Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH3:27])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C(O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH3:27])[CH2:2][CH2:3][CH:4]2[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]=3[O:5]2)=[CH:21][CH:20]=1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Reactant: CNCc1ccc(OC)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(CN(C)CCC2CN(C)C(=S)c3cccnc3O2)cc1
Reaction time: 4 h

Procedure:
To 40 ml of absolute ethanol was added 5.0 g (0.0194 mole) of 2-(2-chloroethyl-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione, 3.53 g (0.021 mole) of 4-methoxy-N-methylbenzenemethanamine and 2.75 g (0.021 mole) of diisopropylethylamine and the reaction solution heated to reflux for 18 hr. Another 1.0 g (0.006 mole) of 4-methoxy-N-methylbenzenemethanamine was added and heating continued for 4 hr. An additional 1.0 g (0.006 mole) of 4-methoxy-N-methylbenzenemethanamine was added and heating continued overnight. Still an additional 0.6 g (0.0036 mole) of 4-methoxy-N-methylbenzenemethanamine was added and heating continued for 24 hr. The ethanol was removed by rotary evaporation. The residue was taken up in 100 ml of methylene chloride and treated with ~8 ml of acetic anhydride overnight. The methylene chloride was extracted with 3×100 ml of 1N hydrochloric acid. The combined aqueous extracts were washed with 2×100 ml of chloroform, cooled, basified with concentrated sodium hydroxide, and extracted into 3×100 ml of chloroform. The combined organic extracts were dried over sodium sulfate, filtered, concentrated by rotary evaporation, and triturated with isopropyl ether. Because the crystals were still impure, they were dissolved in 100 ml of methylene chloride, washed with 2×50 ml of 4N sodium hydroxide, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The residue was crystallized from isopropyl alcohol to give 4 g (56%) of yellow analytically pure crystals, m.p. 128°-30° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
0.4 g (11 mmole) of 60% NaH is introduced into a flask containing 25 ml of anhydrous DMF under an argon atmosphere. A solution of 1.38 g (10 mmole) of 4-nitrophenol in 5 ml of anhydrous DMF is added dropwise, under agitation at 23° C. After 30 minutes a solution of 1.77 g (10 mmole) of 2-(chloromethyl)-quinoline in 5 ml of anhydrous DMF is added dropwise and agitation is continued for 15 hours while heating the mixture at 90° C. At the end of the reaction, the mixture is poured onto ice and an abundant precipitate forms. The suspension is filtered, rinsed twice with 25 ml of water followed by 20 ml of ethyl ether. A white solid is thus obtained with a yield of 75%. Melting point: 154-155° C.
Reaction SMILES: [C:1]1([C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16]C(Cl)Cl.S(=O)(O)[O-].[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:15]([C:4]1[CH:5]=[CH:6][C:1]([C:7]([CH3:13])([CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2][CH:3]=1)=[O:16]
Reactant: CCOC(=O)C(C)(C)c1ccccc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)c1ccc(C=O)cc1
Temperature: 5 °C
Reaction time: 60 h

Procedure:
Ethyl 2-phenyl-2-methylpropionate (10 g) was dissolved in 50 mL of dichloromethane and cooled to 5° C. Titanium tetrachloride (10.5 mL) and 1,1-dichloromethyl methyl ether (7.5 mL) were added and the mixture was stirred at room temperature for 60 hours. The resulting dark solution was diluted with 50 mL of dichloromethane and washed twice with 50 mL of water. The organic solution was concentrated to give an oil which was treated with 30 mL of saturated aqueous sodium bisulfite solution for 12 hours. The precipitate was collected by filtration, washed with hexane, suspended in ethyl acetate and treated with excess potassium carbonate. The organic phase was separated, dried with sodium sulfate and stripped to provide 2 g of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([S:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:29])=[O:28])[CH2:23][CH2:22]1)=[O:20]>C(#N)C>[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[CH:39][C:30]=1[S:27]([N:24]1[CH2:23][CH2:22][N:21]([C:19](=[O:20])[CH2:18][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:26][CH2:25]1)(=[O:29])=[O:28]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CNc1ccccc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A stirred solution of aniline (15.3 g, 0.16 mol) and di-isopropyl ethylamine (DIEA, 56 mL, 0.33 mol) in acetonitrile (120 mL) is heated to 60° C. and 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) is added dropwise. The reaction mixture is kept stirring at this temperature for another 3 h and is then evaporated to dryness. Water is added to the residue, and extracted with ethyl acetate (2×30 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The resultant crude product was purified by column chromatography on silica gel (hexane:ethyl acetate:3:7) to obtain the title compound (300 mg, 76.53%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:8][CH:7]=1.[F:25][C:26]([F:36])([F:35])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:23]([CH3:24])=[CH:22][C:21]2[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:26]([F:36])([F:35])[F:25])[C:7]3[C:6](=[CH:11][C:10]4[C:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([C:26]([F:35])([F:25])[F:36])[C:18]5[C:13]([O:12][C:9]=4[CH:8]=3)=[CH:14][C:15]([CH3:20])=[C:16]([CH3:19])[CH:17]=5)[O:5][C:4]=2[CH:3]=1
Reactant: Cc1ccc(Oc2ccc(Oc3ccc(C)c(C)c3)cc2)cc1C
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: *CC*
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc2c(cc1C)C(c1ccccc1)(C(F)(F)F)c1cc3c(cc1O2)C(c1ccccc1)(C(F)(F)F)c1cc(C)c(C)cc1O3
Temperature: 120 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
A mixture of 45.7 g (0.144 mole) 1,4-bis(3,4 dimethylphenoxy)benzene, 50.0 g (0.288 mole) trifluoroacetylbenzene, and 90 g (4.5 mole) HF was shaken in an autoclave at 120° C. for 8 hours. The clave contents were transferred to a polyethylene jar, half filled with ice-water, and containing 250 ml 50% NaOH. Methylene chloride was added, the slurry was filtered through Celite®, the organic layer was separated and the extracts were stripped. The residue was stirred with acetone and filtered, yielding 19.4 g of white solid. Because of its low solubility in methylene chloride, some product was lost on the Celite® pad. The IR was sharp, and the NMR was consistent with structure: m 7.33-7.45, 2 s 6.85, 2 s 6.67, s 6.55, 2 s 2.21, s 2.07 ppm in 5:1:1:1:3:3 ratio, indicating presence of cis-trans isomers. Analysis: calc. for C38H28F6O2 : C 72.4; H 4.44; found: C 71.3; H 4.57%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:22][C:5]1[CH:4]=[CH:3][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][CH3:28])=[O:26])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 90 °C

Procedure:
5-Bromo-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (5 g), methyl acrylate (1.4 ml), triethylamine (2.1 ml), palladium acetate (0.070 g) and tri-orthotolyl phosphine (0.185 g) were combined in N,N-dimethylformamide (20 ml). The mixture was heated in a sealed tube under nitrogen at 90° C. for 24 h. After cooling, the reaction mixture was partitioned between dichloromethane and dilute hydrochloric acid, the mixed phases were filtered through celite and the phases separated. The organic layer was washed with dilute hydrochloric acid and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residue which was triturated with diethyl ether and filtered to yield the subtitled compound as an off white solid (4.1 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C.Cl>O>[C:4]([C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[N:15]([CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCCCCCCCCCCCCCNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCN(C)c1ccc([N+](=O)[O-])cc1C(=O)O

Procedure:
A mixture of 600g 2-chloro-5-nitrobenzoic acid, 900g methyltetradecylamine (84%, tertiary amines as impurities) and 500 ml triethylamine was heated on a steam bath for 7 hours and then poured into 2 liters of water and made acid with HCl. The reaction product was filtered, air dried and then recrystallized from methanol and then from petroleum ether. Yield: 820g, m.p. = 100°-101°.
Reaction SMILES: [C:1]([N:4]([CH3:25])[NH:5][C:6]([C@H:8]1[CH2:14][CH2:13][C@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[O:16]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:4]([CH3:25])[NH:5][C:6]([C@H:8]1[CH2:14][CH2:13][C@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[OH:16])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 101.4 %

Procedure:
To a solution of (2R,5S)-N′-acetyl-6-(benzyloxy)-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 213 (0.20 g, 0.57 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)-N′-acetyl-6-hydroxy-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 214 (0.15 g, 99%) as a colorless foam.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=[O:16])[NH:8][C:7]2=[O:17].[CH3:18]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=[O:16])[N:8]([CH3:18])[C:7]2=[O:17]
Reactant: CI
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)c2cc(Cl)c([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
NaH (5.30 g, 0.132 mol) was added in portions to a solution of 5-chloro-6-nitroisoindoline-1,3-dione (20.0 g, 88.27 mmol) in 100 mL of anhydrous DMF at 0° C. under argon. The reaction mixture was then stirred at rt for 3 h. MeI (15.0 g, 106 mol) was added dropwise via a syringe at rt under argon. The resulted mixture was stirred for 6 h at rt, hydrolyzed by adding 200 mL of water. The brown precipitate was isolated, washed with water and dried under vacuum. The solid was purified by column chromatography (silica-gel, CH2Cl2/Acetone=19/1 v/v) to give a yellow solid product, 15.6 g, 73.6% yield. MS: 239.2 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 8.54 (s, 1H), 8.32 (s, 1H), 3.07 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28](CC3C=CC(OC)=CC=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:53][N:54]([CH3:58])[C:55](Cl)=[O:56]>C(Cl)Cl>[CH3:53][N:54]([CH3:58])[C:55]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:6][CH2:7]1)=[O:56]
Reactant: CN(C)C(=O)Cl
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide 5C (41.5 mg, 0.051 mmol) and DIEA (0.045 mL, 0.256 mmol) in CH2Cl2 (1 mL) at room temperature was added dimethylcarbamic chloride (4.94 μL, 0.054 mmol), slowly, via syringe. The reaction was stirred overnight at room temperature. Volatiles were removed via a stream of nitrogen and TFA (0.5 mL) was added. The mixture was then heated at 60° C. in an oil bath for 4 h. The reaction was then cooled to room temperature and the TFA was removed under reduced pressure. The resulting crude material was diluted with 1 mL of THF and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=56.165 min. 6-((trans-4-((dimethylcarbamoyl)amino)cyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide, 2TFA (18 mg, 45.2% yield) was obtained as a white foam. LC/MS, m/z 533.1 (M+1). HPLC Rt=4.200 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.31 (1H, s), 9.82 (1 H, s), 8.73 (1H, d, J=2.47 Hz), 8.51 (1H, t, J=6.05 Hz), 8.44 (1H, d, J=5.22 Hz), 8.34 (1H, d, J=3.85 Hz), 8.12 (1H, s), 7.97 (1H, s), 7.68-7.80 (1H, m), 7.50 (1H, d, J=8.52 Hz), 7.17-7.26 (1H, m), 7.02 (1H, dd, J=6.74, 5.36 Hz), 5.84-5.93 (1H, m), 3.77-3.87 (1H, m), 3.40 (1H, d, J=6.05 Hz), 2.78 (6H, s), 2.06 (2H, s), 1.80 (2H, s), 1.34 (4H, d, J=12.10 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[F-].[K+].[NH3:14].CCCCCCCCCCC>CO>[NH2:14][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1
Reactant: N
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCCCCCCC
Product: Nc1ccc(C(F)(F)F)cc1
Temperature: 200 °C
Yield: 12.8 %

Procedure:
A mixture of 4.806 g of para-chlorobenzotrifluoride, 0.4991 g of cuprous chloride, 3.103 g of potassium fluoride, 13 g of ammonia, 17.9241 g of methanol, and 0.1961 g of n-undecane was heated at 200° C for 5 hrs in an 80 ml Hastelloy shaker tube. After cooling and venting the ammonia, the product mixture was removed. Most of the methanol and para-chlorobenzotrifluoride were distilled out of the product mixture. The remaining solution was diluted with diethyl ether and extracted with 0.5 M KOH to remove copper and ammonium salts as well as potassium fluoride. The ether layer was dried over CaSO4. Vacuum distillation of the ether layer gave 0.55 g of para-aminobenzotrifluoride.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C@H:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=2)[O:2]1.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:22]=1[NH2:23].C(N(CC)CC)C>C(Cl)Cl>[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:22]=1[NH:23][C:12](=[O:14])[CH2:11][C@H:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]=12)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC[C@H](CC(=O)O)c1cccc2c1OCO2
Reactant: Nc1c(F)cc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC[C@H](CC(=O)Nc1c(F)cc(F)cc1F)c1cccc2c1OCO2
Reaction time: 8 h
Yield: 86.8 %

Procedure:
In the same manner as in Example 1, 0.86 g (3.25 mmol) of (R)-3-(2, 3-methylenedioxyphenyl) octanoic acid was converted into its acid chloride. This acid chloride was dissolved in 5 ml of methylene chloride and added dropwise to a solution of 571 mg (3.88 mmol) of 2, 4, 6-trifluoroaniline and 0.54 ml (3.9 mmol) of triethylamine in 15 ml of methylene chloride. The reaction mixture was stirred overnight, washed with water, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/5) and recrystallized from a mixed solvent of hexane and a trace of ethyl acetate to give 1.11 g of (R)-N-(2, 4, 6-trifluorophenyl)-3-(2, 3-methylenedioxyphenyl) octanamide as white crystals. Yield, 87%.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[S:9])[NH:2]1.[CH2:12](O)C.[OH-].[Na+].IC>O>[CH3:12][S:9][C:3]1[C:4]2=[CH:8][S:7][CH:6]=[C:5]2[S:1](=[O:10])(=[O:11])[N:2]=1
Reactant: O=S1(=O)NC(=S)c2cscc21
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSC1=NS(=O)(=O)c2cscc21

Procedure:
To a mixture of 0.9 g. (0.0044 mole) of thieno[3,4-d]isothiazole-3(2H)-thione 1,1-dioxide in 4 ml. of ethanol is added a solution of 0.35 g. (0.0044 mole) of 50% sodium hydroxide in 3 ml. of water. To this thick mixture is added 0.62 g. (0.0044 mole) of iodomethane. The mixture is heated under reflux for 5 minutes, and then filtered to give 0.35 g. of product. On cooling, a second crop of 0.1 g. of material is obtained. A small amount of the first crop is recrystallized from ethanol to afford an analytical sample, m.p. 184°-6° C.
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:39]=[CH:40][CH:41]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:39]=[CH:40][CH:41]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:45]([NH:44][C:42](=[O:43])[C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH3:34])[CH:37]=2)=[S:46])=[CH:29][CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1cccc(C(=O)Cl)c1
Agent: COc1cccc(C(=O)N=C=S)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
3-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (70 mg, yield 80%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:6](=[O:13])[NH:5][C:4](=[O:14])[CH:3]=1.[CH3:15]OS(OC)(=O)=O>[OH-].[Na+]>[NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])([CH3:10])[CH3:12])[C:6](=[O:13])[N:5]([CH3:15])[C:4](=[O:14])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)Cn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(=O)cc(N)n(CC(C)(C)C)c1=O
Yield: 90.9 %

Procedure:
6-Amino-1-neopentyluracil (90c) (5.9 g, 0.03 mol) were dissolved in 1 N NaOH (50 ml) and then under vigorous stirring dimethylsulfate (3.9 ml, 0.033 mol) dropwise added at room temp. A precipitate separated and was collected after 2 hours. After washing with water and drying in a vacuum desiccator resulted 5.76 g (91%) of colorless crystals.
Reaction SMILES: [CH:1]1([N:4]2[CH2:17][CH2:16][C:7]3[NH:8][C:9]4[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=4[C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:20][C:21]1([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:23][O:22]1>CN(C=O)C>[CH:1]1([N:4]2[CH2:17][CH2:16][C:7]3[N:8]([CH2:20][C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)([OH:22])[CH3:23])[C:9]4[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=4[C:6]=3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: CC1(c2ccncc2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C1CC1)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncc2)CCN(C2CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
To a stirred solution of 2-cyclopropyl-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.2 mmol) in DMF (10 mL) was added sodium hydride (264 mg, 6.6 mmol). After stirring for 10 min at RT, 4-(2-methyl-oxiranyl)-pyridine (448 mg, 3.3 mmol) was added and stirring continued for another 16 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to afford crude material, which was re-crystallized in ether and hexane to yield 1-(2-cyclopropyl-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (600 mg). 1H NMR (CD3OD, TFA salt) d (ppm): 8.62 (d, 2H), 8.18 (d, 2H), 7.20 (s, 1H), 6.95 (d, 1H), 6.80 (d, 1H), 4.50 (m, 1H), 4.40 (s, 2H), 4.0 (m, 1H), 3.70 (m, 1H), 3.30 (m, 3H), 3.10 (m, 1H), 2.36 (s, 3H), 1.78 (s, 3H), 1.20 (m, 4H).