Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([C:2]2[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=2)[O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]4)[C:15]4[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(Br)c3)cc1)n2C1CCCCC1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(-c4cccc(Cl)c4)c3)cc1)n2C1CCCCC1
Yield: 85.6 %

Procedure:
Ethyl 2-[4-(3-bromophenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate (65 g) obtained in Example 1 and 3-chlorophenylboronic acid (23 g) were treated in the same manner as in Example 5 to give the title compound (59 g, yield 85%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[C:12]([CH3:23])[CH:11]=1.CON(C)[C:27](=[O:29])[CH3:28]>C1COCC1>[Br:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[O:15])=[C:12]([CH2:23][C:27](=[O:29])[CH3:28])[CH:11]=1
Reactant: CON(C)C(C)=O
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(Br)cc1CC(C)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 2M solution of LDA (35.2 mL, 70.3 mmol) in THF (176 mL) cooled to −78° C. was treated with slow addition of 4-bromo-N,N-diethyl-2-methylbenzamide (19 g, 70.3 mmol) in dry THF (176 mL). The reaction was allowed to stir at −78° C. for 1 hour before it was quenched with N-methoxy-N-methylacetamide (22.43 mL, 211 mmol) and allowed to slowly warm to room temp. The reaction was stirred overnight and then partitioned between 1N HCl (200 mL) and EtOAc (400 mL). The aqueous layer was further extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (150 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was an oil out of which the product precipitated. The oil was decanted off and the solid was washed with hexanes and dried using a buchner funnel to afford 4-bromo-N,N-diethyl-2-(2-oxopropyl)benzamide: LC-MS: (M+H)+312.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([I:10])=[CH:4][C:3]=1[O:11][CH3:12].[CH:13](I)([CH3:15])[CH3:14].[H-].[Na+].O>CN(C)C=O>[I:10][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([O:1][CH:13]([CH3:15])[CH3:14])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: CC(C)I
Reactant: COc1cc(I)cc(OC)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(I)cc(OC)c1OC(C)C
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 83.4 %

Procedure:
To a solution of 25.0 g (89.3 mmol) of 4-hydroxy-1-iodo-3,5-dimethoxybenzene in dimethylformamide (125 mL) were added 26.7 mL (267 mmol) of isopropyl iodide and 4.7 g (108 mmol) of a 55 wt. % sodium hydride dispersion in mineral oil. The reaction mixture was stirred at 50° C. for 2.5 hours. With ice cooling, water (125 mL) was added and the mixture was extracted with toluene-hexane (2:1). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield crude crystals. The crude crystals were recrystallized from methanol, whereby 24.0 g of 1-iodo-4-isopropoxy-3,5-dimethoxybenzene was obtained as a colorless crystalline powder (mp: 56.0 to 57.0° C., yield: 83%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:4]=[CH:3]1.[Br:15]N1C(=O)CCC1=O>ClCCl>[Br:15][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a solution of 2-(1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (100 mg, 0.54 mmol) in dichloromethane (5 mL) was added N-bromosuccinimide (102 mg, 0.57 mmol). The reaction mixture was stirred at r.t. for 3 hrs. It was then purified by flash column chromatography (EtOAc/Hexane) to afford 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (140 mg, quantitative yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 3.67 (3H, s), 7.70 (1H, d, J=4.8 Hz), 8.04 (1H, s), 8.19 (1H, s), 8.81 (1H, d, J=4.2 Hz). [M+H] Calc'd for C10H7BrN4, 264. Found, 263, 265.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC1CCCO1.[CH2:13]([NH:16][C:17]([C@@H:19]1[C:23]([CH3:25])([CH3:24])[S:22][CH2:21][N:20]1[C:26](=[O:51])[C@@H:27]([OH:50])[C@@H:28]([NH:36][C:37]([C:39]1[C:40]([CH3:49])=[C:41]([O:45]C(=O)C)[CH:42]=[CH:43][CH:44]=1)=[O:38])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:18])[CH:14]=[CH2:15]>CO>[CH2:13]([NH:16][C:17]([C@@H:19]1[C:23]([CH3:25])([CH3:24])[S:22][CH2:21][N:20]1[C:26](=[O:51])[C@@H:27]([OH:50])[C@@H:28]([NH:36][C:37](=[O:38])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[C:40]=1[CH3:49])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(OC(C)=O)c2C)CSC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: CO
Product: C=CCNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(O)c2C)CSC1(C)C
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
MeOH (330 mL) and K2CO3 (66.9 g; 484 mmol) were sequentially added to a 2-methyltetrahydrofuran solution of crude acetic acid 3-{(1S,2S)-3-[(4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl]-1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl}-2-methyl-phenyl ester (theoretical amount: 405 g; 731 mmol) in a 3-L flask at room temperature. Two and a half hours later, additional K2CO3 (20 g; 144 mmol) was added. Three hours later the reaction mixture was vacuum-filtered on a pad of Celite, using 4:1 2-methyltetrahydrofuran/MeOH (330 mL) for rinsing over the solids and washing the filter cake. The filtrate was transferred to a 6-L separatory funnel, using 4:1 2-methyltetrahydrofuran/MeOH (80 mL) for rinsing. The solution was diluted with i-PrOAc (1.66 L) and was then washed with a solution of NaCl (83.0 g) in H2O (1.60 L). The organic fraction was washed with 0.5 N HCl (1.66 L) and then with a saturated aqueous NaCl solution (400 mL). The resulting organic fraction was transferred to a 4-L Erlenmeyer flask and MgSO4 (120 g) was added. After stirring for 10 min, the mixture was vacuum-filtered directly into a 5-L distillation flask, using 2:1 i-PrOAc/2-methyltetrahydrofuran (600 mL) for rinsing the separatory funnel and Erlenmeyer flask and washing the MgSO4. The 2-methyltetrahydrofuran was displaced by distillation at one atmosphere with the simultaneous addition of i-PrOAc in five portions (a total of 3.60 L was used), while maintaining a minimum pot volume of ˜2.50 L. The resulting crystallizing mixture was cooled to 75° C. and was held at this temperature for 30 min. The suspension was then allowed to slowly cool to room temperature overnight. The suspension was vacuum-filtered, using i-PrOAc (600 mL) for transferring and washing the crystals. After drying in a vacuum oven at 40° C., 204 g (54% from (2S,3S)-3-(3-Acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyric acid) of crystalline (4R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide was obtained. This material was recrystallized as described below.
Reaction SMILES: C(O[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[N:6][NH:7][C:8]([O:10]C)=O)CC.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH2:16]([N:23]1[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[N:6][NH:7][C:8]1=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCOC(=NNC(=O)OC)OCCC
Reactant: NCc1ccccc1
Solvent: CO
Product: CCCOc1n[nH]c(=O)n1Cc1ccccc1
Reaction time: 5 h

Procedure:
In an autoclave, 2.04 g of methyl N′-dipropoxymethylenehydrazinecarboxylate (8.9 mmol) and 3.46 g of benzylamine (31.6 mmol) were initially charged in 25.8 g of methanol. After 5 hours at 110° C., the solvent was distilled off and the 4-methyl-5-propoxy-2,4-dihydro-1,2,4-triazol-3-one was recrystallized from ethyl acetate. This gave 0.57 g (27%) of pure 4-benzyl-5-propoxy-2,4-dihydro-1,2,4-triazol-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[NH:9][CH2:10][CH2:11][OH:12].Cl.[CH:14](O)=O>>[Br:8][C:4]1[C:3]2[N:9]([CH2:10][CH2:11][OH:12])[CH:14]=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=CO
Reactant: Nc1cccc(Br)c1NCCO
Agent: Cl
Product: OCCn1cnc2cccc(Br)c21

Procedure:
2-[(2-Amino-6-bromophenyl)amino]ethanol (0.14 g, 0.54 mmol) was dissolved in formic acid (3 mL) and irradiated in microwave oven at 135° C. for 2 h. The mixture was cooled and treated with 37% hydrochloric acid (1 mL) at 50° C. for 0.5 h. The volatiles were removed under reduced pressure. The residue was partitioned between ethyl acetate and to saturated aqueous sodium bicarbonate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated to yield 2-(7-bromo-1H-benzimidazol-1-yl)ethanol, 0.14 g (90%). MS (ESI) m/z: 241.09 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.76 (q, J=5.5 Hz, 2H) 4.55 (t, J=5.4 Hz, 2H) 4.97 (t, J=5.4 Hz, 1H) 7.12 (m, 1H) 7.43 (m, 1H) 7.66 (dd, J=8.0, 1.0 Hz, 1H) 8.19 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][C:3]=1[CH3:24].[Cl-].[NH+]1C=CC=CC=1.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][C:3]=1[CH3:24]
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)c(C)cc3c1C2=O
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2c3c([nH]c2cc1Cl)C(C)(C)c1cc(O)ccc1C3=O

Procedure:
3-Chloro-8-methoxy-2,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S1-2, 18.9 mg, 0.0556 mmol) and pyridinium chloride (220 mg, 34 eq.) were stirred at 185° C. for 2.5 hr. After cooling, the reaction solution was added with water and ethyl acetate, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:19](=[O:23])[N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[N:6][CH:5]=1.[OH-].[Li+]>C1COCC1.O>[C:28]([O:27][C:25]([NH:24][CH:18]([C:19](=[O:23])[N:20]([CH3:21])[CH3:22])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=2)=[CH:12][CH:13]=1)=[O:26])([CH3:30])([CH3:29])[CH3:31]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C(=O)O)cn2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
Amide 18 (1.0 g, 2.25 mmol) was dissolved in THF (10 mL) and diluted with water (10 mL). Lithium hydroxide (0.107 g, 4.5 mmol) was added and the reaction mixture was stirred at room temperature for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×100 mL). The organic layer was washed with water (1×100 mL) and brine (1×100 mL), dried and concentrated to yield the desired acid compound 19 (1.0 g, 97%). 1H NMR (400 MHz, DMSO-d6): 13.1 (s, 1H), 8.64 (br, 1H), 8.27 (dd, J=8.4 and 2.0 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.08 (m, 3H), 4.56 (m, 1H), 2.94 (s, 3H), 2.85-2.75 (m, 2H), 2.81 (s, 3H), 1.18 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](O)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([Cl:23])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reaction time: 0.33 h

Procedure:
A sample of crude 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (40.8 g, 0.14 mole) was dissolved in methylene chloride (300 mL). The solution was treated with oxalyl chloride (15.7 mL, 0.18 mole), followed by N,N-dimethylformamide (12 drops). Off-gassing began shortly after adding the N,N-dimethylformamide catalyst. The reaction mixture was stirred for about 20 minutes under ambient conditions, then was heated to reflux for a period of 35 minutes. Volatiles were removed by concentrating the reaction mixture on a rotary evaporator at a bath temperature of 55° C. The crude product, approximately 43 g of a light-yellow oil, was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:5]=1.C(OCC)(=O)C>CO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([C:13]([F:14])([F:16])[F:15])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 4.0 g (16.1 mmol) 4-nitro-3-trifluoromethyl-benzoic acid methyl ester in 50 mL methanol 0.4 g 10% palladium on charcoal was added and the suspension stirred for 2 h at room temperature under an atmosphere of hydrogen (1.7 bar). After the addition of 100 mL ethyl acetate the catalyst was filtered off, the filtrate evaporated and dried under high vacuum to give the title compound as a white solid (98%) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][CH:22]=1)[C:6]([CH3:11])=[CH:5]2
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Product: Cc1cc2cc(F)ccc2n1-c1ccc(OCc2ccccc2)cc1
Yield: 23 %

Procedure:
5-Fluoro-2-methylindole (5.0 g, 33.5 mmol) and 4-benzyloxy iodobenzene (10.40 g, 33.5 mmol) were reacted according to the procedure used in Example 1a above to afford a white solid (23%): mp 94-95° C.; 1 H NMR (DMSO-d6): δ 2.23 (3H, s), 5.19 (2H, s), 6.39 (1H, s), 6.84-6.94 (2H, m), 7.19-7.29 (3H, m), 7.34-7.44 (5H, m), 7.51 (2H, d,J=7.1 Hz); MS m/z (M+H)+ 332. Anal. for C22H18NOF: Calc'd: C, 79.74; H, 5.47; N, 4.23. Found: C, 79.54; H, 5.54; N, 4.21.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][N:15]([CH3:20])[CH2:16][CH2:17][NH:18][CH3:19]>CS(C)=O>[CH3:11][N:12]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:13][CH2:14][N:15]([CH3:20])[CH2:16][CH2:17][NH:18][CH3:19]
Reactant: CNCCN(C)CCNC
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Product: CNCCN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
In 7 ml of dimethyl sulfoxide were dissolved 1.41 g of p-fluoronitrobenzene and 14 g of N,N',N"-trimethyldiethylenetriamine, and the mixture was then stirred at 120° C. for 3 hours.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:39])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:38][CH2:37]4)=[N:32]3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:19][C:16]1[CH:17]=[CH:18][C:9]([O:8][CH2:7][C:6]([OH:40])=[O:5])=[C:10]2[C:15]=1[N:14]=[C:13]([O:20][CH:21]([F:22])[F:23])[C:12]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:37][CH2:38]4)=[N:32]3)=[CH:29][CH:30]=1)=[C:11]2[CH3:39]
Reactant: Cc1c(Cc2ccc(-n3ccc(C4CC4)n3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Cc2ccc(-n3ccc(C4CC4)n3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.3 %

Procedure:
A solution of {8-chloro-3-[4-(3-cyclopropylpyrazol-1-yl)benzyl]-2-difluoromethoxy-4-methylquinolin-5-yloxy}acetic acid tert-butyl ester (0.11 g) in dichloromethane (8.0 mL) was treated with trifluoroacetic acid (2.0 mL), and the resulting mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium acetate solution and then extracted with ethyl acetate. The combined extracts were dried over magnesium sulphate and then concentrated under reduced pressure to afford the title compound as a white solid (0.034 g).
Reaction SMILES: O.[NH2:2][NH2:3].CS[C:6]([S:33][CH3:34])=[CH:7][C:8]([C:10]1[N:26](C2CCCCO2)[C:13]2=[CH:14][C:15]3[C:16]([CH3:25])([CH3:24])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=3[CH:20]=[C:12]2[N:11]=1)=O>C(#N)C>[CH2:21]([N:18]1[C:19]2[CH:20]=[C:12]3[N:11]=[C:10]([C:8]4[CH:7]=[C:6]([S:33][CH3:34])[NH:3][N:2]=4)[NH:26][C:13]3=[CH:14][C:15]=2[C:16]([CH3:24])([CH3:25])[C:17]1=[O:23])[CH3:22]
Reactant: NN
Reactant: CCN1C(=O)C(C)(C)c2cc3c(cc21)nc(C(=O)C=C(SC)SC)n3C1CCCCO1
Solvent: O
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4cc(SC)[nH]n4)nc3cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
Hydrazine monohydrate (0.92 g, 1.8 mmol) was added to a suspension of 2-(3,3-bis-methylsulfanyl-acryloyl)-5-ethyl-7,7-dimethyl-1-(tetrahydro-pyran-2-yl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (0.68 g, 1.81 mmol) in acetonitrile (15 mL) and stirred for 24 h. After cooling to room temperature the precipitate was collected, washed with acetonitrile and ether to yield 0.5 g (81%) of a pale white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2>C1COCC1.O>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)nc2)=CCC3(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cn1

Procedure:
A solution of 81.7 mg (0.194 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-methyl-5-pyridyl)-2-naphthalenyl)ethynyl]benzoate (Compound 12) and 40.7 mg (0.969 mmol) of LiOH--H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 8.41 (1H, d, J=1.9 Hz), 7.90 (2H, d, J=8.3 Hz), 7.63 (1H, dd, J=2.3, 7.9 Hz), 7.59 (2H, d, J=8.3 Hz), 7.49 (2H, m), 7.33 (1H, d, J=7.8 Hz), 6.95 (1H, s), 6.11 (1H, t, J=4.5 Hz), 2.52 (3H, s), 2.37 (2H, d, J=4.6 Hz), 1.31 (6H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=3)(=[O:38])=[O:37])[C@H:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:17])([F:16])[F:18])[CH:3]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C(F)(F)F)C[C@H]2C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (R)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-3-methylpiperazine (5.34 g, 21.86 mmol) in anhydrous dichloromethane (20 mL) was added diisopropylethylamine (10.3 mL, 59.1 mmol) at 0° C. The reaction mixture was stirred at room temperature for 15 minutes then 3-Methoxy benzene sulfonyl chloride (2.44 g, 11.82 mmol) dissolved in dichloromethane (10 mL) was introduced dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 0.5 hour. Reaction was complete as determined by TLC. The reaction mixture was diluted with dichloromethane washed with saturated NaHCO3 (aqueous), dried over MgSO4 and concentrated. The crude product was purified via flash column chromatography to yield (R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(3-methoxyphenylsulfonyl)-2-methylpiperazine in quantitative yield (5.10 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:27]=[N:26][CH:25]=[CH:24][C:5]=1[C:6]([CH2:12][S:13]([N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:14])=[N:7]2.[OH-:28].[Na+]>C(O)(=O)C.O>[CH3:23][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:13]([CH2:12][C:6]1[C:5]2[CH:24]=[CH:25][N:26]=[CH:27][C:4]=2[C:3]2[C:2](=[O:28])[NH:11][CH:10]=[CH:9][C:8]=2[N:7]=1)(=[O:14])=[O:15]
Reactant: [OH-]
Reactant: CN(c1ccccc1)S(=O)(=O)Cc1nc2ccnc(Cl)c2c2cnccc12
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(c1ccccc1)S(=O)(=O)Cc1nc2cc[nH]c(=O)c2c2cnccc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(1-chloropyrido[4,3-c]-1,6-naphthyridin-6-yl)-N-methyl-N-phenylmethanesulfonamide (45 mg, 0.113 mmol) in acetic acid (2790 μl) and water (1196 μl) was heated to 100° C. and stirred for 2 h. After cooling to room temperature, the reaction mixture was added to aqueous sodium hydroxide (1M). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford N-methyl-1-(1-oxo-1,2-dihydropyrido[4,3-c]-1,6-naphthyridin-6-yl)-N-phenylmethanesulfonamide as a yellow solid. 1H NMR (500 MHz, C2D6SO) δ 12.17 (s, 1H), 11.19 (s, 1H), 8.87 (d, 1H), 8.30 (d, 1H), 7.71 (t, 1H), 7.48 (d, 2H), 7.38 (t, 2H), 7.29 (t, 1H), 6.95 (d, 1H), 5.36 (s, 2H), 3.22 (s, 3H). LRMS (APCI) calc'd for (C14H14N3O) [M+H]+, 381.1; found 381.0.
Reaction SMILES: O[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.S(Cl)([Cl:33])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:33][CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)c1
Yield: 93.4 %

Procedure:
To a mixture of ethyl (3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (7.50 g) and toluene (300 mL) was added thionyl chloride (2.38 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate as colorless crystals (7.32 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.