 9 g of 2-(4-chlorobenzylidene)-1-(1,2,4-triazol-1-ylmethyl)cyclohexan-1-ol and 14.8 g of m-chloroperbenzoic acid in 50 ml of dichloromethane is stirred for 3 h at room temperature. 200 ml of water are then added and extracted with 3×100 ml of dichloromethane. The organic phase is washed with a potassium carbonate solution. The organic phase is dried over sodium sulphate and evaporated. The residue is crystallised from diisopropyl ether to produce 6 g of white solid (M.p.=150.5° C.)
Reaction SMILES: [N:1]#[N:2].O.Cl.Cl.C[O:7][C:8](=[O:34])[C@H:9]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])[NH:10][S:11]([C:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:19]([N:20]([CH3:22])[CH3:21])[C:18]=2[CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:35]([NH2:37])[CH3:36]>O1CCCC1>[N:1]#[N:2].[OH2:7].[S:11]([NH:10][C@H:9]([C:8]([NH:37][CH2:35][CH3:36])=[O:34])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])([C:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:19]([N:20]([CH3:21])[CH3:22])[C:18]=2[CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Reactant: CCN
Agent: Cl
Agent: N#N
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Reaction time: 72 h
Yield: 93 %

Procedure:
To a suspension of 1.0 gram of N2 -dansyl-L-arginine methyl ester dihydrochloride monohydrate in 1 ml of tetrahydrofuran was added 3 ml of ethylamine with cooling. The mixture was allowed to stand in a sealed tube at room temperature for three days. After the excess amine was removed by evaporation, the residue was poured into 50 ml of water to give a precipitate. Recrystallization from 50% aqueous methanol afforded N2 -dansyl-N-ethyl-L-argininamide monohydrate in 93% yield; mp. 220°-222° C.
Reaction SMILES: C(C(NC1C=CC(C)=C(C)C=1)CC)C.[N+]([O-])(O)=O.N([O-])=O.[Na+].N([N:25]([CH:40]([CH2:43][CH3:44])[CH2:41][CH3:42])[C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][C:29]([CH3:35])=[C:28]([CH3:36])[C:27]=1[N+:37]([O-:39])=[O:38])=O.[N+](N(C(CC)CC)C1CC([N+]([O-])=O)(C)C(C)=CC=1[N+]([O-])=O)([O-])=O>ClC(Cl)C.O>[CH2:41]([CH:40]([NH:25][C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][C:29]([CH3:35])=[C:28]([CH3:36])[C:27]=1[N+:37]([O-:39])=[O:38])[CH2:43][CH3:44])[CH3:42]
Reactant: CCC(CC)N(N=O)c1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Agent: CCC(CC)N(C1=C([N+](=O)[O-])C=C(C)C(C)([N+](=O)[O-])C1)[N+](=O)[O-]
Agent: CCC(CC)Nc1ccc(C)c(C)c1
Agent: O=N[O-]
Solvent: CC(Cl)Cl
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
The dinitration of N-(1-ethylpropyl)-3,4-dimethyl-benzenamine is carried out in a pilot plant in a tubular reactor having a static mixer; the tubular reactor is constituted by a coil in three joined sections, each 5000 mm in length with an internal diameter of 4 mm, with temperature sensors fitted at the junctions between them. The Kenics Static Mixer is a 190 mm long tubular body inserted between the second and third sections. The reactor is immersed in a water-cooled thermostated bath. 67% nitric acid supplemented with 5000 ppm by weight of NaNO2 is fed to the reactor at a rate of 15 l/h at the same time as a solution of 39% by weight N-(1-ethylpropyl)-3,4-dimethyl-benzenamine in dichloroethane; this solution is fed at a rate of 21 l/h. After a period of 15 minutes, during which time the system reaches operating conditions, approximately 6 kg of reaction mass was collected in a separator. After phase separation of the acid phase from the organic phase, this latter which--leaving aside the solvent--is composed of 95% by weight dinitration products and contains 6.8% by weight N-nitroso-N-(1-ethylpropyl)-2,6-dinitro-3,4-dimethyl-benzenamine and 54 ppm p/p N-nitro-N-(1-ethylpropyl)-3,6-dinitro-3,4-dimethyl-benzenamine, is washed and subjected to denitrosation by treatment with aqueous hydrobromic acid and sulphamic acid to transform its N-nitroso derivative co-produced in the course of the reaction into N-(1-ethylpropyl)-2,6-dinitro-3,4-dimethyl-benzenamine. Once the solvent is evaporated, 1.78 kg of crude N-(1-ethylpropyl)-2,6-dinitro-3,4-dimethyl-benzenamine were obtained with a titre of 94.2%.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:31][C@@H:30]2[C@:25]([CH3:39])([CH2:26][CH2:27][C@H:28]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH2:29]2)[C@@H:24]2[C@@H:10]1[C@H:11]1[C@:21]([CH3:40])([CH2:22][CH2:23]2)[C@@H:14]([C@H:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[O:19])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:41]([Mg]Cl)([CH3:43])[CH3:42].[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][C@@H:9]1[CH2:31][CH:30]2[C@:25]([CH3:39])([CH2:26][CH2:27][C@H:28]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH2:29]2)[C@@H:24]2[C@@H:10]1[C@H:11]1[C@:21]([CH3:40])([CH2:22][CH2:23]2)[C@@H:14]([C@H:15]([CH3:20])[CH2:16][CH2:17][CH:18]([OH:19])[CH:41]([CH3:43])[CH3:42])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)CC4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 77.2 %

Procedure:
A solution of compound 2009 (0.374 g, 0.679 mmol) in anhydrous THF (10 ml) under argon was treated with isopropylmagnesium chloride (2 ml, 2M in THF, 5.43 mmol) at room temperature. The reaction was stirred until no starting material remained by TLC. Aqueous NH4Cl solution (10%, 15 ml) was added to quench the reaction and the THF was removed in vacuo. Distilled H2O (5 ml) was added and the solution extracted 3x with 15 ml CH2Cl2. The combined organic layers were washed with aqueous saturated NaCl solution (15 ml), dried over anhydrous MgSO4, filtered and the solvent removed in vacuo. Flash chromatography (SiO2, 2:1 hexanes:EtOAc) gave compound 2010 (0.3117 g, 77%) as a white foam. 1 H NMR (500 MHz, CDCl3) δ: 7.35-7.34 (m, 5H, benzyl Ar-H), 4.71-4.69 (m, 1H, THP ether methine H), 4.585 (d, J =11.9 Hz, 1H, benzyl-CH2), 4.31 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 4.295 (d, J=12.0 Hz, 1/2H, benzyl-CH2) 3.94-3.91 (m, 1H, THP, OCH2), 3.62-3.58 (m, 1H, THP OCH2), 3.50-3.48 (m, 1H, C-3 H), 3.45 (s, 1H, C-7 H), 3.32-3.31 (m, 1H, C-24 H), 0.81 (s, 3H, C-19 H), 0.63 (d J=2.4 Hz, 3H, C-18 H) (Note: product is a mixture of diastereomers); IR (CHCl3) 3605, 2900 cm + ; MS (CI/isobutane) m/z 595 (M+1, 10%), 401 (M+1-THP-Bn-H2O, 25%), 385 (M+1-THP-HOBn, H2O, 100%); m.p. 55°-59° C.; Anal. calcd. for C39H62O4 : C=78.74, H=10.50; Found: C=78.65, H=10.54.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)(=O)=O.CN(C=O)C>C(OCC)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 90 °C
Reaction time: 22 h

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (325 mg, 1.67 mmol), cesium carbonate (600 mg, 1.84 mmol), and tert-butyl 4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (513 mg, 1.84 mmol) followed by DMF (5.6 mL) were added to an oven-dried flask. The reaction mixture was stirred at 90° C. for 22 hours then cooled to room temperature, diluted with diethyl ether, washed with water (3×50 mL), and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate (mixture of cis and trans). 1H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.86 (s, 1H), 2.98 (s, 1H), 2.24-1.85 (m, 5H), 1.75-1.43 (m, 4H), 1.41 (s, 9H), 1.29 (s, 12H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][O:8][C:9]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)=[O:4].S(=O)(=O)(O)O>>[CH3:1][N:2]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:9]2[O:8][N:7]=[C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[C:3]1=[O:4]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: Cn1c(-c2ccccc2)cc2onc(-c3ccccc3)c2c1=O

Procedure:
A mixture of 26.1 g. (0.0815 mole) of N-methyl-5-phenacyl-3-phenyl-4-isoxazole carboxamide and 261 ml. of 2M sulfuric acid is refluxed for 24 hours. The mixture is cooled and extracted with methylene chloride. The methylene chloride layer is washed with water and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is triturated with ether and then recrystallized from ethanol to give 5-methyl-3,6-diphenyl-isoxazolo[4,5-c]pyridin-4(5H)-one, m.p. 149°-151.5° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](O)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: O=C(O)c1cc2ccccc2o1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzofuran-2-carboxylic acid (4.59 g., 28.3 mmol) as a solution in dry ethyl ether (100 mL) was added dropwise over 15 minutes to a suspension of lithium aluminum hydride (4.3 g., 113 mmol) in ethyl ether (180 mL) at 0° C. The reaction mixture was stirred for 2 hours while warming to room temperature. After recooling to 0° C., 4.3 mL of water was added with extreme caution. Sodium hydroxide (4.3 mL, 15% in water) was then added followed by an additional 12.9 mL of water. Magnesium sulfate (about 10 g.) was added and the thick white suspension was stirred briskly for about 30 minutes. The suspension was filtered through silica gel and the filter cake was washed thoroughly with ethyl ether. The filtrate was concentrated and dried under high vacuum to afford 4.15 g. of the title A product as a light yellow oil.
Reaction SMILES: Cl.C([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH:19]=[O:20])[CH:11]([CH2:21][N:22]([CH3:24])[CH3:23])[CH2:10]1)C1C=CC=CC=1>[Pd].CO>[CH3:24][N:22]([CH2:21][CH:11]1[CH2:10][NH:9][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH:19]=[O:20])[CH3:23]
Reactant: CN(C)CC1CN(Cc2ccccc2)c2ccccc2N1C=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)CC1CNc2ccccc2N1C=O
Reaction time: 2 h
Yield: 76.6 %

Procedure:
10% Pd-C (175 mg) and concentrated hydrochloric acid (0.3 ml) were added to a methanol (15 ml) solution of 4-benzyl-2-(N,N-dimethylamino)methyl-1-formyl-1,2,3,4-tetrahydroquinoxaline (350 mg). The reaction mixture was subjected to catalytic hydrogenation at room temperature under 4.5 atmospheric pressure for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated. 10% Aqueous potassium carbonate solution was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated to give 2-(N,N-dimethylamino)methyl-1-formyl-1,2,3,4-tetrahydroquinoxaline (190 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:37]([CH3:38])[C:30]=3[CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1cccc(C=O)c1C
Product: Cc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1C

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,3-dimethyl benzaldehyde. MS (ESI) m/z 497.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@H:7]1[C@H:11]([N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)[CH2:10][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][C@H:7]1[C@H:11]([N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)[CH2:10][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](n2ccnn2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](n2ccnn2)[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Methyl sulfonyl chloride (2.84 g, 24.8 mmole) was added slowly to an ice cooled solution of trans 3-hydroxy-4-(1,2,3-triazol-1-yl)-1-N-(tert.-butoxy carbonyl) pyrrolidine (3.16 g, 12.4 mmol) and triethylamine (4.36 ml, 31.3 mmol) in dry CH2Cl2 (10 ml). The reaction mixture was stirred under N2 at room temperature for 22 hrs and washed with saturated NaHCO3 and brine solution. The dichloromethane layer was dried over Na2SO4 and concentrated to give the title product. Yield 4.0 g (97%). 1H NMR (CDCl3) δ: 1.5 (S, 9H), 3.07 (s, 3H), 4.07 (m, 4H), 5.43 (m, 2H), 7.70 (S, 1H), 7.90 (S, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:35][C:36]1[C:41]([NH:42][NH2:43])=[N:40][CH:39]=[CH:38][N:37]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:14]([NH:43][NH:42][C:41]4[C:36]([Cl:35])=[N:37][CH:38]=[CH:39][N:40]=4)=[O:16])=[CH:17][CH:18]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(Nc2nc3ccc(Cl)cc3s2)cc1
Reactant: NNc1nccnc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NNc1nccnc1Cl)c1ccc(Nc2nc3ccc(Cl)cc3s2)cc1
Reaction time: 0.08 h
Yield: 65.9 %

Procedure:
A suspension of 4-(6-chlorobenzo[d]thiazol-2-ylamino)benzoic acid (63A) (6.62 g, 21.72 mmol), EDC (4.37 g, 22.81 mmol) and HOBt (3.08 mg, 22.81 mmol) in a mixed solvent of DMF (25 mL) and CH2Cl2 (50 mL) was stirred for 5 min, and then 2-chloro-3-hydrazinylpyrazine (61A) (3.14 g, 21.72 mmol) and triethylamine (4.4 g, 43.4 mmol) were added. The mixture was stirred at room temperature over the weekend. Additional EDC (1.5 g, 7.85 mmol) and HOBt (1.15 g, 8.45 mmol) were added in and the reaction mixture stirred for another 2 h before concentrated in vacuo. The obtained residue was partitioned between EtOAc (250 mL) and water (200 mL), and the separated EtOAc layer washed with water (2×200 mL), and concentrated in vacuo. The crude product was triturated with water (50 mL) and EtOAc (20 mL) and isolated by filtration, rinsed with water and then air dried to yield the title compound as a dark brown solid (6.17 g). The second crop of the product was isolated from the concentrated mother liquor using the same trituration process (0.76 g) (total 6.93 g, 74% yield). HPLC/MS (Method C): retention time=2.43 min, [M+H]+=431.1. 1H NMR (500 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.41 (s, 1H), 9.12 (s, 1H), 8.09 (d, J=2.20 Hz, 1H), 7.99 (d, J=2.20 Hz, 1H), 7.91-7.97 (m, 2H), 7.85-7.90 (m, 2H), 7.78 (d, J=2.75 Hz, 1H), 7.65 (d, J=8.80 Hz, 1H), 7.37 (dd, J=8.80, 2.20 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[Cl:8][CH2:9][C:10](=O)[CH2:11][C:12](OCC)=[O:13].C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>>[Cl:8][CH2:9][C:10]1[N:1]=[C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]2[C:12](=[O:13])[CH:11]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1csc(N)n1
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Product: Cc1csc2nc(CCl)cc(=O)n12
Yield: 85.3 %

Procedure:
This compound was synthesized from 2-amino-4-methyl thiazole (5.0 g, 43.710 mmol) and ethyl chloroacetoacetate (9.893 g, 59.561 mmol) in polyphosphoric acid (40.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 8.0 g of the desired compound as a black solid; 1H NMR (300 MHz, DMSO-d6) δ 2.67 (s, 3H), 4.53 (s, 2H), 6.27 (s, 1H), 7.05 (s, 1H); ESI-MS (m/z) 215.39 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([OH:23])[C:19]([F:22])([F:21])[F:20])=[C:14]([N:24]2[CH:28]=[CH:27][C:26]([CH3:29])=[N:25]2)[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:23][C@H:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[N:24]2[CH:28]=[CH:27][C:26]([CH3:29])=[N:25]2)[C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](O)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2ccnc(Cl)c2)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of 2-chloro-4-nitropyridine (200 mg, 1.00 mmol) in 1,4-dioxane (6 mL) was added. (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (368 mg, 1.27 mmol), and Cs2CO3 (828 mg, 2.54 mmol). The reaction was heated to 80° C. for 12 h, then cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (R)-2-chloro-4-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridine as an off-white solid.
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1([CH:40]([CH:52]2CCCC[CH2:53]2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:53][CH2:52][CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Agent: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(CCCc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3-phenylpropanal for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.60 (t, J=6.8, 1H), 7.69-7.63 (m, 2H), 7.39-7.22 (m, 8H), 4.41-4.31 (m, 1H), 3.25 (d, J=10.4, 1H), 2.95 (dd, J=2.5, 8.9, 0.5H), 2.68 (td, J=2.7, 7.2, 2H), 2.65-2.60 (m, 1H), 2.58 (dd, J=2.8, 9.2, 0.5H), 2.56-2.52 (m, 0.5H), 2.51-2.46 (m, 0.5H), 2.44-2.38 (m, 0.5H), 2.37-2.26 (m, 3H), 2.23 (t, J=7.2, 1H), 2.18 (d, J=7.3, 0.5H), 2.13 (t, J=8.8, 1.5H), 1.88 (dd, J=6.1, 12.1, 1H), 1.79 (dd, J=7.2, 14.5, 1.5H), 1.74-1.64 (m, 1.5H), 1.48-1.37 (m, 1H), 1.37-1.28 (m, 0.5H), 1.23 (dd, J=6.5, 12.2, 3H), 0.71 (dd, J=3.0, 6.7, 3H); MS (ESI+) m/z 405 (M+H)+.
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][N:7](C(ON1C(=O)CCC1=O)=[N+](C)C)[CH3:8].[F:21][C:22]1[CH:23]=[C:24]([N:29]([CH3:52])[CH:30]([C:32]2[CH:33]=[C:34]([C:49](O)=[O:50])[CH:35]=[C:36]3[C:41]=2[O:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][C:37]3=[O:48])[CH3:31])[CH:25]=[C:26]([F:28])[CH:27]=1.C(N(C(C)C)C(C)C)C.CNC>C(Cl)Cl.O>[F:28][C:26]1[CH:25]=[C:24]([N:29]([CH3:52])[CH:30]([C:32]2[CH:33]=[C:34]([C:49]([N:7]([CH3:8])[CH3:6])=[O:50])[CH:35]=[C:36]3[C:41]=2[O:40][C:39]([N:42]2[CH2:43][CH2:44][O:45][CH2:46][CH2:47]2)=[CH:38][C:37]3=[O:48])[CH3:31])[CH:23]=[C:22]([F:21])[CH:27]=1
Reactant: CC(c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (2.134 g, 7.09 mmol), was added in one portion to a stirred solution of 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (2.1 g, 4.73 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.646 mL, 9.45 mmol) in DCM (20 mL) at RT and stirred at RT for 90 mins. Dimethylamine (4.73 mL, 9.45 mmol) was then added and the reaction mixture was stirred at RT for 30 min. Water and DCM were added, the organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with DCM/MeCN (1:1) then 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford a foam which crystallised from ethyl acetate (10 mL). Ether (10 mL) was added to complete the crytallisation and the white solid was collected by filtration and dried to give 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (1.65 g, 74%). Mass Spectrum: M+H+ 472. NMR Spectrum (DMSOd6): 1.55 (d, 3H), 2.63 (s, 3H), 2.92 (bs, 3H), 3.01 (bs, 3H), 3.21-3.29 (m, 2H), 3.31-3.39 (m partially hidden by H2O, 2H), 3.41-3.49 (m, 2H), 3.49-3.57 (m, 2H), 5.55 (s, 1H), 5.58 (q, 1H), 6.40 (t, 1H), 6.53 (d, 2H), 7.70 (d, 1H), 7.89 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)[CH3:12]
Reactant: CCI
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-hydroxyindazole (2.68 g) in DMF (50 mL) were added ethyl iodide (3.28 g) and potassium carbonate (4.16 g), and the mixture was stirred at room temperature for 1 day. Then, the mixture was partitioned between ethyl acetate and water, the organic layer was washed with brine and dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate as the eluting solvent) to give Compound Q9 (1.95 g).