Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH2:37][CH3:38])[CH:9]([CH3:26])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[N:16]([CH2:23][CH2:24][OH:25])[CH2:15][CH2:14]2)=O)(C)(C)C.C(N(CC)CC)C.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl>[C:46]([O:25][CH2:24][CH2:23][N:16]1[C:17]2[C:13](=[CH:12][C:11]([CH2:10][CH:9]([NH:8][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH2:37][CH3:38])[CH3:26])=[CH:19][C:18]=2[C:20]([NH2:22])=[O:21])[CH2:14][CH2:15]1)(=[O:48])[CH3:47]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)N(CCO)CC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccccc1OCCNC(C)Cc1cc2c(c(C(N)=O)c1)N(CCOC(C)=O)CC2

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]-1-(2-hydroxyethyl)indoline-7-carboxamide (60 mg) in methylene chloride (3 ml) were added triethylamine (24 μl) and acetic anhydride (13 μl) with stirring under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and to the concentrate was added water. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride (2 ml). To the solution was added trifluoroacetic acid (0.5 ml), the mixture was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated under reduced pressure. To the concentrate was added a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of chloroform and methanol (7/1) as eluent to give 41 mg of 1-(2-acetoxyethyl)-5-[2-[2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14]CC)=[O:13])=[CH:10][N:11]=2)[CH:8]=1)#[N:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:22]>C1COCC1.CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([OH:14])=[O:13])=[CH:10][N:11]=2)[CH:8]=1)(=[O:22])[NH2:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCOC(=O)c1cnc2ccc(C#N)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1ccc2ncc(C(=O)O)n2c1
Temperature: 60 °C

Procedure:
To a stirring solution of ethyl 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (24q) (500 mg, 2.32 mmol) in THF:MeOH (4:1, 5 mL) was added 2N LiOH (4 mL). The reaction was heated at 60° C. for 2 h then acidified with 10% citric acid. The solvent was partially concentrated and the resulting solid was collected by vacuum filtration and was washed with excess water. The product was purified from the crude solid to afford 6-carbamoylimidazo[1,2-a]pyridine-3-carboxylic acid (110). 1H NMR (400 MHz, d6-DMSO) δ 9.80 (s, 1H), 8.33-8.31 (m, 1H), 8.29 (s, 1H), 7.95 (dd, J=2.0, 9.6 Hz, 1H), 7.83 (dd, J=0.8, 9.2 Hz, 1H), 7.69 (s, 1H). MS m/z 205.05 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH:13]=[CH:14][C:15]=1Br)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[C:24]2[CH:36]=[CH:37][N:38]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:23]=2[C:22]1=[O:49]>>[NH2:12][C:11]1[CH:13]=[CH:14][C:15]([C:25]2[C:24]3[CH:36]=[CH:37][N:38]([S:39]([C:42]4[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=4)(=[O:41])=[O:40])[C:23]=3[C:22](=[O:49])[N:21]([CH3:20])[CH:26]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccc(Br)c(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c([N+](=O)[O-])c4OCc4ccccc4)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 3-(benzyloxy)-4-bromo-2-nitroaniline and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C28H25N4O6S (M+H)+: m/z=545.1. found: 545.2.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>CN(C=O)C.C1COCC1>[Br:1][C:24]1[CH:25]=[CH:26][C:27]2[N:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-bromosuccinimide (17.8 g, 100 mmol) in DMF (50 mL) was added slowly to 9-(pyridin-2-yl)-9H-carbazole (24 g, 100 mmol) in THF (250 mL) at 0° C. over 30 min. The reaction was allowed to warm to room temperature and stir overnight. The reaction mixture was then evaporated and extracted with dichloromethane, and the organic layer was dried over magnesium sulfate and the solvent was then evaporated. The residue was then purified by column using toluene:hexane (1:1, v/v) as eluent and the product was further purified by recrystallization from toluene:ethanol (1:1, v/v), and after cooling, 24.3 g (75%) of the product was collected as a white solid after filtration.
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2[C:10]([O:14][C:15]3[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1.Cl.[NH2:23][C@:24]([CH3:30])([CH2:28][CH3:29])[C:25](O)=[O:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C.CC#N.C(OCC)(=O)C.O>[NH2:23][C@:24]([CH3:30])([CH2:28][CH3:29])[C:25]([NH:21][C:18]1[CH:19]=[N:20][C:15]([O:14][C:10]2[C:5]3[C:6]([CH3:8])([CH3:9])[O:7][C:2]([CH3:1])=[N:3][C:4]=3[CH:13]=[CH:12][CH:11]=2)=[CH:16][CH:17]=1)=[O:26]
Reactant: CC1=Nc2cccc(Oc3ccc(N)cn3)c2C(C)(C)O1
Reactant: CC[C@@](C)(N)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC[C@@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)OC(C)=N3)nc1
Temperature: 80 °C
Yield: 57.5 %

Procedure:
To a suspension of 6-[(2,4,4-trimethyl-3,1-benzoxazin-5-yl)oxy]pyridin-3-amine (Intermediate 204, 185 mg, 0.65 mmol) and (R)-2-amino-2-methyl-butanoic acid hydrochloride (100 mg, 0.67 mmol) in ethyl acetate/MeCN (2 mL, 1:3 v/v mixture), a 50% w/w solution in ethyl acetate of T3P (0.43 mL) was added drop wise at 0° C. The mixture was then heated at 60° C. for 3 hours and at 80° C. for 4.5 hours. The mixture was cooled to room temperature diluted with water (5 mL) and ethyl acetate (10 mL), Two phases were separated and the aqueous one was treated with a saturated solution of NaHCO3 (pH=8) and back-extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated and the residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 20:80 as eluent affording the title compound (143 mg) as a yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][C:8]=2[N:9](C(OC(C)(C)C)=O)[CH:10]=1)=[O:5])[CH3:2].[CH3:24][N:25](C(N(C)C)N(C)C)C.Cl.NO>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22]3[O:23][N:25]=[CH:24][C:21]=3[CH2:20][CH2:19][CH2:18][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCCC2
Agent: Cl
Agent: NO
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2c1-c1oncc1CCC2
Temperature: 60 °C
Yield: 76 %

Procedure:
In a sealed tube, 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.6 mmol) and tris(dimethylamino)methane (5.2 mmol) are combined and heated at 60° C. for 3 hours. After cooling to RT the volatile material is removed in vacuo. To the residue were added hydroxylamine hydrochloride (7.8 mmol) and 7 mL EtOH. The mixture is heated at 100° C. for 16 hours. The solvent is evaporated in vacuo and the residue is taken up in CH2Cl2 and washed two times with NaHCO3 (aq). The organic layer is dried over Na2SO4 and evaporated in vacuo and the residue chromatographed using 10% MeOH in CH2Cl2 as mobile phase to yield 4,5,6,7-tetrahydro-1-oxa-2,7-diaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester as a white solid (76%). 1H NMR (CDCl3) 1.19 (t, 3H), 1.95-2.07 (m, 2H), 2.78 (t, 2H), 2.95 (t, 2H), 4.38 (q, 2H), 7.26 (s, 1H), 8.03 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][N:12]1[C:16]([CH3:17])=[CH:15][N:14]=[CH:13]1.N1C=CN=C1.C(Cl)Cl>O>[Si:1]([O:9][CH2:10][CH2:11][N:12]1[C:16]([CH3:17])=[CH:15][N:14]=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cncn1CCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: Cc1cncn1CCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
Tert-butyldimethylsilyl chloride (9.05 g) was added to a stirred mixture of 1-(2-hydroxyethyl)-5-methylimidazole (6.4 g), imidazole (7.5 g) and methylene chloride (30 ml) which was cooled to 0°C. The reaction mixture was stirred at ambient temperature for 4 hours. The mixture was poured into water. The organic layer was washed with brine, dried over magnesium sulphate and evaporated to give 1-(2-tert-butyldimethylsilyloxyethyl)-5-methylimidazole (11.7 g); NMR Spectrum: (CDCl3) −0.04 (s, 6H), 0.85 (s, 6H), 2.2 (s, 3H), 3.8 (m, 2H), 3.94 (m, 2H), 6.75 (s, 1H), 7.43 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)CCC>[C:11]1([S:17][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: Sc1ccccc1
Solvent: CCCCO
Product: c1ccc(Sc2ncnc3[nH]ccc23)cc1
Temperature: 140 °C
Yield: 91.6 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (1.69 g, 11.0 mmol) and TEA (4.60 mL, 33.0 mmol) in 1-butanol (25.0 mL) was added benzenethiol (3.39 mL, 33.0 mmol), and the mixture was refluxed at 140° C. overnight. The reaction was then cooled to rt and concentrated in vacuo. The off-white solid was purified by silica gel chromatography eluting with a gradient of 0 to 35% EtOAc in DCM to afford the product (2.29 g, 92%). LC/MS: Rt=1.55 min, ES+ 228 (FA standard).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[C:16]([F:19])([F:18])[F:17])=[CH:6][CH:5]=1.[CH3:24][CH:25]([C:31]([CH3:33])=O)[C:26](OCC)=[O:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:33][C:31]1[C:25]([CH3:24])=[C:26]([OH:27])[C:14]2[C:12](=[CH:11][C:10]([C:16]([F:17])([F:18])[F:19])=[C:9]([O:8][C:7]3[CH:20]=[CH:21][C:4]([O:3][C:2]([F:22])([F:23])[F:1])=[CH:5][CH:6]=3)[CH:15]=2)[N:13]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Nc1ccc(Oc2ccc(OC(F)(F)F)cc2)c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1nc2cc(C(F)(F)F)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(O)c1C
Yield: 41.1 %

Procedure:
A solution of 3.4 g of 4-(4-trifluoromethoxyphenoxy)-3-trifluoromethyl-aniline, 2.4 g of ethyl 2-methylacetoacetate, and 0.3 g of p-toluenesulfonic acid dissolved in 100 mL of xylene was heated under reflux for 36 hr. This reaction solution was cooled, and the precipitated crystals were collected by filtration to give 1.73 g of 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-7-trifluoromethyl-quinoline. The filtrate was concentrated under the reduced pressure to give 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline. Acetic anhydride (40 mL) was added to 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline obtained from the filtrate, and the mixture was heated at 120 to 125° C. for one hr. This reaction solution was concentrated under the reduced pressure, ethyl acetate was then added to the concentrate, and the mixture was washed with brine. Thereafter, the solvent was removed under the reduced pressure, and the crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 0.35 g of 4-acetoxy-2,3-dimethyl-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[OH:14])([O-:4])=[O:3].[CH3:15]I.[Cl-].[Li+]>CN(C)C=O>[N+:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([O:10][CH3:15])=[O:9])[C:6]=1[OH:14])([O-:4])=[O:3]
Reactant: CI
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Agent: [Cl-]
Agent: [Li+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
In a flask are placed 5.0 g (0.024 mole) of the sodium salt of 3-nitrosalicylic acid, 3.58g (0.0252 mole) of methyl iodide, and 40 mL of N,N-dimethylformamide. This mixture is stirred at ambient temperature for approximately sixteen hours. At the conclusion of this period 200 mL of a 10% aqueous solution of lithium chloride is added to the reaction mixture. This mixture is extracted three times with ethyl acetate. The combined extracts are washed with 200 mL of the 10% aqueous solution of lithium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate is concentrated under reduced pressure, leaving a residue which is then passed through a column of silica gel, eluting with ethyl acetate. The product-containing fractions are combined, and the solvent is evaporated under reduced pressure leaving methyl 3-nitrosalicylate as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH:24]([F:26])[F:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH:24]([F:26])[F:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:27][C:28]3[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:30][CH:29]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Product: CCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
116 mg (0.30 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoic acid (racemate) and 64 mg (0.33 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 127 mg (75% of theory)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(=[O:18])[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>C(Cl)(Cl)Cl>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH2:2][NH:1][C:8](=[O:18])[C:9]1[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1cccs1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccccc1C(=O)NCc1cccs1
Yield: 82.5 %

Procedure:
A solution of 2-aminomethyl-thiophene (2.1 ml, 20.5 mmol) in CHCl3 (25 ml) is treated with phthalic anhydride (3.0 g, 20.5 mmol) at r.t. for 5 min, then at reflux for 20 min, whereupon a white powder precipitated out. This powder is collected by filtration and dried in vacuo to give N-thiophen-2-ylmethyl-phthalamic acid (4.42 g, 83%) as white crystals. An aliquot of this phthalamic acid (2.13 g, 8.12 mmol) is dissolved in MeOH (12 ml), treated with H2SO4 (440 μl, 8.25 mmol) and heated to reflux for 1.5 h, whereupon a white powder precipitated out. This powder is collected by filtration and dried in vacuo to give 1.38 g (70%) of the title phthalimide as white crystals: 1H NMR (DMSO-d6) δ7.92-7.82 (m., 4H), 7.42 (dd, J=5.1, 1.2 Hz, 1H), 7.08 (dd, J=4.0, 0.8 Hz, 1H), 6.95 (dd, J=5.1, 3.5 Hz, 1H), 4.92 (s, 2H).
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:8][S:9]([C:12]1[C:13]([OH:20])=[C:14]([NH:19][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Br:21])=[O:30])[CH:15]=[CH:16][C:17]=1[Cl:18])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O
Reactant: O=C=Nc1ccccc1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1Br)Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O
Yield: 60.2 %

Procedure:
A solution of N-benzyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (80 mg, 0.26 mmol) and 2-bromophenylisocyanate (47 μL, 0.38 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70 to 70/30, v/v), gave the desired product (80 mg, 61%). EI-MS (m/z) 508.1, 510.2, 512.2 (M−).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[CH3:22]C(O)C>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14][CH:15]([CH3:22])[CH3:16])=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: CC(C)O
Product: CC(C)OC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Yield: 10 %

Procedure:
Ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (100 mg, 0.32 mmol) was added to propan-2-ol (1.0 ml, excess) and the reaction mixture was heated at 100 deg C for 14 h. After completion of the reaction (monitored by LCMS) reaction mixture was concentrated and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was concentrated to dryness and the crude obtained was purified by silica gel chromatography (Eluent: 10% MeOH in dichloromethane) to get 10 mg (yield: 10%) of isopropyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate. The free base product (10 mg, 0.03 mmol) was dissolved in THF (1.0 ml), oxalic acid (4 mg, 0.03 mmol) in THF (1.0 ml) was added slowly, the mixture was stirred at RT for 20 minutes and the solid obtained was filtered, washed with ether and dried to get 10 mg (yield: 83%) of isopropyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate as oxalate salt. 1H NMR (DMSO) OXALATE SALT 7.60 (s, 1H), 7.50 (d, 1H), 7.20 (d, 1H), 5.1 (s, 2H), 4.90 (m, 1H), 4.50 (m, 1H), 4.20 (m, 1H), 3.5 (m, 2H), 3.10 (bs, 2H), 3.0 (s, 3H), 1.10 (d, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH:9]1[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=O)(C)(C)C.[ClH:27]>CO>[ClH:27].[CH3:26][N:24]([CH3:25])[C:22](=[O:23])[CH2:21][CH:9]1[NH:8][CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:18])([F:20])[F:19])[N:16]=[C:10]12
Reactant: CN(C)C(=O)CC1c2nc(C(F)(F)F)nn2CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)CC1NCCn2nc(C(F)(F)F)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-N-(tert-butoxycarbonyl)-8-[2-(dimethylamino)-2-oxoethyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine (630 mg, 1.67 mmol) was dissolved in 5 mL of methanol saturated with hydrogen chloride. The reaction was stirred at ambient temperature for 1 h. Concentration in vacuo gave the title compound as an off-white solid. LC/MS 278 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:12])([CH3:11])[CH2:5]2.C([Li])CCC.[N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O1CCCC1>[CH3:11][C:6]1([CH3:12])[CH:5]=[C:4]2[C:8]([CH:9]=[CH:10][C:2]([N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:3]2)=[CH:7]1
Reactant: CC1(C)Cc2ccc(Br)cc2C1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)C=c2ccc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2=C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
5-Bromo-2,2-dimethyl-indan 45b (2.4 g, 10.7 mmol) was dissolved in 20 mL of dry tetrahydrofuran. Upon cooling by a dry ice-ethanol bath to −78° C., n-butyllithium (12.1 mL, 30.2 mmol) was added dropwise. Upon completion of the addition, the mixture was stirred for 2 hours. A solution of di-tert-butyl azodicarboxylate (3.27 g, 14.2 mmol) in 20 mL of dry tetrahydrofuran was added to the above mixture. The reaction mixture was reacted at the same temperature for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials and quenched by addition of 50 mL of water. The mixture was extracted with ethyl acetate (50 mL×2). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound di-tert-butyl 1-(2,2-dimethyl-inden-5-yl)hydrazine-1,2-dicarboxylate 45c (2.68 g, yield 66.8%) as a yellow oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2].[F:16][CH:17]([F:21])[C:18](O)=[O:19].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([O:15][C:18](=[O:19])[CH:17]([F:21])[F:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCC(C2CCC(O)CC2)CC1
Reactant: O=C(O)C(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1CCC(C2CCC(OC(=O)C(F)F)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
In 30 ml of dichloromethane were dissolved 2.2 g (11 mmol) of 4-(4-ethylcyclohexyl)cyclohexanol, 1.9 g (20 mmol) of difluoroacetic acid, and 0.8 g (8 mmol) of triethylamine, and this solution was cooled down to 0° C. To this solution was added dropwise 15 ml of solution of 2.4 g (12 mmol) of dicyclohexylcarbodiimide (DCC) in dichloromethane, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 17 hours. After the crystals in the suspension thus obtained were filtered off, the solvent was distilled off under a reduced pressure. After the residue was purified by column chromatography on silica gel (eluent: heptane/toluene=1/1), the solvent was distilled off, and the residue was subjected twice to recrystallization to give 1.4 g (4.9 mmol) of difluoro-acetic acid 4-(4-ethylcyclohexyl)-cyclohexyl ester. Yield of this compound based on 4-(4-ethylcyclohexyl)cyclohexanol was 45%.
Reaction SMILES: [OH-].[Na+].COCCO.[CH3:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1/[C:19](/[CH3:32])=[CH:20]/[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=1>CCOCC>[CH3:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:16])[CH3:17])[CH:12]=[CH:11][C:10]=1/[C:19](/[CH3:32])=[CH:20]/[C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc(C(C)(C)C)cc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: CCOCC
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc(C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of sodium hydroxide, 2-methoxyethanol and ether was added to 70 mg (0.21 mmol) of ethyl 4-[(E)-2-(2-methyl-4-tert-butylphenyl)propen-1-yl]benzoate (Compound 28) and the resulting mixture stirred at room temperature for 5 hours. Solvent was removed in-vacuo and the resulting solid taken-up in water, acidified using 1N HCl, and extracted with ether. The ether extracts were washed with water, brine and dried (MgSO4). The solvent was removed in-vacuo to give the title compound as a yellow solid.